Phylosophy of Hyper-Information, Hyper-Thinking ...

Phylosophy of Hyper-Information, Hyper-Thinking, Hyper-Consciousness Yerkin Aibassov Maxat Bulenbayev Narymzhan Nakisbekov Bakytzhan Alzhanuly

Scientific & Academic Publishing, USA

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ISBN: 978-1-938681-96-7

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Contents Introduction ......................................................................................... 1 Chapter I:

Kazakh Philosophy of Mind and Consciousness ......... 3

Chapter II:

Philosophy of Brain Chemistry .................................... 9

Chapter III:

Philosophy of Hyper-Information ............................ 255

Chapter IV:

Phylosophy of Hyper-Thinking ................................ 275

Chapter V:

Philosophy of Hyper-Consciousness ........................ 281

Chapter VI:

Phylosophy of Behavioral Chemistry ....................... 309

Conclusions ..................................................................................... 413

Phylosophy of Hyper-Information, Hyper-Thinking, Hyper-Consciousness

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Introduction If the twentieth century was christened by the century of atomic weapons and genetics, then the 21st century will be the century of study, understanding and control of the brain, consciousness and behavior of man. Scientists face the most difficult task in the history of science: to understand the brain. The task is incredibly complex. Can we read and control the thoughts of others? The brain is the most complex and least studied organ of our body. Having a mass of only 1-2 kg, it consumes 20% of energy. More than 70% of genes of our genome actively work in its cells. The gray matter consists of more than 90 billion neurons, each of which has up to 10 thousand links with other neurons. Scientists from the University of California have discovered a gene that is responsible for the human mind. In its essence, this is a variation of the HMGA2 gene. They studied the causes of genetic diseases of the brain. For the experiment, geneticists selected 20 volunteers who agreed to give their genetic material for research. They were representatives from different countries, who are on different continents. The results of the experiment struck scientists, it turned out that people with a certain chemical structure of the HMGA2 gene, really are endowed with high mental abilities. But this is only if all other factors that determine the level of intelligence will be equal. Each participant in the study had to undergo an IQ test, and the holders of the variational gene gave answers much better than those who do not have a similar gene. If to speak about an estimation of test results, on the average the given indicator has made about 1,5 points. Based on the results of the experiment, scientists believe that this gene really can make a person much smarter. They note that the elementary changes in the genetic code can generate real geniuses. At present, genetics are not going to stop there and plan to develop this direction. They hope that the results of their work will help create drugs to enhance the human mind.


Chapter I Kazakh Philosophy of Mind and Consciousness

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Kazakh philosophy is the philosophical ideas of Kazakh thinkers. One of the first Kazakh thinkers is the Sufi of the 12th century Ahmed Yasawi. The next prominent representatives of the Kazakh thought are Abai Kunanbaev and Shakarim Kudaiberdiyev. The Turkic authors Yusuf Balasaguni and Mahmud al-Kashgari are also referred to Kazakh thinkers. Philosophy in Kazakhstan had its rich, centuries-old history. The beginning was laid by folk philosophy expressed in folklore. Until now, their true significance for the development of progressive philosophical, sociological and political ideas has not been revealed. They should rightfully take their place among the outstanding philosophical and sociological literature of the past. If the twentieth century was christened by the century of atomic weapons and genetics, then the 21st century will be the century of study, understanding and control of the brain, consciousness and behavior of man. Scientists face the most difficult task in the history of science: to understand the brain. The task is incredibly complex. Can we read and control the thoughts of others? If the twentieth century was christened by the century of atomic weapons and genetics, then the 21st century will be the century of study, understanding and control of the brain, consciousness and behavior of man. Scientists face the most difficult task in the history of science: to understand the brain. The task is incredibly complex. Can we read and control the thoughts of others? The brain is the most complex and least studied organ of our body. Having a mass of only 1-2 kg, it consumes 20% of energy. More than 70% of genes of our genome actively work in its cells. The gray matter consists of more than 90 billion neurons, each of which has up to 10 thousand links with other neurons. We do not know our true ancient history. When in the Kazakhstan school textbooks children will learn the Modabayev equation, Ospanov's law, Akhmetov's rule? In the United States, one of the founders of neuroscience is al-Farabi, who wrote a treatise "On the Meaning of Reason and the Need for Science". Al-Farabi lived in 870-950, this manuscript means more than 1100 years. It turns out as in an anecdote: "Jehovah's Witnesses come to the Jewish family: - Have you read the Bible? "Dear, we wrote it". Al-Farabi gives the following interpretations about mind and mind: "Good

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character and strength of mind, both together are human dignity in the sense that the doer of each thing consists in excellence and perfection in herself and in her actions. If both of them - good temper and strength of mind - take place, then we get supremacy and excellence in ourselves and in our actions, and through them both we become noble, good and virtuous: our image becomes virtuous, and our behavior is laudable " [1]. "Virtues are of two kinds: ethical and intellectual. Intellectuals are the virtues of the rational part of the soul, such as wisdom, intelligence, intelligence, sharpness of mind, intelligence. Ethical are the virtues of the aspiring soul, such as moderation, courage, generosity, justice. Correspondingly, vices are also divided" [2]. "Virtues can be achieved by two primary ways - education and upbringing." Learning is the endowment with the theoretical virtues of peoples and cities. Education is a way of empowering peoples with ethical virtues and arts based on knowledge" [3]. The only instrument for experiments on the atomic nucleus was alpha particles emitted by radioactive substances. With the help of these particles, Rutherford succeeded in turning in 1919 the atomic nuclei of light elements into each other. He could, The nucleus of nitrogen is converted into a nucleus of oxygen, attaching an alpha particle to the nucleus of nitrogen and at the same time knocking out a proton from it. This was the first example of a process at distances of the order of the atomic radii, which resembled chemical processes, but which led to the artificial transformation of elements. The next decisive success was the artificial acceleration of protons in high-voltage devices to energies sufficient for nuclear transformations. For this purpose, voltage differences of about a million volts are required, Cockcroft and Walton in their decisive experiment succeeded in transforming the atomic nuclei of the lithium element into atomic nuclei of the helium element. This discovery revealed an entirely new field for research that can be called nuclear physics. Electromagnetic fields on the surface of stars that extend to gigantic spaces can, under favorable conditions, accelerate charged atomic particles, electrons and atomic nuclei, which, as it turned out, due to their greater inertia, have more


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opportunity to stay in the accelerating field for a longer time, when they eventually go away from the surface of the star into an empty space, then sometimes the potential fields of many billions of volts pass. The "youngest" antiparticle is a negatively charged proton, which are called antiprotons. experiments showed complete transformability of matter. Consequently, we have in fact the final proof of the unity of matter. All elementary particles are "made" from the same substance, from the same material, which we can now call energy or universal matter; they are only different forms in which matter can manifest itself. A great work for understanding the national self-consciousness of Kazakhs was provided by Olzhas Suleimenov's book "Asia" and the writings of Zhumabek Tashenov. We believe that by touching the priceless spiritual legacy of our outstanding enlighteners, having penetrated into the essence of their progressive ideas and instructions, our contemporaries and descendants will appreciate them and use in their lives and strengthen the spirit of future descendants. REFERENCES [1]

Al-Farabi. Socio-ethical treatises. Alma-Ata, 1973, p. 9.

[2]


[3]



Chapter II Philosophy of Brain Chemistry

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Recently, much attention has been paid to the study of brain chemistry in Israel, the United States and Switzerland. The brain is the most complex and unexplored organ of human. The gray matter of the brain is represented mainly by the bodies of neurons, and the white matter is represented by axons. In connection with this, these parts of the brain differ significantly in their chemical composition. These differences are primarily quantitative. The water content in the gray matter of the brain is noticeably greater than in white matter. In gray matter, proteins make up half of the dense substances, and in white matter - one third. Lipids in white matter account for more than half of the dry residue, in gray matter - 30%. The share of proteins accounts for 40% of the dry mass of the brain. Brain tissue is a difficult object to study the protein composition due to the high content of lipids and the presence of protein-lipid complexes. The main representatives of the protein group in the nervous tissue are histones, which are divided into five main fractions depending on the content of the residues of lysine, arginine and glycine in their polypeptide chains. Neuroscleroproteins can be characterized as structural-supporting proteins. The main representatives of these proteins are neurocollagens, neuroelastins, neurostromins, etc. They constitute 8-10% of all simple proteins of the nervous tissue and are localized mainly in the white matter of the brain and in the peripheral nervous system. Complex proteins of the nervous tissue are represented by nucleoproteins, lipoproteins, proteolipids, phosphoproteins, glycoproteins, etc. In the brain tissue, even more complex supramolecular entities, such as liponucleoproteins, lipoglycoproteins, and lipoglyco-nucleoprotein complexes, are contained in a considerable amount. Nucleoproteins are proteins that belong to either DNP or RNP. Some of these proteins from the brain tissue are extracted with water, the other part - with salt media, and the third with a 0.1 M solution of alkali. Lipoproteins constitute a significant part of water-soluble proteins of the brain tissue. Their lipid component consists mainly of phosphoglycerides and cholesterol.

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Proteolipids are the only complex proteins that are extracted by organic solvents, for example a mixture of chloroform and methanol. In contrast to lipoproteins, the lipid component predominates over the protein component. The greatest number of proteolipids is concentrated in myelin, in small amounts they are included in the composition of synaptic membranes and synaptic vesicles. Phosphoproteins in the brain are contained in a larger number than in other organs and tissues, 2% in relation to all complex brain proteins. Phosphoproteins are found in membranes of various morphological structures of nerve tissue. Glycoproteins are an extremely heterogeneous group of proteins. By the amount of protein and carbohydrates that make up glycoproteins, they can be divided into two main groups. The first group is glycoproteins containing from 5 to 40% carbohydrates and their derivatives; The protein part consists mainly of albumins and globulins. The glycoproteins that make up the second group contain 40-85% carbohydrates, often a lipid component is found; In their composition they can be referred to glycolipoprotein. In the brain tissue contains a large number of enzymes that catalyze the metabolism of carbohydrates, lipids and proteins. However, so far only certain enzymes have been isolated from the mammalian central nervous system (CNS) in crystalline form, in particular acetylcholinesterase and creatine kinase. A significant number of enzymes in the brain tissue are in several molecular forms (isoenzymes): LDH, aldolase, creatine kinase, hexokinase, malate dehydrogenase, glutamate dehydrogenase, cholinesterase, acid phosphatase, mono-aminoxidase and others. Among the chemical components of the brain, lipids occupy a special place, the high content and specific nature of which impart characteristic features to the brain tissue. The cerebral lipids group includes phosphoglycerides, cholesterol, sphingomyelins, cerebrosides, gangliosides and very small amounts of neutral fat (Table 1). In addition, many lipids of the nervous tissue are in close relationship with proteins, forming complex systems such as proteoly-pid. In the gray matter of the brain, phosphoglycerides account for more than


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60% of all lipids, and in white matter - about 40%. On the contrary, in white matter, the content of cholesterol, sphingomyelins and especially cerebrosides is greater than in the gray matter. Table 1. Lipid composition of nerve tissue Gray matter

White matter

Myelin

32,7

54,9

70

Cholesterol

22,0

27,5

27,7

Cerebrosides

5,4

19,8

22,7

Total content of lipids, % of dry weight As a percentage of total lipids

Gangliosides

1,7

5,4

3,8

Phosphatidylethanolamines

22,7

14,9

15,6

Phosphatidylcholines

26,7

12,8

11,2

Phosphatidylserines

8,7

7,9

4,8

Phosphatidylinositols

2,7

0,9

0,6

Plasmagenes

8,8

11,2

12,3

Sphingomyelins

6,9

7,7

7,9

Carbohydrates. In the brain tissue there are glycogen and glucose. However, compared to other tissues, brain tissue is poor in carbohydrates. The total glucose content in the brain of different animals averages 1-4 μmol per 1 g of tissue, and glycogen 2.5-4.5 μmol per 1 g of tissue (based on glucose). It is interesting to note that the total content of glycogen in the brain of embryos and newborn animals is much higher than in the brains of adults. For example, in newborn mice, unlike adults, the glycogen level is 3 times higher. As the brain grows and differentiates, the concentration of glycogen rapidly decreases and remains relatively constant in an adult animal. In the brain tissue, there are also intermediate products of carbohydrate metabolism: hexose- and triose phosphates, lactic, pyruvic and other acids. In Table 2 contains data on the content of some intermediate components of carbohydrate metabolism in the brain.

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Table 2. Average data on the content of some metabolites of carbohydrate metabolism in the brain

Metabolite

Glucose-6-phosphate Fructose-6-phosphate Fructose-1,6-bisphosphate Dioxoacetone phosphate Glyceraldehyde-3-phosphate

Content, μmol per 1 g

Metabolite

of wet tissue weight

Content, μmol per 1 g of wet tissue weight

0,039-0,049 0,017-0,023

3-Phosphoglycerate 2-Phosphoglycerate

0,085-0,100 0,010-0,016

0,010-0,017

Phosphoenolpyruvate

0,035-0,097

0,024 0,021-0,046

Pyruvat

0,120-0,190

Lactate

1,26-1,70

Adenine Nucleotides and Creatine Phosphate Of the free nucleotides in the brain tissue, the fraction of adenine nucleotides accounts for about 84%. The majority of the remaining nucleotides are made up of guanine derivatives. In general, the number of highlyergic compounds in the nervous tissue is small. The content of nucleotides and creatine phosphate in the brain of rats averages (in μmol per 1 g of wet weight): ATP - 2.30 - 2.90; ADP - 0.30-0.50; AMP-0.03-0.05; GTP - 0,20-0,30; GDF - 0,15-0,20; UTP 0,17-0,25; Creatine phosphate - 3,50-4,75. The distribution of the main macroergic compounds is approximately the same in all parts of the brain. The content of cyclic nucleotides (cAMP and cGMP) in the brain is much higher than in many other tissues. The level of cAMP in the brain is on the average 1-2, and cGMP - up to 0.2 nmol per 1 g of tissue. High activity of cyclic nucleotide metabolism enzymes is also characteristic of the brain. Most researchers believe that cyclic nucleotides are involved in synaptic transmission of a nerve impulse. In Table 3 shows Levels of Living Systems. In Table 4 shows Levels of Consciousness The philosophy of brain chemistry is a branch of philosophy that studies fundamental concepts, development problems and the methodology of chemistry as a part of science. Important in the philosophy of chemistry is the philosophical analysis of the development of chemical knowledge and the evolution of the fundamental concepts of chemistry.


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Table 3. Levels of Living Systems Level

Entity

Example Function

Macromolecules

Store information

DNA

Organelles

Transfer energy

Molecular aggregates, mitochondria

I

Cells

Semi-isolate molecular systems within membrane boundary

Eukaryotes

II

Organ systems

Cell populations cardiovascular and nervous systems

III

Organisms

Trees, bacteria, ants, snakes

IV

Populations

Forest, ant colony, human city

0

Example Structure

Table 4. Levels of Consciousness Consciousness Level

Example Species

0

Plant life

I

Reptiles

II

Mammais

III

Humans Large-scale intelligence

IV

Characteristic Behavior Response to weather Moves through space Social interactions Sense of time Advanced knowledge

Representative Brain Structure None Brainstem Limbic system Cerebral cortex Interacting brains

In Hegel's Logic, which describes the history of the formation of an idea, three types of "objectivity" are mentioned: the mechanism, chemistry, and the organism. The philosophy of brain chemistry is an integral part of the philosophy of

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natural science, although there is actually a philosophical form of studying nature. Philosophical study of nature or matter meets the essential needs of humanity in a holistic knowledge of the world. Knowledge of nature as a cosmos performs an important socio-cultural function - only such knowledge can become a form of worldview, on the basis of which new generations of people are brought up. The scientific picture of the world, adapted to the paradigms of universal knowledge, arises on the border between philosophy and natural science. Philosophy does not duplicate chemistry in its own development as a natural science, but considers chemical facts and theories under a "metatheoretical" angle of view. So, if chemistry can act as an "inductive" basis for the philosophy of chemistry, then the latter can serve as a "grandiose education" for the first. It is at this point that the objective necessity of a real interaction between chemistry and philisophy is most clearly revealed. The Chemical Form of the Motion of Matter From the very beginning of its existence, chemistry was interested in changes in substances and bodies, and the processes underlying such changes became the subject of research of this science, which in its development not only freed itself from the influence of religion and philosophy, but separated from other natural sciences. This went to the benefit of accelerating scientific and technological progress with the broad output of individual branches of natural science into the sphere of production of new goods. The philosophy of chemistry begins not with the consideration of particular chemical laws or properties of various substances, not with the history of chemistry, however important and instructive, but with the chemical form of the motion of matter. In this case, matter is taken as the substance of nature, its universal basis and the root cause. The world is represented in the form of a hierarchy of levels of organization of matter from simple to complex, and each such level has its own form of motion of matter. From this point of view, it is possible to rationally justify the unity and integrity of the universe, as well as its cognition, evolution and much more, accepted in modern science as axioms.


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The chemical form of the motion of matter underlies the emergence, destruction and transformation of substances and bodies. Chemical transformations assume the interaction between atoms, therefore it is believed that the chemical form of the motion of matter arises at a certain stage of the development of the universe. This stage is associated with the formation in space (presumably in the bowels of stars) of atoms with a relatively stable core and a more or less stable electron shell. Modern studies in the field of cosmochemistry confirm that the interstellar medium (clouds of dust, gas) contains not only the simplest inorganic molecules, but also complex organic compounds, such as cyanacetylene, acetaldehyde. There are also water molecules in space, which can be indicative not only of the birth in the cosmos of various chemical processes, but also about the possibility of the appearance of life. The chemical processes of transformations become possible in the presence of formed atoms, since in the course of chemical reactions, atoms enter into each other's interactions primarily through external (valence) electrons, which presupposes a stable definiteness of the nucleus and the electron shell. Chemical interaction occurs when a single contact field appears that does not belong to any of the isolated atoms. In this field of contact, a qualitatively new form of organization of matter arises that is not reducible in its physicochemical characteristics to the properties of the substances that have entered into interaction. The formed particles (molecules, ions, radicals) are new quantum mechanical systems in which the initial properties of atoms change and as a result qualitatively new laws of the chemical structure and mutual influence arise. It is curious that, with all this, the nuclear skeletons remain unchanged. Thus, the chemical form of the motion of matter presupposes a change in matter due to the rearrangement or destruction of the old and the emergence of new bonds between relatively stable elements (atomic cores). In other words, the carriers of the chemical form of the motion of matter are atoms. Every form of motion presupposes the existence of an initial contradiction into a single whole, in which motion occurs. This is required by the law of unity and struggle of opposites, which, like other laws of positive dialectics, is

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brilliantly confirmed in numerous chemical discoveries. Thus, the source of the chemical form of the motion of matter is the internal contradiction that arises between the two tendencies characterizing the state of matter. The first trend is related to the stability of the system, the desire to retain its own peculiarity, the structure of the familiar connections, and the second is the attraction of the quantum mechanical system to going beyond, to development, which implies the denial of one's own isolation. The first tendency manifests itself in the kinetic stiffness of the system, when there are energy barriers that prevent the destruction of stable bonds and the chaos of the system. The second tendency is manifested in the striving for the thermodynamically most stable state. Thus, the essence of the chemical motion of matter lies in the fact that as a result of the internal contradiction between the desire for self-preservation and the desire for self-change within the system itself, the energy of "attraction" is manifested, which contributes both to changes in internal bonds (overcoming energy barriers) without attracting energy from outside, and when entering the surface, the same energy contributes to the connection and the emergence of a new quality. In alchemy, the essence of this process was conveyed by the erotic symbolism of the "sacred marriage", where the achievement of a new quality was assumed through the moment of "death-birth". From the point of view of a rational philosophy that studies nature, the principles of dialectical logic should be applied, and then the description of the chemical interaction will look like this. In addition to two or more actors entering into relationship with each other, there is also a special moment of the relationship itself (a single contact field), irreducible to the separately considered actor (contact subjects). When entering into relations, the two correlated subjects cease to be closed conservative systems (self-in-themselves) and acquire new, previously unidentifiable qualities, determined by the entire process of interaction. Here we observe the action of yet another dialectic law-the negation of negation, when the individual substances that come into contact with one another lose their earlier certainty (negation), and then stabilize in new qualities (negation of negation). Thus, in the chemical interaction of substances, an important role is played not only by the properties of the substances that reacted. But also the field of their contact, or the moment of the relation, where there is own certainty. It is in this


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field of contact that a new quality of matter arises that is irreducible to the properties of the substances that have entered into the reaction. Considering the chemical form of the motion of matter, one should not only distinguish its specific specificity associated with the chemical processes of changing substances, but do not forget also that there are other forms of motion of a single matter and the chemical form is in close interaction with some of them. It is a matter of the "quantum mechanical" and biological form of the motion of matter, which are "lower" and "higher" than the chemical form at the levels of the hierarchy of levels of organization of matter. Both levels undoubtedly influence their "mediator": this should be the case, proceeding from the dialectical approach, in accordance with the discoveries of modern science. The appearance of biochemistry and physical chemistry once again confirms the reality and significance of the interaction of various forms of motion of matter. Here the philosophy of chemistry indicates that the logic of the development of chemistry as a science does not coincide with the interests of mundane pragmatism, which thinks only of momentary profit. The former tendency towards the emancipation and separation of various natural sciences is replaced in our day by a tendency to the mutual influence of the sciences that study the single body of nature, as a result of which all the new interdisciplinary sciences appear, designed to fill the gaps that arose during the "differentiation of natural science". Laws and Categories of Dialectics in Chemistry When studying the chemical form of the motion of matter, the universal laws of dialectics are vividly manifested in a special form. The logic of the transition from the previous quality to the new is also reflected in the law of transition of quantitative changes to qualitative ones. The inner content of the transition of the old quality to the new is the struggle of opposites, which again indicates the operation of the first law. The categories of dialectics include, first of all, such concepts as quality and quantity, essence and phenomenon, necessity and chance, and also categories expressing the completeness of concepts, such as singular, special and universal. The consideration of chemical processes from the point of view of

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the laws of dialectics and the application of dialectic categories promotes a deeper insight into the essence of what is happening, since the subject of research is encompassed in all logical completeness and development. Universal laws and categories of dialectics in physical, chemical, biological and other forms of motion of matter are manifested differently, taking into account the specific nature of the concrete form of material motion. For example, the basic law of dialectics - the law of unity and struggle of opposites - indicates that any phenomenon in the world contains its own contradiction, which causes the given thing to develop and determines the properties of the developing thing. It is the contradiction with the struggle of opposites that sets the direction of development of each object and its parameters. If the above basic contradiction is characteristic of the entire chemical form of the motion of matter, then the main contradiction plays an equally decisive role, but in relation to individual substances, that is, the main contradictions are a special contradiction characterizing the properties of one or another kind of substances. For example, the main internal contradiction of amino acids is the contradiction between the basic nature of the amino group and the acidity of the carboxyl group. These groups express directly opposite properties and the interaction between them determines the essence of amino acids as a known class of organic compounds, with their own properties and ability to reactions. Secondary contradictions can lead to a change in certain properties without a quality transformation, that is, the basic contradiction determining the substance in its quality will be retained. The resolution of a secondary contradiction can influence one of the opposites of the main contradiction, which will affect the properties of the obtained chemical substance. In the case of amino acids, this is due to the production of the following derivatives. Thus, carboxyl groups can, by reactions, form salts of amino acids, esters, and acid chlorides. At the same time, the characteristic reactions of the amino group are the formation of salts when interacting with acids, as well as N-acylated derivatives when amino acids are treated with acid chlorides in an alkaline medium. The resolution of non-principal contradictions does not lead to a qualitative transformation of matter, which is explained by the preservation of the main


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contradiction. In the case of the same amino acids, if we carry out a reaction, for example, deamination, then a qualitatively new substance will be obtained. This is already connected from another class of substances, determined by another main contradiction, where as one of the opposites there is already no amino group. The law of transition of quantitative changes to qualitative changes in chemistry also manifests itself very specifically. Chemistry is particularly closely related to the dialectical categories of quality and quantity. For example, any chemical reaction can be considered as a quality, and the amount of participating substances or the rate of reaction can express quantity. It should be specially emphasized that quality and quantity are not just some abstract terms, but real properties that belong to all the bodies and processes of the world around us, without exception. The law of transition of quantitative changes to qualitative changes and back expresses the relationship between these opposing sides of one whole. For the transition to a new quality, it is necessary that the quantitative changes exceed the limit of the measure that relates the quality and quantity. The effect of this law in chemistry is manifested in special forms. Here, quantitative changes are associated not only with changes in the chemical composition of substances, but also with changes in the spatial structure of molecules. Atoms, when combined into molecules, mutually influence one another, and therefore the molecule formed by its properties can not be reduced to the sum of the properties of the atoms forming it. This is a qualitatively different education, as already mentioned above. The study of the essence of isomerism from the facts that, for the same number of atoms of different elements, chemical compounds may develop, different in their properties. It turned out that the reason for this lies in a different order of bonding of atoms. Quantum mechanics confirmed Butlerov's position that the structure is the most important property of a molecule that determines all its other properties and features. Thus, not only the change in the chemical composition, but also the change in the structure of molecules, is linked in chemistry with a change in the quality of substances, what is the main specificity of the manifestation of the dialectical law of the transition of quantitative changes to qualitative changes in

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the sphere of the chemical motion of matter. The fruitfulness of the application of dialectical categories in chemistry can be demonstrated by the example of such categories as phenomenon and essence. The body or substance given to us in sensory perception is a phenomenon that usually makes up the actual side of the natural sciences, especially chemistry, where empirical studies far outnumber theoretical, which is one of the characteristic features of this science. From the point of view of philosophy, a chemist almost always deals with the subject of research in the form of a phenomenon or available being, easily subject to external observation and experiment. On the other hand, the goal of science is truth, which speaks the language of laws, and laws do not lie on the surface of phenomena. Dialectics connects the categories of phenomenon and essence with each other as contradictory moments of a contradictory relationship. When they talk about the essence, they have first of all in mind that the thing is not really what it is. Representations arise on the basis of perception of the phenomenon, for example, when observing an acid, one can form an idea of an acid, but it has long been known that manipulation in consciousness by forms of representation does not lead to a deepening of knowledge about the subject. First of all, it is necessary to understand the essence of the phenomenon being studied. The etymological concept of "essence" or "essence" is connected with the concept of being and in a simplified form one can say that the essence of the phenomenon is that there is a phenomenon truly. The essence is opposite to the phenomenon, since the first indicates the universal, the generic, and the second is always given as a kind of single thing or process. If the phenomenon is always given to us in feelings, then the essence is revealed exclusively through thinking. Here is the simplest example: lightning and thunder during a thunderstorm is a phenomenon, but from the observation of this phenomenon it is impossible to derive the essence that we are dealing with a kind of electric disch. Philosophy, based on the rational method of positive dialectics, argues that essence and phenomena are inextricably linked, being in a contradictory unity, while the phenomenon contains the essence as a basis, and the essence reveals itself in the phenomenon. Thus, it can be said that observation and experiment


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in themselves are only the empirical side of research, and while the transition to the theoretical level should be mediated by revealing the essence of the phenomena being studied. When looking for the essence of the phenomena being studied, one has to abstract from the set of observed moments. For example, chemical reactions are usually accompanied by absorption or release of heat, precipitation, color change, evolution of the gaseous component, but this diversity is "insignificant". In fact, the essence of the chemical reaction consists in the destruction and formation of bonds between atoms and atomic groups, in the change in composition, molecular structural and, accordingly, properties of substances. The essence of an object is at the same time a true concept of an object expressed in a term, and the law in its logical form is an inference connecting the concept in itself. Dialectics of the relationship of essence and phenomenon in the course of cognition indicates the possibility of a multiple movement from phenomenon to essence and vice versa, as a result of which the depth of knowledge of the subject increases, which appears more and more concrete. Each natural law only then acquires special scientific significance when practical consequences can be extracted from it, that is, such logical conclusions that explain the unexplained yet point to phenomena not yet known, especially when the law makes it possible to give such predictions that then can be confirmed by practical experience. If you look at the examples, you can recall the discovery of the laws of stoichiometry, which allowed to produce chemical reactions with an understanding of their quantitative aspect. At the same time, the laws of shares and equivalents could be called no more than external regularities, since they were isolated from each other, and their internal meaning remained unclear. According to the dialectical approach to the study of nature, quantity is one of the external characteristics of matter, so these regularities did not for nothing look "purely empirical" until D. Dalton applied the atomistic hypothesis to explaining chemical phenomena. The latter made it possible to understand the essence of a chemical substance, based on the fact that any substance consists of elementary particles, called atoms, with different atomic weight. As a result, Dalton managed to open the third law of stoichiometry - the law of simple

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multiple relations. Later the atomistic hypothesis began to develop into an atomic-molecular theory and all stoichiometric laws became apparent in the symbolic formulas of chemical substances, the essence of which was now a molecule, since the molecule expresses the composition, structure and all the properties of any chemical compound. The formula record, based on the atomic-molecular theory, made it possible to clearly visualize the essence of chemical transformations, using chemical formulas to calculate the molecular weight of a substance, to compose the equations of chemical reactions. All this, in the final analysis, allowed the calculations that underlie the organic chemistry that was beginning to develop, as well as the discovery of the periodic law of elements by DI Mendeleev. There was a further deepening in the essence of the fact that there is substance truly. Now the atomic weight of the elements and the structure of the molecules turned out to be extremely important. The atomic-molecular theory was supplemented by in-depth knowledge of the internal structure of matter, and chemistry as a whole reached a new level of empirical research and practical possibilities. Thus, the dialectic of phenomenon and essence is brilliantly confirmed in the history of the development of chemistry, as are other aspects of the dialectical level applied to the process of studying nature. No less useful to a modern chemist, for example, can be applied to his subject of research and other dialectical categories, including such as form and content, necessity and chance. The Subject and Methods of Cognition of Chemical Science Translating modern scientific discoveries into the universal language of universal concepts, philosophers not only study physics, chemistry, biology, but allocate whole scientific concepts and methodological forms. Thus, philosophy deals with the theory of science within its own wider natural history research, as already mentioned earlier. It is clear that the philosophy of chemistry pays special influence on the subject and methods of knowledge of chemical science. The object of the study of brain chemistry is the material world of the brain in the variety of its internal connections and the constant dynamics of


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development. Chemistry deals with successive transformations of matter, it delves into the origin of bodies, explores their past and future. Chemistry is interested in a special kind of processes in the material world, the essence of which is not a simple physical displacement of objects, but a complete change of various materials, their transformation and mutual transition, which is the basis of any chemical transformation. It should be clarified that in the light of new scientific data, the chemical transformation of a substance is a transformation in which a change in the structure of a substance, its composition, and properties takes place in accordance with specific chemical laws. Chemical transformations occur at the atomic level and are carried out in the process of specific interactions of certain structures of particles of matter. Chemical transformations are accompanied by the appearance or redistribution of chemical bonds. Already these chemical transformations are significantly different from other species by the transformation of matter (nuclear, geological, biological). The basic methods of cognition used in chemistry. 1. Induction. In this case, cognition moves from the private, the individual to the general. On the basis of the study of individual chemical phenomena, available judgments and facts, generalizing conclusions are made, general properties, and essential and regular connections of substances are established. The inductive method is based on experience, observation, accumulation and analysis of individual facts. The inductive method is the basis of empirical knowledge. An example of a successful application of induction in chemistry is the discovery of the law of conservation of the mass of substances by MVLomonosov in the process of testing Boyle's experiments with the burning of metals, and the derivation of empirical rules for the constancy of the composition, Proust and Richter. Rules, which became concomitant theories of stoichiometry on the basis of atomic representations. Usually inductive way it is possible to establish quantitative and other external characteristics of the observed phenomena and processes given to the researcher in direct sensory perception. Induction can also be defined as the accumulation of facts of observation, analysis and systematization of facts, and, finally, a generalization

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of the results obtained with a view to deriving objective laws. 2. Deduction. This is a way of logical reasoning, coming from the general (chemical law, postulate, rule) - to a particular, that is, to individual chemical facts. As the method of deduction is directly opposite to induction, since reliance is made on creative thinking, giving birth to ideas, assumptions, hypotheses and even theories, all this can then be compared with facts and tested experimentally, while in the inductive method everything is done in the reverse order. Deduction in chemistry as in other natural sciences not only complements induction, but plays the role of the basis of theoretical research. The creation of laws is impossible without deductive discoveries, since it is impossible to derive their essence from observations of phenomena. As an example, it should be remembered that the rules of Proust and Richter became the corresponding theories of stoichiometry only because of the first successes in the development of the atomic-molecular theory. It was necessary to find a mental answer to the question, for example, what is the reason for the action of the permanent rule, but such an answer does not follow from the observation of chemical reactions, as it does not follow from the most discovered rule. After the works of Descartes and especially Kant and Hegel, philosophy came to the conclusion that any theories, including scientific ones, are not logically derived from empirical facts and regularities, are not their inductive generalization, but are built on empirical knowledge as a description of a special kind reality, as a sphere of ideal objects with a system of their own interrelations. The theoretical level characterizes the maturity of science, although it should not be forgotten that true theory is impossible without its empirical soil, as the form is inseparable from content and vice versa. 3. Analysis and synthesis. In the process of knowledge of chemicals and processes, an important place is occupied by methods of analysis and synthesis. Objects of scientific interest in the analytical study are dismembered, then their constituent parts, connections and parties are singled out for more detailed study. Analysis allows us to separate the universal from the individual, necessary from the accidental, the main thing from the secondary. On such principles, the whole branch of chemical science is based - analytical chemistry,


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where the determination of the chemical composition is solved by the qualitative and quantitative method of analysis. At the same time, analysis is only the beginning of the process of cognition, because knowledge of the individual parts of the subject does not yet give knowledge about the subject as a whole. In scientific and theoretical thought, the notion that the whole can not be reduced to the mechanical sum of its parts has long been established. In the process of synthesis, there is a practical or mental connection of the constituent parts of the studied object, its properties and connections, dissected as a result of analysis, in a new qualitative form. As a result, the object appears as an inseparable dialectical unity of the parts and the whole. Passing through analysis and synthesis, the subject of research necessarily changes, becoming more differentiated in content, which is in close relationship with the growth of the difference in our understanding of the studied subject in all its properties, connections and qualities. 4. Scientific abstraction. One of the characteristic features of modern science and, in particular, chemistry is the widespread use of the method of scientific abstraction. Abstraction presupposes a mental abstraction from a number of secondary, inessential properties and connections, as well as the sides of the object under study when one common, essential feature, property or relation is singled out. The resulting concept is called abstraction. In chemistry, scientific abstractions are such important concepts as acid, element, alcohol, homology series, valency, chemical structure. The method of scientific abstraction is especially necessary in the mental search for essences and laws. 5. Modeling. In close connection with the abstraction is a method of modeling, which is also widely used in modern science. Simulation is a special kind of experiment, often mental. In chemistry, the modeling method has been used for a relatively long time. For example, chemical symbols, the first formulas of Berzelius compounds really represented sign models reflecting the composition of the compound, as well as the stoichiometric relationships between the elements. The development of the theory of the chemical structure made it possible to create a model of a molecule in the form of a structural formula that expresses the order of the bond of atoms. In recent years, due to the constant development of computer technology, the role of the modeling

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method has significantly increased. 6. The method of the experiment. This method can not be wholly attributed to the field of purely empirical research, although at first glance the experiment is directly related to practice. Better to say, the method of the experiment is universal and suitable also for theoretical studies, for example, a so-called thought experiment is possible. Even in the case of experiment, the form of laboratory experience, as is often the case in chemistry, it should be noted that any experience is pre-prepared and carefully thought out from the perspective of a hypothesis, and therefore we are dealing with a practice that is mediated by theory. In other words, the experiment is not self-sufficient and is not a method of pure empiricism, independent of theoretical concepts. On the contrary, the entire structure of the experiment as well as its purpose, as a rule, are coordinated in advance with any explanatory concept, theory, or system of ideas of the whole scientific school. Such a "duality" can be attributed to the merits of the experimental method, which includes a real unity of theory and practice, form and content. But this method is not available to all sciences that study nature, in a number of sciences it is either impossible or extremely difficult. At the same time, it is the chemical form of the motion of matter that represents an infinite field of possibilities for the experimenter. Philosophical Meaning of Chemical Laws and the Problem of Cognition in Chemistry Laws can be considered idealized images of objective laws of the material world. If we resort to a logical formulation, then the law of nature is an essential and repetitive connection between phenomena: bodies and their properties. Such a connection is not accidental, it is universal and necessary, that is, it is always and everywhere under certain conditions. The main laws and theories on which modern chemical science is based are the laws of stereochemistry, the theory of the chemical structure and the periodic law of chemical elements. On the basis of these laws, the nature of the chemical structure and composition of the substance, the chemical bonds, the nature of the chemical transformations were combined. Based on these laws, a methodology for the study of chemicals and phenomena has been developed.


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Chemical laws are conventionally divided into qualitative and quantitative laws. Quantitative laws formed the basis of many theories, for example, on the law of constancy of composition, a study was made of the qualitative composition of matter. Laws in chemistry have their own characteristics. 1. Chemical laws are established in the study of macrosystems and act in processes that converts large masses of particles, that is, substances. 2. Chemical laws do not take into account the significant changes in the properties and behavior of a substance that are inevitable in the transition from particle masses to individual particles, considering that the behavior of each particle, like its properties, coincides with the behavior and properties of the substance. 3. Chemical laws are static in nature, that is, they consider that individual deviations (individual, elementary chemical acts) from a statically mean value are unimportant, and the conclusions of probability theory have the force of law. Similar features of chemical laws lead the philosophy of chemistry to a whole series of problems of cognition in chemical science. For a chemist, the material world appears first and foremost as the world of concrete bodies, which enter into complex interactions with each and every material body itself consists of a set of individual individual bodies (molecules, atoms). The world of a chemist is a world of constantly interacting multiplicity of material objects, in which multiplicity is concrete and manifested, and unity is an idea, a hypothesis or an assumption that keeps this set from being disintegrated into a concept. According to Hegel, chemical processes are manifested between bodily individuals, where there is no connection with the substance that gave rise to these individuals; the connection with the substance is not obvious. Thus, if the struggle of opposites in chemistry is expressed quite clearly, the moment of unifying unity is lost in the field of "first-matter", devoid of individuality and manifested in chemical reactions solely in the form of the chemical transformations of matter itself, where there is a triumph of the laws of transition of quantitative changes to qualitative and negation of negation.

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This feature of the chemical worldview is the main source of knowledge problems in chemistry. 1. The problem of the complexity of building a unified theory of chemical processes, which leads to the disintegration of a single science of chemistry into a number of special specific areas of research that poorly match their theoretical findings with each other, and often give alternative descriptions of the same processes. 2. The problem of the predominance of the actual side and applied empirical research on the theoretical side of science. 3. The problem of the extra-history of chemistry. This problem manifests itself primarily in the replacement of motion in time by the sum of stationary states, when they attempt to represent a chemical transformation as a chain of intermediate products. 4. The problem of the complexity of the theoretical establishment of internal genetic links between individual homologous substances. For example, formic, acetic, propionic and many other acids as representatives of the class of homologues should have an internal unity, but so far no link between them has been established between them. One can get another from one acid, which is done in practical chemistry, but these transitions are multiple, arbitrary and do not contain any internal line of development. These and other problems of chemical knowledge are objective in nature, due to the specific features of the studied subject. They can be overcome only through contacts of chemistry with other sciences, both natural (physics, biology), and humanitarian. Here, first of all, there is philosophy in mind, as a science possessing a developed concept of the nature of the universal and developing methods of theoretical cognition. Neuropharmacology Neuropharmacology is the study of how drugs affect cellular function in the nervous system, and the neural mechanisms through which they influence behavior. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior (neuropsychopharmacology), including the study of how drug dependence and addiction affect the human brain. Molecular


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neuropharmacology involves the study of neurons and their neurochemical interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral nervous systems. Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, psychological disorders, addiction, and many others. Neuropharmacology did not appear in the scientific field until, in the early part of the 20th century, scientists were able to figure out a basic understanding of the nervous system and how nerves communicate between one another. Before this discovery, there were drugs that had been found that demonstrated some type of influence on the nervous system. In the 1930s, French scientists began working with a compound called phenothiazine in the hope of synthesizing a drug that would be able to combat malaria. Though this drug showed very little hope in the use against malaria-infected individuals, it was found to have sedative effects along with what appeared to be beneficial effects toward patients with Parkinson’s disease. This black box method, wherein an investigator would administer a drug and examine the response without knowing how to relate drug action to patient response, was the main approach to this field, until, in the late 1940s and early 1950s, scientists were able to identify specific neurotransmitters, such as norepinephrine (involved in the constriction of blood vessels and the increase in heart rate and blood pressure), dopamine (the chemical whose shortage is involved in Parkinson’s disease), and serotonin(soon to be recognized as deeply connected to depression). In the 1950s, scientists also became better able to measure levels of specific neurochemicals in the body and thus correlate these levels with behavior. The invention of the voltage clamp in 1949 allowed for the study of ion channels and the nerve action potential. These two major historical events in neuropharmacology allowed scientists not only to study how information is transferred from one neuron to another but also to study how a neuron

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processes this information within itself. Neuropharmacology is a very broad region of science that encompasses many aspects of the nervous system from single neuron manipulation to entire areas of the brain, spinal cord, and peripheral nerves. To better understand the basis behind drug development, one must first understand how neurons communicate with one another. This article will focus on both behavioral and molecular neuropharmacology; the major receptors, ion channels, and neurotransmitters manipulated through drug action and how people with a neurological disorder benefit from this drug action. Neurochemical Interactions To understand the potential advances in medicine that neuropharmacology can bring, it is important to understand how human behavior and thought processes are transferred from neuron to neuron and how medications can alter the chemical foundations of these processes. Neurons are known as excitable cells because on its surface membrane there are an abundance of proteins known as ion-channels that allow small charged particles to pass in and out of the cell. The structure of the neuron allows chemical information to be received by its dendrites, propagated through the perikaryon (cell body) and down its axon, and eventually passing on to other neurons through its axon terminal.

Figure 1. Labeling of different parts of a neuron

These voltage-gated ion channels allow for rapid depolarization throughout the cell. This depolarization, if it reaches a certain threshold, will cause an


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action potential. Once the action potential reaches the axon terminal, it will cause an influx of calcium ions into the cell. The calcium ions will then cause vesicles, small packets filled with neurotransmitters, to bind to the cell membrane and release its contents into the synapse. This cell is known as the pre-synaptic neuron, and the cell that interacts with the neurotransmitters released is known as the post-synaptic neuron. Once the neurotransmitter is released into the synapse, it can either bind to receptors on the post-synaptic cell, the pre-synaptic cell can re-uptake it and save it for later transmission, or it can be broken down by enzymes in the synapse specific to that certain neurotransmitter. These three different actions are major areas where drug action can affect communication between neurons. There are two types of receptors that neurotransmitters interact with on a post-synaptic neuron. The first types of receptors are ligand-gated ion channels or LGICs. LGIC receptors are the fastest types of transduction from chemical signal to electrical signal. Once the neurotransmitter binds to the receptor, it will cause a conformational change that will allow ions to directly flow into the cell. The second types are known as G-protein-coupled receptors or GPCRs. These are much slower than LGICs due to an increase in the amount of biochemical reactions that must take place intracellularly. Once the neurotransmitter binds to the GPCR protein, it causes a cascade of intracellular interactions that can lead to many different types of changes in cellular biochemistry, physiology, and gene expression. Neurotransmitter/receptor interactions in the field of neuropharmacology are extremely important because many drugs that are developed today have to do with disrupting this binding process. Molecular Neuropharmacology Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, and receptors on neurons, with the goal of developing new drugs that will treat neurological disorders such as pain, neurodegenerative diseases, and psychological disorders (also known in this case as neuropsychopharmacology). There are a few technical words that must be defined when relating neurotransmission to receptor action:

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1. Agonist – a molecule that binds to a receptor protein and activates that receptor 2. Competitive antagonist – a molecule that binds to the same site on the receptor protein as the agonist, preventing activation of the receptor 3. Non-competitive antagonist – a molecule that binds to a receptor protein on a different site than that of the agonist, but causes a conformational change in the protein that does not allow activation. The following neurotransmitter/receptor interactions can be affected by synthetic compounds that act as one of the three above. Sodium/potassium ion channels can also be manipulated throughout a neuron to induce inhibitory effects of action potentials. GABA The GABA neurotransmitter mediates the fast synaptic inhibition in the central nervous system. When GABA is released from its pre-synaptic cell, it will bind to a receptor (most likely the GABAA receptor) that causes the post-synaptic cell to hyperpolarize (stay below its action potential threshold). This will counteract the effect of any excitatory manipulation from other neurotransmitter/receptor interactions. This GABAA receptor contains many binding sites that allow conformational changes and are the primary target for drug development. The most common of these binding sites, benzodiazepine, allows for both agonist and antagonist effects on the receptor. A common drug, diazepam, acts as an allosteric enhancer at this binding site. [4] Another receptor for GABA, known as GABAB, can be enhanced by a molecule called baclofen. This molecule acts as an agonist, therefore activating the receptor, and is known to help control and decrease spastic movement. Dopamine The dopamine neurotransmitter mediates synaptic transmission by binding to five specific GPCRs. These five receptor proteins are separated into two classes due to whether the response elicits an excitatory or inhibitory response on the post-synaptic cell. There are many types of drugs, legal and illegal, that effect dopamine and its interactions in the brain. With Parkinson's disease, a


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disease that decreases the amount of dopamine in the brain, the dopamine precursor Levodopa is given to the patient due to the fact that dopamine cannot cross the blood–brain barrier and L-dopa can. Some dopamine agonists are also given to Parkinson's patients that have a disorder known as restless leg syndrome or RLS. Some examples of these are ropinirole and pramipexole. Psychological disorders like that of attention deficit hyperactivity disorder (ADHD) can be treated with drugs like methylphenidate (also known as Ritalin), which block the re-uptake of dopamine by the pre-synaptic cell, thereby providing an increase of dopamine left in the synaptic gap. This increase in synaptic dopamine will increase binding to receptors of the post-synaptic cell. This same mechanism is also used by other illegal and more potent stimulant drugs such as cocaine. Serotonin The serotonin neurotransmitter has the ability to mediate synaptic transmission through either GPCR's or LGIC receptors. Depending on what part of the brain region serotonin is being acted upon, will depend on whether the output is either increasing or decreasing post-synaptic responses. The most popular and widely used drugs in the regulation of serotonin during depression are known as SSRIs or selective serotonin reuptake inhibitors. These drugs inhibit the transport of serotonin back into the pre-synaptic neuron, leaving more serotonin in the synaptic gap to be used. Before the discovery of SSRIs, there were also very many drugs that inhibited the enzyme that breaks down serotonin. MAOIs or monoamine oxidase inhibitors increased the amount of serotonin in the pre-synaptic cell, but had many side-effects including intense migraines and high blood pressure. This was eventually linked to the drug's interacting with a common chemical known as tyramine found in many types of food. Ion Channels Ion channels located on the surface membrane of the neuron allows for an influx of sodium ions and outward movement of potassium ions during an action potential. Selectively blocking these ion channels will decrease the likelihood of an action potential to occur. The drug riluzole is a neuroprotective

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drug that blocks sodium ion channels. Since these channels cannot activate, there is no action potential, and the neuron does not perform any transduction of chemical signals into electrical signals and the signal does not move on. This drug is used as an anesthetic as well as a sedative. Behavioral Neuropharmacology One form of behavioral neuropharmacology focuses on the study of drug dependence and how drug addiction affects the human mind. Most research has shown that the major part of the brain that reinforces addiction through neurochemical reward is the nucleus accumbens. The image to the right shows how dopamine is projected into this area. Chronic alcohol abuse can cause dependence and addiction. How this addiction occurs is described below. Ethanol Alcohol's rewarding and reinforcing (i.e., addictive) properties are mediated through its effects on dopamine neurons in the mesolimbic reward pathway, which connects the ventral tegmental area to the nucleus accumbens (NAcc). One of alcohol's primary effects is the allosteric inhibition of NMDA receptors and facilitation of GABAA receptors (e.g., enhanced GABAAreceptor-mediated chloride flux through allosteric regulation of the receptor). At high doses, ethanol inhibits most ligand gated ion channels and voltage gated ion channels in neurons as well. Alcohol inhibits sodium-potassium pumps in the cerebellum and this is likely how it impairs cerebellar computation and body co-ordination. With acute alcohol consumption, dopamine is released in the synapses of the mesolimbic pathway, in turn heightening activation of postsynaptic D1 receptors. The activation of these receptors triggers postsynaptic internal signaling events through protein kinase A which ultimately phosphorylate cAMP response element binding protein (CREB), inducing CREB-mediated changes in gene expression. With chronic alcohol intake, consumption of ethanol similarly induces CREB phosphorylation through the D1 receptor pathway, but it also alters NMDA receptor function through phosphorylation mechanisms; an adaptive downregulation of the D1 receptor pathway and CREB function occurs as well. Chronic consumption is also associated with an effect on CREB


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phosphorylation and function via postsynaptic NMDA receptor signaling cascades through a MAPK/ERK pathway and CAMK-mediated pathway. These modifications to CREB function in the mesolimbic pathway induce expression (i.e., increase gene expression) of ΔFosB in the NAcc, where ΔFosB is the "master control protein" that, when overexpressed in the NAcc, is necessary and sufficient for the development and maintenance of an addictive state (i.e., its overexpression in the nucleus accumbens produces and then directly modulates compulsive alcohol consumption). Parkinson's Disease Parkinson's disease is a neurodegenerative disease described by the selective loss of dopaminergic neurons located in the substantia nigra. Today, the most commonly used drug to combat this disease is levodopa or L-DOPA. This precursor to dopamine can penetrate through the blood–brain barrier, whereas the neurotransmitter dopamine cannot. There has been extensive research to determine whether L-dopa is a better treatment for Parkinson's disease rather than other dopamine agonists. Some believe that the long-term use of L-dopa will compromise neuroprotection and, thus, eventually lead to dopaminergic cell death. Though there has been no proof, in-vivo or in-vitro, some still believe that the long-term use of dopamine agonists is better for the patient. Alzheimer's Disease While there are a variety of hypotheses that have been proposed for the cause of Alzheimer's disease, the knowledge of this disease is far from complete to explain, making it difficult to develop methods for treatment. In the brain of Alzheimer's patients, both neuronal nicotinic acetylcholine (nACh) receptors and NMDA receptors are known to be down-regulated. Thus, four anticholinesterases have been developed and approved by the U.S. Food and Drug Administration (FDA) for the treatment in the U.S.A. However, these are not ideal drugs, considering their side-effects and limited effectiveness. One promising drug, nefiracetam, is being developed for the treatment of Alzheimer's and other patients with dementia, and has unique actions in potentiating the activity of both nACh receptors and NMDA receptors.

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Future With advances in technology and our understanding of the nervous system, the development of drugs will continue with increasing drug sensitivity and specificity. Structure-activity relationships are a major area of research within neuropharmacology; an attempt to modify the effect or the potency (i.e., activity) of bioactive chemical compounds by modifying their chemical structures. Structure–activity Relationship The structure–activity relationship (SAR) is the relationship between the chemical or 3D structure of a molecule and its biological activity. The analysis of SAR enables the determination of the chemical group responsible for evoking a target biological effect in the organism. This allows modification of the effect or the potency of a bioactive compound (typically a drug) by changing its chemical structure. Medicinal chemists use the techniques of chemical synthesis to insert new chemical groups into the biomedical compound and test the modifications for their biological effects. This method was refined to build mathematical relationships between the chemical structure and the biological activity, known as quantitative structure–activity relationships (QSAR). A related term is structure affinity relationship (SAFIR). Neuropsychopharmacology Neuropsychopharmacology, an interdisciplinary science related to psychopharmacology (how drugs affect the mind) and fundamental neuroscience, is the study of the neural mechanisms that drugs act upon to influence behavior. It entails research of mechanisms of neuropathology, pharmacodynamics (drug action), psychiatric illness, and states of consciousness. These studies are instigated at the detailed level involving neurotransmission/receptor activity, bio-chemical processes, and neural circuitry. Neuropsychopharmacology supersedes psychopharmacology in the areas of "how" and "why", and additionally addresses other issues of brain function. Accordingly, the clinical aspect of the field includes psychiatric (psychoactive) as well as neurologic (non-psychoactive) pharmacology-based


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treatments. Developments in neuropsychopharmacology may directly impact the studies of anxiety disorders, affective disorders, psychotic disorders, degenerative disorders, eating behavior, and sleep behavior. Drugs such as opium, alcohol, and certain plants have been used for millennia by humans to ease suffering or change awareness, but until the modern scientific era nobody knew how these substances worked. The first half of the 20th century saw psychology and psychiatry as largely phenomenological, in that behaviors or themes which were observed in patients could often be correlated to a limited variety of factors such as childhood experience, inherited tendencies, or injury to specific brain areas. Models of mental function and dysfunction were based on such observations. Indeed, the behavioral branch of psychology dispensed altogether with what actually happened inside the brain, regarding most mental dysfunction as what could be dubbed as "software" errors. In the same era, the nervous system was progressively being studied at the microscopic and chemical level, but there was virtually no mutual benefit with clinical fields—until several developments after World War II began to bring them together. Neuropsychopharmacology may be regarded to have begun in the earlier 1950s with the discovery of drugs such as MAO inhibitors, tricyclic antidepressants, thorazine and lithium which showed some clinical specificity for mental illnesses such as depression and schizophrenia. Until that time, treatments that actually targeted these complex illnesses were practically non-existent. The prominent methods which could directly affect brain circuitry and neurotransmitter levels were the pre-frontal lobotomy, and electroconvulsive therapy, the latter of which was conducted without muscle relaxants which often caused the patient great physical injury. The field now known as neuropsychopharmacology has resulted from the growth and extension of many previously isolated fields which have met at the core of psychiatric medicine, and engages a broad range of professionals from psychiatrists to researchers in genetics and chemistry. The use of the term has gained popularity since 1990 with the founding of several journals and institutions such as the Hungarian College of Neuropsychopharmacology. [1] This rapidly maturing field shows some degree of flux, as research hypotheses

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are often restructured based on new information. An implicit premise in neuropsychopharmacology with regard to the psychological aspects is that all states of mind, including both normal and drug-induced altered states, and diseases involving mental or cognitive dysfunction, have a neuro-chemical basis at the fundamental level, and certain circuit pathways in the central nervous system at a higher level. (See also: Neuron doctrine) Thus the understanding of nerve cells or neurons in the brain is central to understanding the mind. It is reasoned that the mechanisms involved can be elucidated through modern clinical and research methods such as genetic manipulation in animal subjects, imaging techniques such as functional magnetic resonance imaging (fMRI), and in vitro studies using selective binding agents on live tissue cultures. These allow neural activity to be monitored and measured in response to a variety of test conditions. Other important observational tools include radiological imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). These imaging techniques are extremely sensitive and can image tiny molecular concentrations on the order of 10−10 M such as found with extrastriatal D1 receptor for dopamine. One of the ultimate goals is to devise and develop prescriptions of treatment for a variety of neuro-pathological conditions and psychiatric disorders. More profoundly, though, the knowledge gained may provide insight into the very nature of human thought, mental abilities like learning and memory, and perhaps consciousness itself. A direct product of neuropsychopharmacological research is the knowledge base required to develop drugs which act on very specific receptors within a neurotransmitter system. These "hyperselective-action" drugs would allow the direct targeting of specific sites of relevant neural activity, thereby maximizing the efficacy (or technically the potency) of the drug within the clinical target and minimizing adverse effects. The groundwork is currently being paved for the next generation of pharmacological treatments which will improve quality of life with increasing efficiency. For example, contrary to previous thought, it is now known that the adult brain does to some extent grow new neurons—the study of which, in addition to neurotrophic factors, may hold hope for neuro-degenerative


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diseases like Alzheimer's, Parkinson's, ALS, and types of chorea. All of the proteins involved in neurotransmission are a small fraction of the more than 100,000 proteins in the brain. Thus there are many proteins which are not even in the direct path of signal transduction, any of which may still be a target for specific therapy. At present, novel pharmacological approaches to diseases or conditions are reported at a rate of almost one per week. Neurotransmission So far as we know, everything we perceive, feel, think, know, and do are a result of neurons firing and resetting. When a cell in the brain fires, small chemical and electrical swings called the action potential may affect the firing of as many as a thousand other neurons in a process called neurotransmission. In this way signals are generated and carried through networks of neurons, the bulk electrical effect of which can be measured directly on the scalp by an EEG device. By the last decade of the 20th century, the essential knowledge of all the central features of neurotransmission had been gained. These features are:  The synthesis and storage of neurotransmitter substances,  The transport of synaptic vesicles and subsequent release into the synapse,  Receptor activation and cascade function,  Transport mechanisms (reuptake) and/or enzyme degradation The more recent advances involve understanding at the organic molecular level; biochemical action of the endogenous ligands, enzymes, receptor proteins, etc. The critical changes affecting cell firing occur when the signalling neurotransmitters from one neuron, acting as ligands, bind to receptors of another neuron. Many neurotransmitter systems and receptors are well known, and research continues toward the identification and characterization of a large number of very specific sub-types of receptors. For the six more important neurotransmitters Glu, GABA, Ach, NE, DA, and 5HT (listed at neurotransmitter) there are at least 29 major subtypes of receptor. Further "sub-subtypes" exist together with variants, totalling in the hundreds for just these 6 transmitters. - (see serotonin receptor for example.) It is often found that receptor subtypes have differentiated function, which in principle opens up

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the possibility of refined intentional control over brain function. It has previously been known that ultimate control over the membrane voltage or potential of a nerve cell, and thus the firing of the cell, resides with the trans-membrane ion channels which control the membrane currents via the ions K+, Na+, and Ca++, and of lesser importance Mg++ and Cl−. The concentration differences between the inside and outside of the cell determine the membrane voltage.

Figure 2. Abstract simplified diagram showing overlap between neurotransmission and metabolic activity. Neurotransmitters bind to receptors which cause changes to ion channels (black, yellow), metabotropic receptors also affect DNA transcription (red), transcription is responsible for all cell proteins including enzymes which manufacture neurotransmitters (blue)


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Precisely how these currents are controlled has become much clearer with the advances in receptor structure and G-protein-coupled processes. Many receptors are found to be pentameric clusters of five trans-membrane proteins (not necessarily the same) or receptor subunits, each a chain of many amino acids. Transmitters typically bind at the junction between two of these proteins, on the parts that protrude from the cell membrane. If the receptor is of the ionotropic type, a central pore or channel in the middle of the proteins will be mechanically moved to allow certain ions to flow through, thus altering the ion concentration difference. If the receptor is of the metabotropic type, G-proteins will cause metabolism inside the cell that may eventually change other ion channels. Researchers are better understanding precisely how these changes occur based on the protein structure shapes and chemical properties. The scope of this activity has been stretched even further to the very blueprint of life since the clarification of the mechanism underlying gene transcription. The synthesis of cellular proteins from nuclear DNA has the same fundamental machinery for all cells; the exploration of which now has a firm basis thanks to the Human Genome Project which has enumerated the entire human DNA sequence, although many of the estimated 35,000 genes remain to be identified. The complete neurotransmission process extends to the genetic level. Gene expressiondetermines protein structures through type II RNA polymerase. So enzymes which synthesize or breakdown neurotransmitters, receptors, and ion channels are each made from mRNA via the DNA transcription of their respective gene or genes. But neurotransmission, in addition to controlling ion channels either directly or otherwise through metabotropic processes, also actually modulates gene expression. This is most prominently achieved through modification of the transcription initiation process by a variety of transcription factors produced from receptor activity. Aside from the important pharmacological possibilities of gene expression pathways, the correspondence of a gene with its protein allows the important analytical tool of gene knockout. Living specimens can be created using homolog recombination in which a specific gene cannot be expressed. The organism will then be deficient in the associated protein which may be a specific receptor. This method avoids chemical blockade which can produce

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confusing or ambiguous secondary effects so that the effects of a lack of receptor can be studied in a purer sense. Drugs The inception of many classes of drugs is in principle straightforward: any chemical that can enhance or diminish the action of a target protein could be investigated further for such use. The trick is to find such a chemical that is receptor-specific (cf. "dirty drug") and safe to consume. The 2005 Physicians' Desk Reference lists twice the number of prescription drugs as the 1990 version. Many people by now are familiar with "selective serotonin reuptake inhibitors", or SSRIs which exemplify modern pharmaceuticals. These SSRI anti-depressant drugs, such as Paxil and Prozac, selectively and therefore primarily inhibit the transport of serotonin which prolongs the activity in the synapse. There are numerous categories of selective drugs, and transport blockage is only one mode of action. The FDA has approved drugs which selectively act on each of the major neurotransmitters such as NE reuptake inhibitor antidepressants, DAblocker anti-psychotics, and GABA agonist tranquilizers (benzodiazepines). New endogenous chemicals are continually identified. Specific receptors have been found for the drugs THC (cannabis) and GHB, with endogenous transmitters anandamide and GHB. Another recent major discovery occurred in 1999 when orexin, or hypocretin, was found to have a role in arousal, since the lack of orexin receptors mirrors the condition of narcolepsy. Orexin agonism may explain the anti-narcoleptic action of the drug modafinil which was already being used only a year prior. The next step, which major pharmaceutical companies are currently working hard to develop, are receptor subtype-specific drugs and other specific agents. An example is the push for better anti-anxiety agents (anxiolytics) based on GABAA(α2) agonists, CRF1 blockers, and 5HT2c blockers. Another is the proposal of new routes of exploration for anti-psychotics such as glycine reuptake inhibitors. Although the capabilities exist for receptor-specific drugs, a shortcoming of drug therapy is the lack of ability to provide anatomicalspecificity. By altering receptor function in one part of the brain,


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abnormal activity can be induced in other parts of the brain due to the same type of receptor changes. A common example is the effect of D2 altering drugs (neuroleptics) which can help schizophrenia, but cause a variety of dyskinesias by their action on motor cortex. Modern studies are revealing details of mechanisms of damage to the nervous system such as apoptosis (programmed cell death) and free-radical disruption. PCP has been found to cause cell death in striatopallidal cells and abnormal vacuolization in hippocampal and other neurons. The hallucinogen persisting perception disorder (HPPD), also known as post-psychedelic perception disorder, has been observed in patients as long as 26 years after LSD use. The plausible cause of HPPD is damage to the inhibitory GABA circuit in the visual pathway (GABA agonists such as midazolam can decrease some effects of LSD intoxication). The damage may be the result of an excitotoxic response of 5HT2 interneurons. The vast majority of LSD users do not experience HPPD. Its manifestation may be equally dependent on individual brain chemistry as on the drug use itself. As for MDMA, aside from persistent losses of 5HT and SERT, long-lasting reduction of serotonergic axons and terminals is found from short-term use, and regrowth may be of compromised function. Neural Circuits It is a not-so-recent discovery that many functions of the brain are localized to associated areas like motor and speech ability. Functional associations of brain anatomy are now being complemented with clinical, behavioral, and genetic correlates of receptor action, completing the knowledge of neural signalling. The signal paths of neurons are hyper-organized beyond the cellular scale into often complex neural circuit pathways. Knowledge of these pathways is perhaps the easiest to interpret, being most recognizable from a systems analysis point of view, as may be seen in the following abstracts. Progress has been made on central mechanisms of hallucination believed to be common to psychedelic drugs and psychosis. It is likely the effect of partial agonistic action on the serotonin system. The 5HT2A receptor and possibly the 5HT1C are involved by releasing glutamate in the frontal cortex, while

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simultaneously in the locus coeruleus sensory information is promoted and spontaneous activity decreases. One hypothesis suggests that in the frontal cortex, 5HT2A promotes late asynchronous excitatory post-synaptic potentials, a process antagonized by serotonin itself through 5HT1 which may explain why SSRI's and other serotonin-affecting drugs do not normally cause a patient to hallucinate.

Figure 3. Diagram of neural circuit which regulates melatonin production via actual circuit pathways. Green light in the eye inhibits pineal production of melatonin (Inhibitory connections shown in red). Also shown: reaction sequence for melatonin synthesis

Circadian rhythm, or sleep/wake cycling, is centered in the suprachiasmatic nucleus (SCN) within the hypothalamus, and is marked by melatonin levels 2000-4,000% higher during sleep than in the day. A circuit is known to start with melanopsincells in the eye which stimulate the SCN through glutamate neurons of the hypothalamic tract. GABA-ergic neurons from the SCN inhibit the paraventricular nucleus, which signals the superior cervical ganglion (SCG) through sympathetic fibers. The output of the SCG, stimulates NE


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receptors (β) in the pineal gland which produces N-acetyltransferase, causing production of melatonin from serotonin. Inhibitory melatonin receptors in the SCN then provide a positive feedback pathway. Therefore, light inhibits the production of melatonin which "entrains" the 24-hour cycle of SCN activity. [10, 11] The SCN also receives signals from other parts of the brain, and its (approximately) 24-hour cycle does not only depend on light patterns. In fact, sectioned tissue from the SCN will exhibit daily cycle in vitro for many days. Additionally, (not shown in diagram), the basal nucleus provides GABA-ergic inhibitory input to the pre-optic anterior hypothalamus (PAH). When adenosine builds up from the metabolism of ATP throughout the day, it binds to adenosine receptors, inhibiting the basal nucleus. The PAH is then activated, generating slow-wave sleep activity. Caffeine is known to block adenosine receptors, thereby inhibiting sleep among other things. Research in neuropsychopharmacology comes from a wide range of activities in neuroscience and clinical research. This has motivated organizations such as the American College of Neuropsychopharmacology (ACNP), the European College of Neuropsychopharmacology (ECNP), and the Collegium Internationale Neuro-psychopharmacologicum (CINP) to be established as a measure of focus. The ECNP publishes European Neuropsychopharmacology, and as part of the Reed Elsevier Group, the ACNP publishes the journal Neuropsychopharmacology, and the CINP publishes the journal International Journal of Neuropsychopharmacology with Cambridge University Press. In 2002, the most recent comprehensive collected work of the ACNP, "Neuropsychopharmacology: The Fifth Generation of Progress" was compiled. It is one measure of the current state of knowledge, and might be said to represent a landmark in the century-long goal to establish the basic neuro-biological principles which govern the actions of the brain. Neuropeptides Neuropeptides are small protein-like molecules (peptides) used by neurons to communicate with each other. They are neuronal signaling molecules that influence the activity of the brain and the body in specific ways. Different neuropeptides are involved in a wide range of brain functions, including

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analgesia, reward, food intake, metabolism, reproduction, social behaviors, learning and memory. Neuropeptides are related to peptide hormones, and in some cases peptides that function in the periphery as hormones also have neuronal functions as neuropeptides. The distinction between neuropeptide and peptide hormone has to do with the cell types that release and respond to the molecule; neuropeptides are secreted from neuronal cells (primarily neurons but also glia for some peptides) and signal to neighboring cells (primarily neurons). In contrast, peptide hormones are secreted from neuroendocrine cells and travel through the blood to distant tissues where they evoke a response. Both neuropeptides and peptide hormones are synthesized by the same sets of enzymes, which include prohormone convertases and carboxypeptidases that selectively cleave the peptide precursor at specific processing sites to generate the bioactive peptides. Neuropeptides modulate neuronal communication by acting on cell surface receptors. Many neuropeptides are co-released with other small-molecule neurotransmitters. The human genome contains about 90 genes that encode precursors of neuropeptides. At present about 100 different peptides are known to be released by different populations of neurons in the mammalian brain. [2] Neurons use many different chemical signals to communicate information, including neurotransmitters, peptides, and gasotransmitters. Peptides are unique among these cell-cell signaling molecules in several respects. One major difference is that peptides are not recycled back into the cell once secreted, unlike many conventional neurotransmitters (glutamate, dopamine, serotonin). Another difference is that after secretion, peptides are modified by extracellular peptidases; in some cases, these extracellular cleavages inactivate the biological activity, but in other cases the extracellular cleavages increase the affinity of a peptide for a particular receptor while decreasing its affinity for another receptor. These extracellular processing events add to the complexity of neuropeptides as cell-cell signaling molecules. Many populations of neurons have distinctive biochemical phenotypes. For example, in one subpopulation of about 3000 neurons in the arcuate nucleus of the hypothalamus, three anorectic peptides are co-expressed: α-melanocyte-stimulating hormone (α-MSH), galanin-like peptide, and


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cocaine-and-amphetamine-regulated transcript (CART), and in another subpopulation two orexigenic peptides are co-expressed, neuropeptide Y and agouti-related peptide (AGRP). These are not the only peptides in the arcuate nucleus; β-endorphin, dynorphin, enkephalin, galanin, ghrelin, growth-hormone releasing hormone, neurotensin, neuromedin U, and somatostatin are also expressed in subpopulations of arcuate neurons. These peptides are all released centrally and act on other neurons at specific receptors. The neuropeptide Y neurons also make the classical inhibitory neurotransmitter GABA. Invertebrates also have many neuropeptides. CCAP has several functions including regulating heart rate, allatostatin and proctolin regulate food intake and growth, bursiconcontrols tanning of the cuticle and corazonin has a role in cuticle pigmentation and moulting. Peptide signals play a role in information processing that is different from that of conventional neurotransmitters, and many appear to be particularly associated with specific behaviours. For example, oxytocin and vasopressin have striking and specific effects on social behaviours, including maternal behaviour and pair bonding. Function Generally, peptides act at metabotropic or G-protein-coupled receptors expressed by selective populations of neurons. In essence they act as specific signals between one population of neurons and another. Neurotransmitters generally affect the excitability of other neurons, by depolarising them or by hyperpolarising them. Peptides have much more diverse effects; amongst other things, they can affect gene expression, local blood flow, synaptogenesis, and glial cell morphology. Peptides tend to have prolonged actions, and some have striking effects on behaviour. Neurons very often make both a conventional neurotransmitter (such as glutamate, GABA or dopamine) and one or more neuropeptides. Peptides are generally packaged in large dense-core vesicles, and the co-existing neurotransmitters in small synaptic vesicles. The large dense-core vesicles are often found in all parts of a neuron, including the soma, dendrites, axonal

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swellings (varicosities) and nerve endings, whereas the small synaptic vesicles are mainly found in clusters at presynaptic locations. Release of the large vesicles and the small vesicles is regulated differently. Examples The following is a list of neuroactive peptides coexisting with other neurotransmitters. Transmitter names are shown in bold. Norepinephrine (noradrenaline). In neurons of the A2 cell group in the nucleus of the solitary tract), norepinephrine co-exists with:  Galanin  Enkephalin  Neuropeptide Y GABA  Somatostatin (in the hippocampus)  Cholecystokinin  Neuropeptide Y (in the arcuate nucleus) Acetylcholine  VIP  Substance P Dopamine  Cholecystokinin  Neurotensin  Glucagon-like peptide-1 (in the nucleus accumbens) Epinephrine (adrenaline)  Neuropeptide Y  Neurotensin Serotonin (5-HT)  Substance P  TRH  Enkephalin Some neurons make several different peptides. For instance, Vasopressin co-exists with dynorphin and galanin in magnocellular neurons of the supraoptic nucleus and paraventricular nucleus, and with CRF (in parvocellular


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neurons of the paraventricular nucleus). Oxytocin in the supraoptic nucleus co-exists with enkephalin, dynorphin, cocaine-and amphetamine regulated transcript (CART) and cholecystokinin. Diabetes Link A 2006 discovery might have important implications for treatment of diabetes. [3, 4] Researchers at the Toronto Hospital for Sick Children injected capsaicin into NOD mice (Non-obese diabetic mice, a strain that is genetically predisposed to develop the equivalent of Type 1 diabetes) to kill the pancreatic sensory nerves. This treatment reduced the development of diabetes in these mice by 80%, suggesting a link between neuropeptides and the development of Type 1 diabetes. When the researchers injected the pancreas of the diabetic mice with substance P, they were cured of the diabetes for as long as 4 months. Also, insulin resistance (characteristic of type 2 diabetes) was reduced. These research results are in the process of being confirmed, and their applicability in humans will have to be established in the future. Any treatment that could result from this research is probably years away. REFERENCE [1]

Neuropeptides and Other Bioactive Peptides: From Discovery to Function, L.D.Fricker, Morgan & Claypool Publishers, 2012.

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Physico-chemical Properties of Neuropeptides Norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone and neurotransmitter. The name "noradrenaline," derived from Latin roots meaning "at/alongside the kidneys," is more commonly used in the United Kingdom; in the United States, "norepinephrine," derived from Greek roots having that same meaning, is usually preferred. "Norepinephrine" is also the international nonproprietary name given to the drug. Regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic.

NE, NA,и Noradrenaline, (R)-(–)-Norepinephrine, l-1-(3,4-Dihydroxyphenyl)-2-aminoethanol

In the brain, norepinephrine is produced in nuclei that are small yet exert powerful effects on other brain areas. The most important of these nuclei is the locus coeruleus, located in the pons. Outside the brain, norepinephrine is used as a neurotransmitter by sympathetic ganglia located near the spinal cord or in the abdomen, and it is also released directly into the bloodstream by the adrenal glands. Regardless of how and where it is released, norepinephrine acts on target cells by binding to and activating noradrenergic receptors located on the cell surface. The general function of norepinephrine is to mobilize the brain and body for action. Norepinephrine release is lowest during sleep, rises during wakefulness, and reaches much higher levels during situations of stress or danger, in the so-called fight-or-flight response. In the brain, norepinephrine increases arousal and alertness, promotes vigilance, enhances formation and retrieval of memory, and focuses attention; it also increases restlessness and anxiety. In the


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rest of the body, norepinephrine increases heart rateand blood pressure, triggers the release of glucose from energy stores, increases blood flow to skeletal muscle, reduces blood flow to the gastrointestinal system, and inhibits voiding of the bladder and gastrointestinal motility. A variety of medically important drugs work by altering the actions of norepinephrine systems. Norepinephrine itself is widely used as an injectable drug for the treatment of critically low blood pressure. Beta blockers, which counter some of the effects of norepinephrine, are frequently used to treat glaucoma, migraine, and a range of cardiovascular problems. Alpha blockers, which counter a different set of norepinephrine effects, are used to treat several cardiovascular and psychiatric conditions. Alpha-2 agonistsoften have a sedating effect, and are commonly used as anesthesia-enhancers in surgery, as well as in treatment of drug or alcohol dependence. Many important psychiatric drugs exert strong effects on norepinephrine systems in the brain, resulting in side-effects that may be helpful or harmful. Structure Norepinephrine is a catecholamine and a phenethylamine. Its structure differs from that of epinephrine only in that epinephrine has a methyl group attached to its nitrogen, whereas the methyl group is replaced by a hydrogen atom in norepinephrine. The prefix nor- is derived as an abbreviation of the word "normal", used to indicate a demethylatedcompound.

Norepinephrine structure

Epinephrine structure

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Catechol structure

Biochemical mechanisms Biosynthesis Biosynthetic pathways for catecholamines and trace amines in the human brain

Norepinephrine is synthesized from dopamine in the human body by the dopamine β-hydroxylase(DBH) enzyme


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Norepinephrine is synthesized from the amino acid tyrosine by a series of enzymatic steps in the adrenal medulla and postganglionic neurons of the sympathetic nervous system. While the conversion of tyrosine to dopamine occurs predominantly in the cytoplasm, the conversion of dopamine to norepinephrine by dopamine β-monooxygenase occurs predominantly inside neurotransmitter vesicles. The metabolic pathway is: Phenylalanine → Tyrosine → L-DOPA → Dopamine → Norepinephrine Thus the direct precursor of norepinephrine is dopamine, which is synthesized indirectly from the essential amino acid phenylalanine or the non-essential amino acid tyrosine. These amino acids are found in nearly every protein and, as such, are provided by ingestion of protein-containing food, with tyrosine being the most common. Phenylalanine is converted into tyrosine by the enzyme phenylalanine hydroxylase, with molecular oxygen (O2) and tetrahydrobiopterin as cofactors. Tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase, with tetrahydrobiopterin, O2, and probably ferrous iron (Fe2+) as cofactors. L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (also known as DOPA decarboxylase), with pyridoxal phosphateas a cofactor. Dopamine is then converted into norepinephrine by the enzyme dopamine β-monooxygenase (formerly known as dopamine β-hydroxylase), with O2 and ascorbic acid as cofactors. Norepinephrine itself can further be converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase with S-adenosyl-L-methionine as cofactor. Degradation In mammals, norepinephrine is rapidly degraded to various metabolites. The initial step in the breakdown can be catalyzed by either of the enzymes monoamine oxidase (mainly monoamine oxidase A) or COMT. From there the breakdown can proceed by a variety of pathways. The principal end products are either Vanillylmandelic acid or a conjugated form of MHPG, both of which are thought to be biologically inactive and are excreted in the urine.

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Norepinephrine degradation. Metabolizing enzymes are shown in boxes

Functions Cellular Effects Adrenergic receptors in the mammal brain and body Family Receptor

Type

Mechanism

α1

Gq-coupled.

Increase IP3 and calcium by activating phospholipase C.

α2

Gi/Go-coupled.

Decrease cAMP by inhibiting adenylate cyclase.

Gs-coupled.

Increase cAMP by activating adenylate cyclase.

Alpha

β1 Beta

β2 β3


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Like many other biologically active substances, norepinephrine exerts its effects by binding to and activating receptors located on the surface of cells. Two broad families of norepinephrine receptors have been identified, known as alpha and beta adrenergic receptors. Alpha receptors are divided into subtypes α1and α2; beta receptors into subtypes β1, β2, and β3. All of these function as G protein-coupled receptors, meaning that they exert their effects via a complex second messenger system. Alpha-2 receptors usually have inhibitory effects, but many are located pre-synaptically (i.e., on the surface of the cells that release norepinephrine), so the net effect of alpha-2 activation is often a decrease in the amount of norepinephrine released. Alpha-1 receptors and all three types of beta receptors usually have excitatory effects. Storage, Release, and Reuptake

Norepinephrine (labeled "noradrenaline" in this drawing) processing in a synapse. After release norepinephrine can either be taken up again by the presynaptic terminal, or broken down by enzymes

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Inside the brain norepinephrine functions as a neurotransmitter, and is controlled by a set of mechanisms common to all monoamine neurotransmitters. After synthesis, norepinephrine is transported from the cytosolinto synaptic vesicles by the vesicular monoamine transporter (VMAT). Norepinephrine is stored in these vesicles until it is ejected into the synaptic cleft, typically after an action potential causes the vesicles to release their contents directly into the synaptic cleft through a process called exocytosis. Once in the synapse, norepinephrine binds to and activates receptors. After an action potential, the norepinephrine molecules quickly become unbound from their receptors. They are then absorbed back into the presynaptic cell, via reuptake mediated primarily by the norepinephrine transporter (NET). Once back in the cytosol, norepinephrine can either be broken down by monoamine oxidase or repackaged into vesicles by VMAT, making it available for future release. Sympathetic Nervous System Norepinephrine is the main neurotransmitter used by the sympathetic nervous system, which consists of about two dozen sympathetic chain ganglia located next to the spinal cord, plus a set of prevertebral ganglia located in the chest and abdomen. These sympathetic ganglia are connected to numerous organs, including the eyes, salivary glands, heart, lungs, liver, gallbladder, stomach, intestines, kidneys, urinary bladder, reproductive organs, muscles, skin, and adrenal glands. Sympathetic activation of the adrenal glands causes the part called the adrenal medulla to release norepinephrine into the bloodstream, from which, functioning as a hormone, it gains further access to a wide variety of tissues. Broadly speaking, the effect of norepinephrine on each target organ is to modify its state in a way that makes it more conducive to active body movement, often at a cost of increased energy use and increased wear and tear. This can be contrasted with the acetylcholine-mediated effects of the parasympathetic nervous system, which modifies most of the same organs into a state more conducive to rest, recovery, and digestion of food, and usually less costly in terms of energy expenditure.


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The sympathetic effects of norepinephrine include:  In the eyes, an increase in production of tears, making the eyes more moist., and pupil dilation through contraction of the iris dilator.  In the heart, an increase in the amount of blood pumped.  In brown adipose tissue, an increase in calories burned to generate body heat.  Multiple effects on the immune system. The sympathetic nervous system is the primary path of interaction between the immune system and the brain, and several components receive sympathetic inputs, including the thymus, spleen, and lymph nodes. However the effects are complex, with some immune processes activated while others are inhibited.  In the arteries, constriction of blood vessels, causing an increase in blood pressure.  In the kidneys, release of renin and retention of sodium in the bloodstream.  In the liver, an increase in production of glucose, either by glycogenolysis after a meal or by gluconeogenesis when food has not recently been consumed. Glucose is the body's main energy source in most conditions.  In the pancreas, increased release of glucagon, a hormone whose main effect is to increase the production of glucose by the liver.  In skeletal muscles, an increase in glucose uptake.  In adipose tissue (i. e., fat cells), an increase in lipolysis, that is, conversion of fat to substances that can be used directly as energy sources by muscles and other tissues.  In the stomach and intestines, a reduction in digestive activity. This results from a generally inhibitory effect of norepinephrine on the enteric nervous system, causing decreases in gastrointestinal mobility, blood flow, and secretion of digestive substances. Central Nervous System The noradrenergic neurons in the brain form a neurotransmitter system, that, when activated, exerts effects on large areas of the brain. The effects are manifested in alertness, arousal, and readiness for action. Noradrenergic neurons (i.e., neurons whose primary neurotransmitter is

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norepinephrine) are comparatively few in number, and their cell bodies are confined to a few relatively small brain areas, but they send projections to many other brain areas and exert powerful effects on their targets. These noradrenergic cell groups were first mapped in 1964 by Annica Dahlström and Kjell Fuxe, who assigned them labels starting with the letter "A" (for "aminergic"). In their scheme, areas A1 through A7 contain the neurotransmitter norepinephrine (A8 through A14 contain dopamine). Noradrenergic cell group A1 is located in the caudal ventrolateral part of the medulla, and plays a role in the control of body fluid metabolism. Noradrenergic cell group A2 is located in a brainstem area called the solitary nucleus; these cells have been implicated in a variety of responses, including control of food intake and responses to stress. [24] Cell groups A5 and A7 project mainly to the spinal cord. The most important source of norepinephrine in the brain is the locus coeruleus, which contains noradrenergic cell group A6 and adjoins cell group A4. The locus coeruleus is quite small in absolute terms—in primates it is estimated to contain around 15,000 neurons, less than one millionth of the neurons in the brain—but it sends projections to every major part of the brain and also to the spinal cord. The level of activity in the locus coeruleus correlates broadly with vigilance and speed of reaction. LC activity is low during sleep and drops to virtually nothing during the REM (dreaming) state. It runs at a baseline level during wakefulness, but increases temporarily when a person is presented with any sort of stimulus that draws attention. Unpleasant stimuli such as pain, difficulty breathing, bladder distension, heat or cold generate larger increases. Extremely unpleasant states such as intense fear or intense pain are associated with very high levels of LC activity. Norepinephrine released by the locus coeruleus affects brain function in a number of ways. It enhances processing of sensory inputs, enhances attention, enhances formation and retrieval of both long term and working memory, and enhances the ability of the brain to respond to inputs by changing the activity pattern in the prefrontal cortex and other areas. The control of arousal level is strong enough that drug-induced suppression of the LC has a powerful sedating


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effect. There is great similarity between situations that activate the locus coeruleus in the brain and situations that activate the sympathetic nervous system in the periphery: the LC essentially mobilizes the brain for action while the sympathetic system mobilizes the body. It has been argued that this similarity arises because both are to a large degree controlled by the same brain structures, particularly a part of the brainstem called the nucleus gigantocellularis. Pharmacology A large number of important drugs exert their effects by interacting with norepinephrine systems in the brain or body. Their uses include treatment of cardiovascular problems, shock, and a variety of psychiatric conditions. Sympathomimetic and Sympatholytic Drugs Sympathomimetic drugs mimic or enhance at least some of the effects of norepinephrine released by the sympathetic nervous system; sympatholytic drugs, in contrast, block at least some of the effects. Both of these are large groups with diverse uses, depending on exactly which effects are enhanced or blocked. Norepinephrine itself is classified as a sympathomimetic drug: its effects when given by intravenous injection of increasing heart rate and force and constricting blood vessels make it very useful for treating medical emergencies that involve critically low blood pressure. Beta Blockers These are drugs that block the effects of beta noradrenergic receptors while having little or no effect on alpha receptors. They are sometimes used to treat high blood pressure, atrial fibrillation and congestive heart failure, but recent reviews have concluded that other types of drugs are usually superior for those purposes. Beta blockers may be a viable choice for other cardiovascular conditions, though, including angina and Marfan syndrome. They are also widely used to treat glaucoma, either in pill form or in eyedrops. Because of their effects in reducing anxiety symptoms and tremor, they have sometimes been used by entertainers, public speakers and athletes to reduce performance anxiety, although they are not medically approved for that purpose and are banned by the International Olympic Committee.

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However, the usefulness of beta blockers is limited by a range of serious side effects, including slowing of heart rate, a drop in blood pressure, asthma, and reactive hypoglycemia. The negative effects can be particularly severe in people who suffer from diabetes. Alpha Blockers These are drugs that block the effects of noradrenergic alpha receptors while having little or no effect on beta receptors. Drugs belonging to this group can have very different effects, however, depending on whether they primarily block alpha-1 receptors, alpha-2 receptors, or both. Alpha-2 receptors, as described elsewhere in this article, are frequently located on norepinephrine-releasing neurons themselves and have inhibitory effects on them; consequently blockage of alpha-2 receptors usually results in an increase in norepinephrine release. Alpha-1 receptors are usually located on target cells and have excitatory effects on them; consequently blockage of alpha-1 receptors usually results in blocking some of the effects of norepinephrine. Drugs such as phentolamine that act on both types of receptors can produce a complex combination of both effects. In most cases when the term "alpha blocker" is used without qualification, it refers to a selective alpha-1 antagonist. Selective alpha-1 blockers have a variety of uses. Because one of their effects is to relax the muscles in the neck of the bladder, they are often used to treat benign prostatic hyperplasia, and to help with the expulsion of bladder stones. Their effects on the central nervous system make them useful for treating generalized anxiety disorder, panic disorder, and posttraumatic stress disorder. They may, however, have significant side-effects, including a drop in blood pressure. Some antidepressants function partly as selective alpha-2 blockers, but the best-known drug in that class is yohimbine, which is extracted from the bark of the African yohimbetree. Yohimbine acts as a male potency enhancer, but its usefulness for that purpose is limited by serious side-effects including anxiety and insomnia. Overdoses can cause a dangerous increase in blood pressure. Yohimbine is banned in many countries, but in the United States, because it is extracted from a plant rather than chemically synthesized, it is sold over the


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counter as a nutritional supplement. Alpha-2 Agonists These are drugs that activate alpha-2 receptors or enhance their effects. Because alpha-2 receptors are inhibitory and many are located presynaptically on norepinephrine-releasing cells, the net effect of these drugs is usually to reduce the amount of norepinephrine released. Drugs in this group that are capable of entering the brain often have strong sedating effects, due to their inhibitory effects on the locus coeruleus. Clonidine, for example, is used for the treatment of anxiety disorders and insomnia, and also as a sedative premedication for patients about to undergo surgery. Xylazine, another drug in this group, is also a powerful sedative and is often used in combination with ketamine as a general anaesthetic for veterinary surgery—in the United States it has not been approved for use in humans. Stimulants and Antidepressants These are drugs whose primary effects are thought to be mediated by different neurotransmitter systems (dopamine for stimulants, serotonin for antidepressants), but many also increase levels of norepinephrine in the brain. Amphetamine, for example, is a stimulant that increases release of norepinephrine as well as dopamine. Monoamine oxidase inhibitors are antidepressants that inhibit the metabolic degradation of norepinephrine as well as serotonin. In some cases it is difficult to distinguish the norepinephrine-mediated effects from the effects related to other neurotransmitters. Diseases and Disorders A number of important medical problems involve dysfunction of the norepinephrine system in the brain or body. Sympathetic Hyperactivation Hyperactivation of the sympathetic nervous system is not a recognized condition in itself, but it is a component of a number of conditions, as well as a possible consequence of taking sympathomimetic drugs. It causes a distinctive set of symptoms including aches and pains, rapid heartbeat, elevated blood

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pressure, sweating, palpitations, anxiety, headache, paleness, and a drop in blood glucose. If sympathetic activity is elevated for an extended time, it can cause weight loss and other stress-related body changes. The list of conditions that can cause sympathetic hyperactivation includes severe brain injury, spinal cord damage, heart failure, high blood pressure, kidney disease, and various types of stress. Pheochromocytoma A pheochromocytoma is a rarely occurring tumor of the adrenal medulla, caused either by genetic factors or certain types of cancer. The consequence is a massive increase in the amount of norepinephrine and epinephrine released into the bloodstream. The most obvious symptoms are those of sympathetic hyperactivation, including particularly a rise in blood pressure that can reach fatal levels. The most effective treatment is surgical removal of the tumor. Stress Stress, to a physiologist, means any situation that threatens the continued stability of the body and its functions. Stress affects a wide variety of body systems: the two most consistently activated are the hypothalamic-pituitary-adrenal axis and the norepinephrine system, including both the sympathetic nervous system and the locus coeruleus-centered system in the brain. Stressors of many types evoke increases in noradrenergic activity, which mobilizes the brain and body to meet the threat. Chronic stress, if continued for a long time, can damage many parts of the body. A significant part of the damage is due to the effects of sustained norepinephrine release, because of norepinephrine's general function of directing resources away from maintenance, regeneration, and reproduction, and toward systems that are required for active movement. The consequences can include slowing of growth (in children), sleeplessness, loss of libido, gastrointestinal problems, impaired disease resistance, slower rates of injury healing, depression, and increased vulnerability to addiction. ADHD Attention deficit hyperactivity disorder is a psychiatric condition involving problems with attention, hyperactivity, and impulsiveness. It is most


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commonly treated using stimulantdrugs such as methylphenidate (Ritalin), whose primary effect is to increase dopamine levels in the brain, but drugs in this group also generally increase brain levels of norepinephrine, and it has been difficult to determine whether these actions are involved in their clinical value. Also there is substantial evidence that many people with ADHD show "biomarkers" involving altered norepinephrine processing. Several drugs whose primary effects are on norepinephrine, including guanfacine, clonidine, and atomoxetine, have been tried as treatments for ADHD, and found to have effects comparable to those of stimulants. Autonomic Failure Several conditions, including Parkinson's disease, diabetes and so-called pure autonomic failure, can cause a loss of norepinephrine-secreting neurons in the sympathetic nervous system. The symptoms are widespread, the most serious being a reduction in heart rate and an extreme drop in resting blood pressure, making it impossible for severely affected people to stand for more than a few seconds without fainting. Treatment can involve dietary changes or drugs. Comparative Biology and Evolution

Chemical structure of octopamine, which serves as the homologue of norepinephrine in many invertebrate species

Norepinephrine has been reported to exist in a wide variety of animal species, including protozoa, placozoa and cnidaria (jellyfish and related species), but not in ctenophores (comb jellies), whose nervous systems differ greatly from those of other animals. It is generally present in deuterostomes (vertebrates, etc.), but in protostomes (arthropods, molluscs, flatworms, nematodes, annelids, etc.) it is replaced by octopamine, a closely related chemical with a closely related synthesis pathway. In insects, octopamine has alerting and activating functions that correspond (at least roughly) with the functions of

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norepinephrine in vertebrates. It has been argued that octopamine evolved to replace norepinephrine rather than vice versa; however, the nervous system of amphioxus (a primitive chordate) has been reported to contain octopamine but not norepinephrine, which presents difficulties for that hypothesis. Early in the twentieth century Walter Cannon, who had popularized the idea of a sympathoadrenal system preparing the body for fight and flight, and his colleague Arturo Rosenblueth developed a theory of two sympathins, sympathin E (excitatory) and sympathin I (inhibitory), responsible for these actions. The Belgian pharmacologist Zénon Bacq as well as Canadian and US-American pharmacologists between 1934 and 1938 suggested that noradrenaline might be a sympathetic transmitter. In 1939, Hermann Blaschko and Peter Holtz independently identified the biosynthetic mechanism for norepinephrine in the vertebrate body. In 1945 Ulf von Euler published the first of a series of papers that established the role of norepinephrine as a neurotransmitter. He demonstrated the presence of norepinephrine in sympathetically innervated tissues and brain, and adduced evidence that it is the sympathin of Cannon and Rosenblueth. Galanin Galanin is a neuropeptide encoded by the GAL gene, that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors. The functional role of galanin remains largely unknown; however, galanin is predominantly involved in the modulation and inhibition of action potentials in neurons. Galanin has been implicated in many biologically diverse functions, including: nociception, waking and sleep regulation, cognition, feeding, regulation of mood, regulation of blood pressure, it also has roles in development as well as acting as a trophic factor. Galanin neurons in the medial preoptic area of the hypothalamus may govern parental behaviour. Galanin is linked to a number of diseases including Alzheimer's disease, epilepsy as well as depression, eating disorders and cancer. Galanin appears to have neuroprotective activity as its biosynthesis is increased 2-10 fold upon axotomy in the peripheral nervous system as well as when seizure activity occurs in the


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brain. It may also promote neurogenesis. Galanin is predominantly an inhibitory, hyperpolarizing neuropeptide [11] and as such inhibits neurotransmitter release. Galanin is often co-localized with classical neurotransmitters such as acetylcholine, serotonin, and norepinephrine, and also with other neuromodulators such as neuropeptide Y, substance P, and vasoactive intestinal peptide. Galanin was first identified from porcine intestinal extracts in 1978 by Professor Viktor Mutt and colleagues at the Karolinska Institute, Sweden using a chemical assay technique that detects peptides according to its C-terminal alanine amide structure. Galanin is so-called because it contains an N-terminal glycine residue and a C-terminal alanine. The structure of galanin was determined in 1983 by the same team, and the cDNA of galanin was cloned from a rat anterior pituitary library in 1987. Tissue distribution Galanin is located predominantly in the central nervous system and gastrointestinal tract. Within the central nervous system, highest concentrations are found in the hypothalamus, with lower levels in the cortex and brainstem. Gastrointestinal galanin is most abundant in the duodenum, with lower concentrations in the stomach, small intestine, and colon. Structure Endogenously occurring galanin sequences Species

1

6

11

16

21

26 !

Pig

GWTLN

SAGYL

LGPHA

IDNHR

SFHDK

YGLA*

Human

GWTLN

SAGYL

LGPHA

VGNHR

SFSDK

N G L T S **

Cow

GWTLN

SAGYL

LGPHA

LDSHR

SFQDK

HGLA*

Rat

GWTLN

SAGYL

LGPHA

IDNHR

SFSDK

H G L T*

* C-terminal amide ** C-terminal free acid

Galanin is a peptide consisting of a chain of 29 amino acids (30 amino acids in humans) produced from the cleavage of a 123-amino acid protein known as prepro galanin, which is encoded by the GAL gene. The sequence of this gene is highly conserved among mammals, showing over 85% homology between rat,

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mouse, porcine, bovine, and human sequences. In these animal forms, the first 15 amino acids from the N-terminus are identical, but amino acids differ at several positions on the C-terminal end of the protein. These slight differences in protein structure have far-reaching implications on their function. For example, porcine and rat galanin inhibit glucose-induced insulin secretion in rats and dogs but have no effect on insulin secretion in humans. This demonstrates that it is essential to study the effects of galanin and other regulatory peptides in their autologous species. The galanin family of protein consists of four proteins, of which GAL was the first to be identified. The second was galanin message-associated protein (GMAP), a 59- or 60-amino acid peptide also formed from the cleavage of prepro galanin. The other two peptides, galanin-like peptide (GALP) and alarin, were identified relatively recently and are both encoded for in the same gene, the prepro GALP gene. GALP and alarin are produced by different post-transcriptional splicing of this gene. Galanin Identifiers Symbol

Galanin

Pfam

PF01296

InterPro

IPR008174

PROSITE

PDOC00673

Available protein structures:

Galanin message associated peptide (GMAP) Identifiers Symbol

GMAP

Pfam

PF06540

InterPro

IPR013068



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Receptors Galanin signalling occurs through three classes of receptors, GALR1, GALR2, and GALR3, which are all part of the G protein-coupled receptor (GPCR) superfamily. Galanin receptors are expressed in the central nervous system, in the pancreas, and on solid tumours. The level of expression of the different receptors varies at each location, and this distribution changes after injury to neurons. Experiments into the function of the receptor subtypes involve mostly genetic knockout mice. The location of the receptor and the combination of receptors that are inhibited or stimulated heavily affect the outcome of galanin signaling. Clinical Characteristics Alzheimer's Disease One of the pathological features of the brain in the later stages of Alzheimer's disease is the presence of overgrown GAL-containing fibres innervating the surviving cholinergicneurons. Another feature is an increase in the expression of GAL and GAL receptors, in which increases of up to 200% have been observed in postmortem brains of Alzheimer's patients. The cause and role of this increase is poorly understood. It has been suggested that the hyper-innervation acts to promote the death of these neurons and that the inhibitory effect of galanin on cholinergic neurons worsened the degeneration of cognitive function in patients by decreasing the amount of acetylcholine available to these neurons. A second hypothesis has been generated based on data that suggest GAL is involved in protecting the hippocampus from excitotoxic damage and the neurons in the cholinergic basal forebrain from amyloid toxicity. It is interesting to note that studies of gene expression of CBF tissue suggests that the hyperinnervation of cholinergic neurons by GAL up regulates the transcription of factors that promote neuron function and survival. It is still unclear as to whether galanin acts to protect cholinergic neurons and promote their firing or whether it worsens the symptoms of this disease. Epilepsy Galanin in the hippocampus is an inhibitor of glutamate but not of GABA.

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This means that galanin is capable of increasing the seizure threshold and, therefore, is expected to act as an anticonvulsant. To be specific, GalR1 has been linked to the suppression of spontaneous seizures. An agonist antiepileptic drug candidate is NAX 5055. In Development It has been shown that galanin plays a role in the control of the early post-natal neural development of the dorsal root ganglion (DRG). Galanin-mutant animals show a 13% decrease in the number of adult DRG cells as well as a 24% decrease in the percentage of cells expressing substance P. This suggests that the cell loss by apoptosis that usually occurs in the developing DRG is regulated by galanin and that the absence of galanin results in an increase in the number of cells that die. After Injury In vitro experiments show that DRG cells removed from galanin mutants have impaired abilities to extend neurites in culture, in that the number of cells producing neurites is decreased by a third and the mean length of these processes was halved when compared to wild-type controls. In vivo, many of the actions of galanin in the brain after an injury are similar to those observed in the developing DRG. Adult mutant animals have been shown to be 35% less capable of regenerating the sciatic nerve after crush injury, which is linked to long-term functional problems. Parental Role in Mice Galanin-expressing neurons in the medial preoptic area of the brain would be responsible for regulating aggression towards pups by male mice. Enkephalin An enkephalin (encephalin) is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin were discovered, one containing leucine ("leu"), and the other containing methionine ("met"). Both are products of the proenkephalin gene.


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 Met-enkephalin is Tyr-Gly-Gly-Phe-Met.  Leu-enkephalin has Tyr-Gly-Gly-Phe-Leu. Endogenous Opioid Peptides There are three well-characterized families of opioid peptides produced by the body: enkephalins, endorphins, and dynorphins. The met-enkephalin peptide sequence is coded for by the enkephalin gene; the leu-enkephalin peptide sequence is coded for by both the enkephalin gene and the dynorphin gene. The proopiomelanocortin gene (POMC) also contains the met-enkephalin sequence on the N-terminus of beta-endorphin, but the endorphin peptide is not processed into enkephalin. Enkephalin Receptor The receptors for enkephalin are the delta opioid receptors and mu opioid receptors. Opioid receptors are a group of G-protein-coupled receptors, with other opioids as ligands as well. The other endogenous opioids are dynorphins (that bind to kappa receptors), endorphins (mu receptors), endomorphins, and nociceptin/orphanin FQ. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs). Neuropeptide Y Neuropeptide Y (NPY) is a 36-amino acid neuropeptide that acts as a neurotransmitter in the brain and in the autonomic nervous system of humans; slight variations of the peptide are found in many other animals. In the autonomic system it is produced mainly by neurons of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue. In the brain, it is produced in various locations including the hypothalamus, and is thought to have several functions, including: increasing food intake and storage of energy as fat, reducing anxiety and stress, reducing pain perception, affecting the circadian rhythm, reducing voluntary alcohol intake, lowering blood pressure, and controlling epileptic seizures. Discovery Following the isolation of neuropeptide-y (NPY) from the porcine hypothalamus in 1982, researchers began to speculate about the involvement of

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NPY in hypothalamic-mediated functions. In a 1983 study, NPY-ergic axon terminals were located in the paraventricular nucleus (PVN) of the hypothalamus, and the highest levels of NPY immunoreactivity was found within the PVN of the hypothalamus. Six years later, in 1989, Morris et al. homed in on the location of NPYergic nuclei in the brain. Furthermore, in situ hybridization results from the study showed the highest cellular levels of NPY mRNA in the arcuate nucleus (ARC) of the hypothalamus. In 1989, Haas & George reported that local injection of NPY into the PVN resulted in an acute release of corticotropin-releasing hormone (CRH) in the rat brain, proving that NPYergic activity directly stimulates the release and synthesis of CRH. The latter became a hallmark paper in NPY studies. A significant amount of work had already been done in the 1970s on CRH and its involvement in stress and eating disorders such as obesity. These studies, collectively, marked the beginning of the role of NPY in orexigenesis or food intake. Role in Food Intake Behaviorial assays in orexigenic studies, in which rats are the model organism, have been done collectively with immunoassays and in situ hybridization studies to confirm that elevating NPY-ergic activity does indeed increase food intake. In these studies, exogenous NPY, an NPY agonist such as dexamethasone or N-acetyl [Leu 28, Leu 31] NPY (24-36) are injected into the third ventricle or at the level of the hypothalamus with a cannula. Furthermore, these studies unanimously demonstrate that the stimulation of NPYergic activity via the administration of certain NPY agonists increases food intake compared to baseline data in rats. The effects of NPYergic activity on food intake is also demonstrated by the blockade of certain NPY receptors (Y1 and Y5 receptors), which, as was expected, inhibited NPYergic activity; thus, decreases food intake. However, a 1999 study by King et al. demonstrated the effects of the activation of the NPY autoreceptor Y2, which has been shown to inhibit the release of NPY and thus acts to regulate food intake upon its activation. In this study a highly selective Y2 antagonist, BIIE0246 was


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administered locally into the ARC. Radioimmunoassay data, following the injection of BIIE0246, shows a significant increase in NPY release compared to the control group. Though the pharmacological half-life of exogenous NPY, other agonists, and antagonist is still obscure, the effects are not long lasting and the rat body employs an excellent ability to regulate and normalize abnormal NPY levels and therefore food consumption. Role in Obesity Dryden et al., conducted a study in 1995 using genetically obese rats to demonstrate the role of NPY in eating disorders such as obesity. The study revealed four underlying factors that contributed to obesity in rats:  an increase in glucocorticosteroid concentrations in plasma;  insensitivity or resistance to insulin;  mutation of leptin receptor; and  an increase in NPY mRNA and NPY release. In obesity chronically elevated levels of NPY can be seen, this has been seen in rats fed on a high fat diet for 22 weeks and resulted in a genetic mutation increasing NPY release due to a defective leptin signal compared to control rats. In humans increased levels of free NPY were found in obese women and not in their leaner counterparts, analysing human hypothalamus' for NYP concentration however is more difficult than rats. During weaning in rats there is an early expression of gene mutations that increase hypothalamic release of NPY in rats, however in humans multiple genes are commonly associated with the results of obesity and metabolic syndrome. In most obesity cases the increased secretion of NPY is a central / hypothalamic resistance to energy excess hormone signals such as leptin, that can be a result of a variety of reasons in the CNS. In rodents resistant to obesity when fed on an obesogenic diet they had a significantly lower amount of NPY receptor in the hypothalamus suggesting an increased activity of NPY neurones in obese rats meaning that the reduction in the release of NPY may be beneficial to the reduction of obesity incidence alongside the consumption of a healthy diet and exercise. This would need to be seen in human research before looking at this avenue of weight loss although currently there is some evidence that suggests

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NPY is a significant predictor in weight regain after weight loss to maintain old levels of energy storage. Furthermore, these factors correlate with each other. The sustained high levels of glucocorticosteroids stimulate gluconeogenesis, which subsequently causes an increase of blood glucose that activates the release of insulin to regulate glucose levels by causing its reuptake and storage as glycogen in the tissues in the body. In the case of obesity, which researchers speculate to have a strong genetic and a dietary basis, insulin resistance prevents high blood glucose regulation, resulting in morbid levels of glucose and diabetes mellitus. In addition, high levels of glucocorticosteroids causes an increase of NPY by directly activating type II glucocorticosteroids receptors (which are activated only by relatively high levels of glucocorticosteroids) and, indirectly, by abolishing the negative feedback of corticotropin-releasing factor (CRF) on NPY synthesis and release. Meanwhile, obesity-induced insulin resistance and the mutation of the leptin receptor (ObRb) results in the abolition of inhibition of NPYergic activity and ultimately food intake via other negative feedback mechanisms to regulate them. Obesity in rats was significantly reduced by adrenalectomy or hypophysectomy. Correlation with Stress and Diet Studies of mice and monkeys show that repeated stress—and a high-fat, high-sugar diet—stimulate the release of neuropeptide Y, causing fat to build up in the abdomen. Researchers believe that by manipulating levels of NPY, they could eliminate fat from areas where it was not desired and accumulate at sites where it is needed. Conversely, higher levels of NPY may be associated with resilience against and recovery from posttraumatic stress disorder and with dampening the fear response, allowing individuals to perform better under extreme stress. Alcoholism Two results suggest that NPY might protect against alcoholism:  knock-out mice in which a type of NPY receptor has been removed show a higher voluntary intake of alcohol and a higher resistance to alcohol's sedating effects, compared to normal mice;


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 the common fruit fly has a neuropeptide that is similar to NPY, known as neuropeptide F. The levels of neuropeptide F are lowered in sexually frustrated male flies, and this causes the flies to increase their voluntary intake of alcohol. Receptors The receptor protein that NPY operates on is a G protein-coupled receptor in the rhodopsin like 7-transmembrane GPCR family. Five subtypes of the NPY receptor have been identified in mammals, four of which are functional in humans. Subtypes Y1 and Y5 have known roles in the stimulation of feeding while Y2 and Y4 seem to have roles in appetite inhibition (satiety). Some of these receptors are among the most highly conserved neuropeptide receptors. GABA gamma-Aminobutyric acid (γ-Aminobutyric acid) /' ɡ æmə ə'miːno ʊ bjuː'tɪrɪk 'æ sɪd/ (GABA /'ɡæbə/) is the chief inhibitoryneurotransmitter in the mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone.

4-aminobutanoic acid

Function Neurotransmitter

GABA metabolism, involvement of glial cells

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In vertebrates, GABA acts at inhibitory synapses in the brain by binding to specific transmembrane receptors in the plasma membraneof both pre- and postsynaptic neuronal processes. This binding causes the opening of ion channels to allow the flow of either negatively charged chloride ions into the cell or positively charged potassium ions out of the cell. This action results in a negative change in the transmembrane potential, usually causing hyperpolarization. Two general classes of GABA receptor are known:  GABAA in which the receptor is part of a ligand-gated ion channel complex  GABAB metabotropic receptors, which are G protein-coupled receptors that open or close ion channels via intermediaries (G proteins)

The production, release, action, and degradation of GABA at a stereotyped GABAergic synapse


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Neurons that produce GABA as their output are called GABAergic neurons, and have chiefly inhibitory action at receptors in the adult vertebrate. Medium spiny cells are a typical example of inhibitory central nervous system GABAergic cells. In contrast, GABA exhibits both excitatory and inhibitory actions in insects, mediating muscle activation at synapses between nerves and muscle cells, and also the stimulation of certain glands. In mammals, some GABAergic neurons, such as chandelier cells, are also able to excite their glutamatergic counterparts. GABAA receptors are ligand-activated chloride channels: when activated by GABA, they allow the flow of chloride ions across the membrane of the cell. Whether this chloride flow is depolarizing (makes the voltage across the cell's membrane less negative), shunting (has no effect on the cell's membrane potential), or inhibitory/hyperpolarizing (makes the cell's membrane more negative) depends on the direction of the flow of chloride. When net chloride flows out of the cell, GABA is depolarising; when chloride flows into the cell, GABA is inhibitory or hyperpolarizing. When the net flow of chloride is close to zero, the action of GABA is shunting. Shunting inhibition has no direct effect on the membrane potential of the cell; however, it reduces the effect of any coincident synaptic input by reducing the electrical resistance of the cell's membrane. Shunting inhibition can "override" the excitatory effect of depolarising GABA, resulting in overall inhibition even if the membrane potential becomes less negative. It was thought that a developmental switch in the molecular machinery controlling concentration of chloride inside the cell changes the functional role of GABA between neonatal and adult stages. As the brain develops into adulthood, GABA's role changes from excitatory to inhibitory. However, this theory of excitatory GABA in the developing brain has been questioned and subsequent studies in live neonatal rodents have directly shown GABA to be inhibitory in its action (see next section). Brain Development While GABA is an inhibitory transmitter in the mature brain, its actions were thought to be primarily excitatory in the developing brain. The gradient of chloride was reported to be reversed in immature neurons, with its reversal

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potential higher than the resting membrane potential of the cell; activation of a GABA-A receptor thus leads to efflux of Cl− ions from the cell (that is, a depolarizing current). The differential gradient of chloride in immature neurons was shown to be primarily due to the higher concentration of NKCC1 co-transporters relative to KCC2 co-transporters in immature cells. GABA itself is partially responsible for orchestrating the maturation of ion pumps. GABAergic interneurons mature faster in the hippocampus and the GABA signalling machinery appears earlier than glutamatergic transmission. Thus, GABA was considered the major excitatory neurotransmitter in many regions of the brain before the maturation of glutamatergic synapses. However, this theory has been questioned based on results showing that in brain slices of immature mice incubated in artificial cerebrospinal fluid (ACSF) (modified in a way that takes into account the normal composition of the neuronal milieu in sucklings by adding an energy substrate alternative to glucose, beta-hydroxybutyrate) GABA action shifts from excitatory to inhibitory mode. [11] This effec has been later repeated when other energy substrates, pyruvate and lactate, supplemented glucose in the slices' media. Later investigations of pyruvate and lactate metabolism found that the original results were not due to energy source issues but to changes in pH resulting from the substrates acting as "weak acids". These arguments were later rebutted by further findings showing that changes in pH even greater than that caused by energy substrates do not affect the GABA-shift described in the presence of energy substrate-fortified ACSF and that the mode of action of beta-hydroxybutyrate, pyruvate and lactate (assessed by measurement NAD(P)H and oxygen utilization) was energy metabolism-related. The true nature GABA effect in the developing brain has remained elusive until 2015, when the first study to directly show GABA action in live rodent brain has reported GABA to not be excitatory in its effect even though it slightly depolarised some neurons, confirming the dominance of shunting inhibition. In 2016, another study in live developing brains using optogenetics have shown GABA to be inhibitory, with GABAergic synapse activation leading to a reduction of network activity. That study has also shown that the same technique when used in brain slices instead


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records excitatory GABA effects, confirming the fact that excitatory GABA is most likely an artefact of in-vitro slice recordings. In the developmental stages preceding the formation of synaptic contacts, GABA is synthesized by neurons and acts both as an autocrine (acting on the same cell) and paracrine (acting on nearby cells) signalling mediator. The ganglionic eminences also contribute greatly to building up the GABAergic cortical cell population. GABA regulates the proliferation of neural progenitor cells the migration and differentiation the elongation of neurites and the formation of synapses. GABA also regulates the growth of embryonic and neural stem cells. GABA can inﬂuence the development of neural progenitor cells via brain-derived neurotrophic factor (BDNF) expression. GABA activates the GABAA receptor, causing cell cycle arrest in the S-phase, limiting growth. Beyond the Nervous System GABAergic mechanisms have been demonstrated in various peripheral tissues and organs, which include the intestines, the stomach, the pancreas, the Fallopian tubes, the uterus, the ovaries, the testes, the kidneys, the urinary bladder, the lungs, and the liver. In 2007, an excitatory GABAergic system was described in the airway epithelium. The system is activated by exposure to allergens and may participate in the mechanisms of asthma. GABAergic systems have also been found in the testis and in the eye lens. GABA Occurs in Plants. Structure and Conformation GABA is found mostly as a zwitterion (i.e. with the carboxy group deprotonated and the amino group protonated). Its conformationdepends on its environment. In the gas phase, a highly folded conformation is strongly favored due to the electrostatic attraction between the two functional groups. The stabilization is about 50 kcal/mol, according to quantum chemistry calculations. In the solid state, an extended conformation is found, with a trans conformation at the amino end and a gauche conformation at the carboxyl end. This is due to the packing interactions with the neighboring molecules. In solution, five

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different conformations, some folded and some extended, are found as a result of solvationeffects. The conformational flexibility of GABA is important for its biological function, as it has been found to bind to different receptors with different conformations. Many GABA analogues with pharmaceutical applications have more rigid structures in order to control the binding better. In 1883, GABA was first synthesized, and it was first known only as a plant and microbe metabolic product. In 1950, GABA was discovered as an integral part of the mammalian central nervous system. Biosynthesis Exogenous GABA does not penetrate the blood–brain barrier; [41] it is synthesized in the brain. It is synthesized from glutamate using the enzyme glutamate decarboxylase (GAD) and pyridoxal phosphate (which is the active form of vitamin B6) as a cofactor. This process converts glutamate, the principal excitatory neurotransmitter, into the principal inhibitory neurotransmitter (GABA). GABA is converted back to glutamate by a metabolic pathway called the GABA shunt. Catabolism GABA transaminase enzyme catalyzes the conversion of 4-aminobutanoic acid (GABA) and 2-oxoglutarate (α-ketoglutarate) into succinic semialdehyde and glutamate. Succinic semialdehyde is then oxidized into succinic acid by succinic semialdehyde dehydrogenase and as such enters the citric acid cycle as a usable source of energy. Pharmacology Drugs, that act as allosteric modulators of GABA receptors (known as GABA analogues or GABAergic drugs) or increase the available amount of GABA, typically have relaxing, anti-anxiety, and anti-convulsive effects. Many of the substances below are known to cause anterograde amnesia and retrograde amnesia. In general, GABA does not cross the blood–brain barrier, although certain areas of the brain that have no effective blood–brain barrier, such as the periventricular nucleus, can be reached by drugs such as systemically injected


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GABA. At least one study suggests that orally administered GABA increases the amount of human growth hormone (HGH). GABA directly injected to the brain has been reported to have both stimulatory and inhibitory effects on the production of growth hormone, depending on the physiology of the individual. Certain pro-drugs of GABA (ex. picamilon) have been developed to permeate the blood–brain barrier, then separate into GABA and the carrier molecule once inside the brain. This allows for a direct increase of GABA levels throughout all areas of the brain, in a manner following the distribution pattern of the pro-drug prior to metabolism. GABA enhanced the catabolism of serotonin into N-acetylserotonin (the precursor of melatonin) in rats. It is thus suspected that GABA is involved in the synthesis of melatonin and thus might exert regulatory effects on sleep and reproductive functions. Chemistry Although in chemical terms, GABA is an amino acid (as it has both a primary amine and a carboxylic acid functional group), it is rarely referred to as such in the professional, scientific, or medical community. By convention the term "amino acid", when used without a qualifier, refers specifically to an alpha amino acid. GABA is not an alpha amino acid, meaning the amino group is not attached to the alpha carbon so it is not incorporated into proteins. GABAergic drugs GABAA receptor ligands  Agonists/positive allosteric modulators: alcohol (ethanol), barbiturates, benzodiazepines, carisoprodol, chloral hydrate, etaqualone, etomidate, glutethimide, kava, methaqualone, muscimol, neuroactive steroids, z-drugs, propofol, skullcap, valerian, theanine, volatile/inhaled anaesthetics.  Antagonists/negative allosteric modulators: bicuculline, cicutoxin, flumazenil, furosemide, gabazine, oenanthotoxin, picrotoxin, Ro15-4513, thujone, amentoflavone. GABAB receptor ligands  Agonists: baclofen, GBL, propofol, GHB, phenibut.

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 Antagonists: phaclofen, saclofen.  GABA reuptake inhibitors: deramciclane, hyperforin, tiagabine.  GABA-transaminase inhibitors: gabaculine, phenelzine, valproate, vigabatrin, lemon balm (Melissa officinalis).  GABA analogues: pregabalin and gabapentin,  Others: GABA (itself), L-glutamine, picamilon, progabide. In Plants GABA is also found in plants. It is the most abundant amino acid in the apoplast of tomatoes. [59] Evidence also suggests a role in cell signalling in plants. Somatostatin Somatostatin, also known as growth hormone–inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin inhibits insulin and glucagon secretion. Somatostatin has two active forms produced by alternative cleavage of a single preproprotein: one of 14 amino acids (shown in infobox to right), the other of 28 amino acids.


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Among the vertebrates, there exist six different somatostatin genes that have been named SS1, SS2, SS3, SS4, SS5, and SS6. Zebrafish have all 6. The six different genes along with the five different somatostatin receptors allows somatostatin to possess a large range of functions. Humans have only one somatostatin gene, SST. Nomenclature Synonyms of somatostatin are as follows:  growth hormone–inhibiting hormone (GHIH)  growth hormone release–inhibiting hormone (GHRIH)  somatotropin release–inhibiting factor (SRIF)  somatotropin release–inhibiting hormone (SRIH) Production Digestive system Somatostatin is secreted at several locations in the digestive system:  Delta cells in the pyloric antrum, the duodenum and the pancreatic islets Somatostatin released in the pyloric antrum travels via the portal venous system to the heart, then enters the systemic circulation to reach the locations where it will exert its inhibitory effects. In addition, somatostatin release from delta cells can act in a paracrine manner. In the stomach, somatostatin acts directly on the acid-producing parietal cells via a G-protein coupled receptor (which inhibits adenylate cyclase, thus effectively antagonising the stimulatory effect of histamine) to reduce acid secretion. Somatostatin can also indirectly decrease stomach acid production by preventing the release of other hormones, including gastrin, secretin and histamine which effectively slows down the digestive process. Brain Somatostatin is produced by neuroendocrine neurons of the ventromedial nucleus of the hypothalamus. These neurons project to the median eminence, where somatostatin is released from neurosecretory nerve endings into the hypothalamo-hypophysial system through neuron axons. Somatostatin is then carried to the anterior pituitary gland, where it inhibits the secretion of growth

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hormone from somatotrope cells. The somatostatin neurons in the periventricular nucleus mediate negative feedback effects of growth hormone on its own release; the somatostatin neurons respond to high circulating concentrations of growth hormone and somatomedins by increasing the release of somatostatin, so reducing the rate of secretion of growth hormone. Somatostatin is also produced by several other populations that project centrally, i.e., to other areas of the brain, and somatostatin receptors are expressed at many different sites in the brain. In particular, there are populations of somatostatin neurons in the arcuate nucleus the hippocampus, and the brainstem nucleus of the solitary tract. Actions

D cell is visible at upper-right, and somatostatin is represented by middle arrow pointing left


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Somatostatin is classified as an inhibitory hormone, and is induced by low pH. Its actions are spread to different parts of the body. Anterior Pituitary In the anterior pituitary gland, the effects of somatostatin are:  Inhibit the release of growth hormone (GH) (thus opposing the effects of growth hormone–releasing hormone (GHRH))  Inhibit the release of thyroid-stimulating hormone (TSH)  Inhibit adenylyl cyclase in parietal cells.  Inhibits the release of prolactin (PRL) Gastrointestinal System Somatostatin is homologous with cortistatin (see somatostatin family) and suppresses the release of gastrointestinal hormones  Gastrin  Cholecystokinin (CCK)  Secretin  Motilin  Vasoactive intestinal peptide (VIP)  Gastric inhibitory polypeptide (GIP)  Enteroglucagon Decrease rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine Suppresses the release of pancreatic hormones  Somatostatin release is triggered by the beta cell peptide Urocortin3 (Ucn3) to inhibit insulin release.  Inhibits the release of glucagon Suppresses the exocrine secretory action of pancreas. Synthetic Substitutes Octreotide (brand name Sandostatin, Novartis Pharmaceuticals) is an octapeptide that mimics natural somatostatin pharmacologically, though is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone and has a much longer half-life (approximately 90 minutes, compared to 2–3 minutes for somatostatin). Since it is absorbed poorly from the

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gut, it is administered parenterally (subcutaneously, intramuscularly, or intravenously). It is indicated for symptomatic treatment of carcinoid syndromeand acromegaly. It is also finding increased use in polycystic diseases of the liver and kidney. Lanreotide (brand name Somatuline, Ipsen Pharmaceuticals) is a medication used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome. It is a long-acting analog of somatostatin, like octreotide. It is available in several countries, including the United Kingdom, Australia, and Canada, and was approved for sale in the United States by the Food and Drug Administration (FDA) on August 30, 2007. Evolutionary History There are six somatostatin genes that have been discovered in vertebrates. The current proposed history as to how these six genes arose is based on the three whole-genome duplication events that took place in vertebrate evolution along with local duplications in teleost fish. An ancestral somatostatin gene was duplicated during the first whole-genome duplication event (1R) to create SS1 and SS2. These two genes were duplicated during the second whole-genome duplication event (2R) to create four new somatostatin genes: SS1, SS2, SS3, and one gene that was lost during the evolution of vertebrates. Tetrapods retained SS1 (also known as SS-14 and SS-28) and SS2 (also known as cortistatin) after the split in the sarcopterygii and actinopterygii lineage split. In teleost fish, SS1, SS2, and SS3 were duplicated during the third whole-genome duplication event (3R) to create SS1, SS2, SS4, SS5, and two genes that were lost during the evolution of teleost fish. SS1 and SS2 went through local duplications to give rise to SS6 and SS3. Cholecystokinin Cholecystokinin (CCK or CCK-PZ; from Greek chole, "bile"; cysto, "sac"; kinin, "move"; hence, move the bile-sac (gallbladder)) is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein. Cholecystokinin, previously called pancreozymin, is synthesized and secreted by enteroendocrine cells in the duodenum, the first segment of the


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small intestine. Its presence causes the release of digestive enzymes and bile from the pancreas and gallbladder, respectively, and also acts as a hunger suppressant. Structure The existence of CCK was first suggested in 1905 by the British physiologist Joy Simcha Cohen. It is a member of the gastrin/cholecystokinin family of peptide hormones and is very similar in structure to gastrin, another gastrointestinal hormone. CCK and gastrin share the same five C-terminal amino acids. CCK is composed of varying numbers of amino acids depending on post-translational modification of the 150-amino acid precursor, preprocholecystokinin. Thus, the CCK peptide hormone exists in several forms, each identified by the number of amino acids it contains, e.g., CCK58, CCK33, CCK22 and CCK8. CCK58 assumes a helix-turn-helix configuration. [8] Biological activity resides in the C-terminus of the peptide. Most CCK peptides have a sulfate-group attached to a tyrosine located seven residues from the C-terminus. [7] This modification is crucial for the ability of CCK to activate the cholecystokinin A receptor. Nonsulfated CCK peptides also occur, which consequently cannot activate the CCK-A receptor. Function CCK plays important physiologic roles both as a neuropeptide in the central nervous system and as a peptide hormone in the gut. It participates in a number of physiological processes such as digestion, satiety and anxiety. Gastrointestinal CCK is synthesized and released by enteroendocrine cells in the mucosal lining of the small intestine (mostly in the duodenum and jejunum), called I cells, neurons of the enteric nervous system, and neurons in the brain. It is released rapidly into the circulation in response to a meal. The greatest stimulator of CCK release is the presence of fatty acids and/or certain amino acids in the chyme entering the duodenum. In addition, release of CCK is stimulated by monitor peptide (released by pancreatic acinar cells), CCK-releasing protein (via paracrine signalling mediated by enterocytes in the gastric and intestinal mucosa), and acetylcholine (released by the

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parasympathetic nerve fibers of the vagus nerve). Once in the circulatory system, CCK has a relatively short half-life. Digestion CCK mediates digestion in the small intestine by inhibiting gastric emptying. It stimulates the acinar cells of the pancreas to release a juice rich in pancreatic digestive enzymes (hence an alternate name, pancreozymin) that catalyze the digestion of fat, protein, and carbohydrates. Thus, as the levels of the substances that stimulated the release of CCK drop, the concentration of the hormone drops as well. The release of CCK is also inhibited by somatostatin and pancreatic peptide. Trypsin, a protease released by pancreatic acinar cells, hydrolyzes CCK-releasing peptide and monitor peptide, in effect turning off the additional signals to secrete CCK. CCK also causes the increased production of hepatic bile, and stimulates the contraction of the gall bladder and the relaxation of the sphincter of Oddi (Glisson's sphincter), resulting in the delivery of bile into the duodenal part of the small intestine. Bile salts form amphipathic lipids, micelles that emulsify fats, aiding in their digestion and absorption. Satiety As a peptide hormone, CCK mediates satiety by acting on the CCK receptors distributed widely throughout the central nervous system. The mechanism for hunger suppression is thought to be a decrease in the rate of gastric emptying. CCK also has stimulatory effects on the vagus nerve, effects that can be inhibited by capsaicin. The stimulatory effects of CCK oppose those of ghrelin, which has been shown to inhibit the vagus nerve. The effects of CCK vary between individuals. For example, in rats, CCK administration significantly reduces hunger in adult males, but is slightly less effective in younger subjects, and even slightly less effective in females. The hunger-suppressive effects of CCK also are reduced in obese rats. Neurological CCK is found extensively throughout the central nervous system, with high concentrations found in the limbic system. CCK is synthesized as a 115 amino acid preprohormone, that is then converted into multiple isoforms. The


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predominant form of CCK in the central nervous system is the sulfated octapeptide, CCK-8S. Anxiogenic In both humans and rodents, studies clearly indicate that elevated CCK levels causes increased anxiety. The site of the anxiety-inducing effects of CCK seems to be central with specific targets being the basolateral amygdala, hippocampus, hypothalamus, peraqueductal grey, and cortical regions. Panicogenic The CCK tetrapeptide fragment CCK-4 (Trp-Met-Asp-Phe-NH2) reliably causes anxiety and panic attacks (panicogenic effect) when administered to humans and is commonly used in scientific research for this purpose of in order to test new anxiolytic drugs. Positron emission tomography visualization of regional cerebral blood flow in patients undergoing CCK-4 induced panic attacks show changes in the anterior cingulate gyrus, the claustrum-insular-amygdala region, and cerebellar vermis. Hallucinogenic Several studies have implicated CCK as a cause of visual hallucinations in Parkinson’s disease. Mutations in CCK receptors in combination with mutated CCK genes potentiate this association. These studies also uncovered potential racial/ethnic differences in the distribution of mutated CCK genes. Interactions CCK has been shown to interact with the Cholecystokinin A receptor located mainly on pancreatic acinar cells and Cholecystokinin B receptor mostly in the brain and stomach. CCKB receptor also binds gastrin, a gastrointestinal hormone involved in stimulating gastric acid release and growth of the gastric mucosa. CCK has also been shown to interact with calcineurin in the pancreas. Calcineurin will go on to activate the transcription factors NFAT 1–3, which will stimulate hypertrophy and growth of the pancreas. CCK can be stimulated by a diet high in protein, or by protease inhibitors. CCK has been shown to interact with orexin neurons, which control appetite and wakefulness (sleep). CCK can have indirect effects on sleep regulation.

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CCK in the body cannot cross the blood-brain barrier, but certain parts of the hypothalamus and brainstem are not protected by the barrier. Acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals, including humans, as a neurotransmitter—a chemical released by nerve cells to send signals to other cells. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic. Substances that interfere with acetylcholine activity are called anticholinergics.

Acetylcholine is the neurotransmitter used at the neuromuscular junction—in other words, it is the chemical that motor neurons of the nervous system release in order to activate muscles. This property means that drugs that affect cholinergic systems can have very dangerous effects ranging from paralysis to convulsions. Acetylcholine is also used as a neurotransmitter in the autonomic nervous system, both as an internal transmitter for the sympathetic nervous system and as the final product released by the parasympathetic nervous system. In the brain, acetylcholine functions as a neurotransmitter and as a neuromodulator. The brain contains a number of cholinergic areas, each with distinct functions. They play an important role in arousal, attention, memory and motivation. Partly because of its muscle-activating function, but also because of its functions in the autonomic nervous system and brain, a large number of important drugs exert their effects by altering cholinergic transmission. Numerous venoms and toxins produced by plants, animals, and bacteria, as well as chemical nerve agents such as Sarin, cause harm by inactivating or hyperactivating muscles via their influences on the neuromuscular junction. Drugs that act on muscarinic acetylcholine receptors, such as atropine, can be poisonous in large quantities, but in smaller doses they are commonly used to


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treat certain heart conditions and eye problems. Scopolamine, which acts mainly on muscarinic receptors in the brain, can cause delirium and amnesia. The addictive qualities of nicotine are derived from its effects on nicotinic acetylcholine receptors in the brain. Functions Acetylcholine functions in both the central nervous system (CNS) and the peripheral nervous system (PNS). In the CNS, cholinergic projections from the basal forebrain to the cerebral cortex and hippocampus support the cognitive functions of those target areas. In the PNS, acetylcholine activates muscles and is a major neurotransmitter in the autonomic nervous system. Cellular Effects

Acetylcholine processing in a synapse. After release acetylcholine is broken down by the enzyme acetylcholinesterase

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Like many other biologically active substances, acetylcholine exerts its effects by binding to and activating receptors located on the surface of cells. There are two main classes of acetylcholine receptor, nicotinic and muscarinic. They are named for chemicals that can selectively activate each type of receptor without activating the other: muscarine is a compound found in the mushroom Amanita muscaria; nicotine is found in tobacco. Nicotinic acetylcholine receptors are ligand-gated ion channels permeable to sodium, potassium, and calcium ions. In other words, they are ion channels embedded in cell membranes, capable of switching from a closed to open state when acetylcholine binds to them; in the open state they allow ions to pass through. Nicotinic receptors come in two main types, known as muscle-type and neuronal-type. The muscle-type can be selectively blocked by curare, the neuronal-type by hexamethonium. The main location of muscle-type receptors is on muscle cells, as described in more detail below. Neuronal-type receptors are located in autonomic ganglia (both sympathetic and parasympathetic), and in the central nervous system. Muscarinic acetylcholine receptors have a more complex mechanism, and affect target cells over a longer time frame. In mammals, five subtypes of muscarinic receptors have been identified, labeled M1 through M5. All of them function as G protein-coupled receptors, meaning that they exert their effects via a second messenger system. The M1, M3, and M5 subtypes are Gq-coupled; they increase intracellular levels of IP3 and calcium by activating phospholipase C. Their effect on target cells is usually excitatory. The M2 and M4 subtypes are Gi/Go-coupled; they decrease intracellular levels of cAMP by inhibiting adenylate cyclase. Their effect on target cells is usually inhibitory. Muscarinic acetylcholine receptors are found in both the central nervous system and the peripheral nervous system of the heart, lungs, upper gastrointestinal tract, and sweat glands. Neuromuscular Junction Acetylcholine is the substance the nervous system uses to activate skeletal muscles, a kind of striated muscle. These are the muscles used for all types of voluntary movement, in contrast to smooth muscle tissue, which is involved in


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a range of involuntary activities such as movement of food through the gastrointestinal tract and constriction of blood vessels. Skeletal muscles are directly controlled by motor neurons located in the spinal cord or, in a few cases, the brainstem. These motor neurons send their axons through motor nerves, from which they emerge to connect to muscle fibers at a special type of synapse called the neuromuscular junction.

Muscles contract when they receive signals from motor neurons. The neuromuscular junction is the site of the signal exchange. The steps of this process in vertebrates occur as follows: (1) The action potential reaches the axon terminal. (2) Calcium ions flow into the axon terminal. (3) Acetylcholine is released into the synaptic cleft. (4) Acetylcholine binds to postsynaptic receptors. (5) This binding causes ion channels to open and allows sodium ions to flow into the muscle cell. (6) The flow of sodium ions across the membrane into the muscle cell generates an action potential which induces muscle contraction. Labels: A: Motor neuron axon B: Axon terminal C: Synaptic cleft D: Muscle cell E: Part of a Myofibril.

When a motor neuron generates an action potential, it travels rapidly along the nerve until it reaches the neuromuscular junction, where it initiates an electrochemical process that causes acetylcholine to be released into the space

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between the presynaptic terminal and the muscle fiber. The acetylcholine molecules then bind to nicotinic ion-channel receptors on the muscle cell membrane, causing the ion channels to open. Calcium ions then flow into the muscle cell, initiating a sequence of steps that finally produce muscle contraction. Autonomic Nervous System The autonomic nervous system controls a wide range of involuntary and unconscious body functions. Its main branches are the sympathetic nervous system and parasympathetic nervous system. Broadly speaking, the function of the sympathetic nervous system is to mobilize the body for action: the slogan often used for it is fight-or-flight. The function of the parasympathetic nervous system is to put the body in a state conducive to rest, regeneration, digestion, and reproduction: it is sometimes described using the slogans "rest and digest" or "feed and breed". Both branches use acetylcholine, but in different ways. At a schematic level, the sympathetic and parasympathetic nervous systems are both organized in essentially the same way: preganglionic neurons in the central nervous system send projections to neurons located in autonomic ganglia; these neurons then send output projections to virtually every tissue of the body. In both branches the internal connections—the projections from the central nervous system to the autonomic ganglia—use acetylcholine as neurotransmitter, and the receptors it activates are of the nicotinic type. In the parasympathetic nervous system the output connections—the projections from ganglion neurons to tissues that don't belong to the nervous system—also release acetylcholine, acting on muscarinic receptors. In the sympathetic nervous system the output connections mainly release noradrenaline, although acetylcholine is released at a few points, such as the sudomotor innervation of the sweat glands. Direct Vascular Effects Acetylcholine in the serum exerts a direct effect on vascular tone by binding to muscarinic receptors present on vascular endothelium. These cells respond by increasing production of nitric oxide, which signals the surrounding smooth muscle to relax, leading to vasodilation. [2]


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Central Nervous System In the central nervous system, ACh has a variety of effects on plasticity, arousal and reward. ACh has an important role in the enhancement of alertness when we wake up, [3] in sustaining attention [4] and in learning and memory. Damage to the cholinergic (acetylcholine-producing) system in the brain has been shown to be associated with the memory deficits associated with Alzheimer's disease. [6] ACh has also been shown to promote REM sleep. In the brainstem acetylcholine originates from the Pedunculopontine nucleus and laterodorsal tegmental nucleus collectively known as the mesopontine tegmentum area or pontomesencephalotegmental complex. In the basal forebrain, it originates from the basal nucleus of Meynert and medial septal nucleus:  The pontomesencephalotegmental complex acts mainly on M1 receptors in the brainstem, deep cerebellar nuclei, pontine nuclei, locus coeruleus, raphe nucleus, lateral reticular nucleus and inferior olive. It also projects to the thalamus, tectum, basal ganglia and basal forebrain.  Basal nucleus of Meynert acts mainly on M1 receptors in the neocortex.  Medial septal nucleus acts mainly on M1 receptors in the hippocampus and parts of the cerebral cortex. In addition, ACh acts as an important internal transmitter in the striatum, which is part of the basal ganglia. It is released by cholinergic interneurons. In humans, non-human primates and rodents, these interneurons respond to salient environmental stimuli with responses that are temporally aligned with the responses of dopaminergic neurons of the substantia nigra. Memory Acetylcholine has been implicated in learning and memory in several ways. The anticholinergic drug, scopolamine, impairs acquisition of new information in humans and animals. In animals, disruption of the supply of acetylcholine to the neocortex impairs the learning of simple discrimination tasks, comparable to the acquisition of factual information and disruption of the supply of acetylcholine to the hippocampus and adjacent cortical areas produces forgetting comparable to anterograde amnesia in humans.

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Diseases and Disorders Myasthenia Gravis The disease myasthenia gravis, characterized by muscle weakness and fatigue, occurs when the body inappropriately produces antibodies against acetylcholine nicotinic receptors, and thus inhibits proper acetylcholine signal transmission. Over time, the motor end plate is destroyed. Drugs that competitively inhibit acetylcholinesterase (e.g., neostigmine, physostigmine, or primarily pyridostigmine) are effective in treating this disorder. They allow endogenously released acetylcholine more time to interact with its respective receptor before being inactivated by acetylcholinesterase in the synaptic cleft (the space between nerve and muscle). Pharmacology Blocking, hindering or mimicking the action of acetylcholine has many uses in medicine. Drugs acting on the acetylcholine system are either agonists to the receptors, stimulating the system, or antagonists, inhibiting it. Acetylcholine receptor agonists and antagonists can either have an effect directly on the receptors or exert their effects indirectly, e.g., by affecting the enzyme acetylcholinesterase, which degrades the receptor ligand. Agonists increase the level of receptor activation, antagonists reduce it. Acetylcholine itself does not have therapeutic value as a drug for intravenous administration because of its multi-faceted action (non-selective) and rapid inactivation by cholinesterase. However, it is used in the form of eye drops to cause constriction of the pupil during cataract surgery, which facilitates quick post-operational recovery. Nicotine Nicotine binds to and activates nicotinic acetylcholine receptors, mimicking the effect of acetylcholine at these receptors. When ACh interacts with a nicotinic ACh receptor, it opens a Na+ channel and Na+ ions flow into the membrane. This causes a depolarization, and results in an EPSP. Thus, ACh is excitatory on skeletal muscle; the electrical response is fast and short-lived.


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Atropine Atropine is a non-selective competitive antagonist with Acetylcholine at muscarinic receptors. Cholinesterase Inhibitors Many ACh receptor agonists work indirectly by inhibiting the enzyme acetylcholinesterase. The resulting accumulation of acetylcholine causes continuous stimulation of the muscles, glands, and central nervous system, which can result in fatal convulsions if the dose is high. They are examples of enzyme inhibitors, and increase the action of acetylcholine by delaying its degradation; some have been used as nerve agents (Sarin and VX nerve gas) or pesticides (organophosphates and the carbamates). Many toxins and venoms produced by plants and animals also contain cholinesterase inhibitors. In clinical use, they are administered in low doses to reverse the action of muscle relaxants, to treat myasthenia gravis, and to treat symptoms of Alzheimer's disease (rivastigmine, which increases cholinergic activity in the brain). Curare Synthesis Inhibitors Organic mercurial compounds, such as methylmercury, have a high affinity for sulfhydryl groups, which causes dysfunction of the enzyme choline acetyltransferase. This inhibition may lead to acetylcholine deficiency, and can have consequences on motor function. Release Inhibitors Botulinum toxin (Botox) acts by suppressing the release of acetylcholine, whereas the venom from a black widow spider (alpha-latrotoxin) has the reverse effect. ACh inhibition causes paralysis. When bitten by a black widow spider, one experiences the wastage of ACh supplies and the muscles begin to contract. If and when the supply is depleted, paralysis occurs. Comparative Biology and Evolution Biochemical Mechanisms Acetylcholine is synthesized in certain neurons by the enzyme choline

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acetyltransferase from the compounds choline and acetyl-CoA. Cholinergic neurons are capable of producing ACh. An example of a central cholinergic area is the nucleus basalis of Meynert in the basal forebrain. The enzyme acetylcholinesterase converts acetylcholine into the inactive metabolites choline and acetate. This enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free acetylcholine from the synapse is essential for proper muscle function. Certain neurotoxins work by inhibiting acetylcholinesterase, thus leading to excess acetylcholine at the neuromuscular junction, causing paralysis of the muscles needed for breathing and stopping the beating of the heart. Chemistry Acetylcholine is a choline molecule that has been acetylated at the oxygen atom. Because of the presence of a highly polar, charged ammonium group, acetylcholine does not penetrate lipid membranes. Because of this, when the drug is introduced externally, it remains in the extracellular space and does not pass through the blood–brain barrier. A synonym of this drug is miochol. Acetylcholine (ACh) was first identified in 1915 by Henry Hallett Dale for its actions on heart tissue. It was confirmed as a neurotransmitter by Otto Loewi, who initially gave it the name Vagusstoff because it was released from the vagus nerve. Both received the 1936 Nobel Prize in Physiology or Medicine for their work. Acetylcholine was also the first neurotransmitter to be identified. Vasoactive Intestinal Peptide Vasoactive intestinal peptide, also known as vasoactive intestinal polypeptide or VIP, is a peptide hormone that is vasoactive in the intestine. VIP is a peptide of 28 amino acid residues that belongs to a glucagon/secretin superfamily, the ligand of class II G protein–coupled receptors. VIP is produced in many tissues of vertebrates including the gut, pancreas, and suprachiasmatic nuclei of the hypothalamus in the brain. VIP stimulates contractility in the heart, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gall bladder. In humans, the vasoactive intestinal peptide is encoded by the VIP gene.


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VIP has a half-life (t½ ) in the blood of about two minutes. Function The leading hypothesis of VIP function points to the neurons using VIP to communicate with specific postsynaptic targets to regulate circadian rhythm. The depolarization of the VIP expressing neurons by light appears to cause the release of VIP and co-transmitters (including GABA) that can in turn, alter the properties of the next set of neurons with the activation of VPAC2. Another hypothesis supports VIP sending a paracrine signal from a distance rather than the adjacent postsynaptic neuron. In the Body VIP has an effect on several tissues: With respect to the digestive system, VIP seems to induce smooth muscle relaxation (lower esophageal sphincter, stomach, gallbladder), stimulate secretion of water into pancreatic juice and bile, and cause inhibition of gastric acid secretion and absorption from the intestinal lumen. Its role in the intestine is to greatly stimulate secretion of water and electrolytes, as well as relaxation of enteric smooth muscle, dilating peripheral blood vessels, stimulating pancreatic bicarbonate secretion, and inhibiting gastrin-stimulated gastric acid secretion. These effects work together to increase motility. It also has the function of stimulating pepsinogen secretion by chief cells. It is also found in the heart and has significant effects on the cardiovascular system. It causes coronary vasodilation as well as having a positive inotropic and chronotropiceffect. Research is being performed to see if it may have a beneficial role in the treatment of heart failure. VIP provokes vaginal lubrication in normal women, doubling the total volume of lubrication produced. In the Brain It is also found in the brain and some autonomic nerves: One region includes a specific area of the suprachiasmatic nuclei (SCN), the location of the 'master circadianpacemaker'. See SCN and circadian rhythm below. VIP in the pituitary helps to regulate prolactin secretion; it stimulates prolactin release in the domestic turkey. Additionally, the

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growth-hormone-releasing hormone (GH-RH) is a member of the VIP family and stimulates growth hormone secretion in the anterior pituitary gland. Mechanisms VIP innervates on both VPAC1 and VPAC2. When VIP binds to VPAC2 receptors, a G-alpha-mediated signalling cascade is triggered. In a number of systems, VIP binding activates adenyl cyclase activity leading to increases in cAMP and PKA. The PKA then activates other intracellular signaling pathways like the phosphorylation of CREB and other transcriptional factors. The mPer1 promoter has CRE domains and thus provides the mechanism for VIP to regulate the molecular clock itself. Then it will activate gene expression pathways such as Per1 and Per2 in circadian rhythm. In addition, GABA levels are connected to VIP in that they are co-released. Sparse GABAergic connections are thought to decrease synchronized firing. While GABA controls the amplitude of SCN neuronal rhythms, it is not critical for maintaining synchrony. However, if GABA release is dynamic, it may mask or amplify synchronizing effects of VIP inappropriately. Circadian time is likely to affect the synapses rather than the organization of VIP circuits. SCN and Circadian Rhythm The SCN coordinates daily timekeeping in the body and VIP plays a key role in communication between individual brain cellswithin this region. At a cellular level, the SCN expresses different electrical activity in circadian time. Higher activity is observed during the day, while during night there is lower activity. This rhythm is thought to be important feature of SCN to synchronize with each other and control rhythmicity in other regions. VIP acts as a major synchronizing agent among SCN neurons and plays a role in synchronizing the SCN with light cues. The high concentration of VIP and VIP receptor containing neurons are primarily found in the ventrolateral aspect of the SCN, which is also located above the optic chiasm. The neurons in this area receive retinal information from the retinohypothalamic tractand then relay the environmental information to the SCN. Further, VIP is also involved in synchronizing the timing of SCN function with the environmental light-dark


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cycle. Combined, these roles in the SCN make VIP a crucial component of the mammalian circadian timekeeping machinery. After finding evidence of VIP in the SCN, researchers began contemplating its role within the SCN and how it could affect circadian rhythm. The VIP also plays a pivotal role in modulating oscillations. Previous pharmacological research has established that VIP is needed for normal light-induced synchronization of the circadian systems. Application of VIP also phase shifts the circadian rhythm of vasopressin release and neural activity. The ability of the population to remain synchronized as well as the ability of single cells to generate oscillations is composed in VIP or VIP receptor deficient mice. While not highly studied, there is evidence that levels of VIP and its receptor may vary depending on each circadian oscillation. Signaling Pathway In SCN, there is an abundant amount of VPAC2. The presence of VPAC2 in ventrolateral side suggests that VIP signals can actually signal back to regulate VIP secreting cells. SCN has neural multiple pathways to control and modulate endocrine activity. VIP and vasopressin are both important for neurons to relay information to different targets which will impose effect on neuroendocrine function. They transmit info through relay nuclei such as SPZ, DMH (dorsomedial hypothalamic nucleus), MPOA (medial preoptic area) and PVN (paraventricular nucleus of hypothalamus). Social Behavior VIP neurons located in the hypothalamus, specifically the dorsal anterior hypothalamus and ventromedial hypothalamus, have an effect on social behaviors in many species of vertebrates. Studies suggest that VIP cascades can be activated in the brain in response to a social situation that stimulates the areas of the brain that are known to regulate behavior. This social circuit includes many areas of the hypothalamus along with the amygdala and the ventral tegmental area. The production and release of the neuropeptide VIP is centralized in the hypothalamic and extrahypothalamic regions of the brain and from there it is able to modulate the release of prolactin secretion. Once

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secreted from the pituitary gland, prolactin can increase many behaviors such as parental care and aggression. In certain species of birds with a knockout VIP gene there was an observable decrease in overall aggression over nesting territory. Pathology VIP is overproduced in VIPoma. In addition to VIPoma, VIP has a role in osteoarthritis (OA). While there is existing conflict in whether down-regulation or up-regulation of VIP contributes to OA, VIP has been shown to prevent cartilage damage in animals. Substance P Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) member of the tachykininneuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its closely related neurokinin A (NKA) are produced from a polyprotein precursor after differential splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows: Arg Pro Lys Pro Gln Gln Phe Phe Gly Leu Met (RPKPQQFFGLM) with an amidation at the C-terminus. Substance P is released from the terminals of specific sensory nerves. It is found in the brain and spinal cord and is associated with inflammatory processes and pain. The original discovery of Substance P (SP) was in 1931 by Ulf von Euler and John H. Gaddum as a tissue extract that caused intestinal contraction in vitro. Its tissue distribution and biologic actions were further investigated over the following decades. [1] The eleven-amino-acid structure of the peptide was determined by Susan Leeman in 1971. In 1983, NKA (previously known as substance K or neuromedin L) was isolated from porcine spinal cord and was also found to stimulate intestinal contraction. Receptor The endogenous receptor for substance P is neurokinin 1 receptor (NK1-receptor, NK1R). [8] It belongs to the tachykinin receptor sub-family of GPCRs. Other neurokinin subtypes and neurokinin receptors that interact with


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SP have been reported as well. Amino acid residues that are responsible for the binding of SP and its antagonists are present in the extracellular loops and transmembrane regions of NK-1. Binding of SP to NK-1 results in internalization by the clathrin-dependent mechanism to the acidified endosomeswhere the complex disassociates. Subsequently, SP is degraded and NK-1 is re-expressed on the cell surface. Substance P and the NK1 receptor are widely distributed in the brain and are found in brain regions that are specific to regulating emotion (hypothalamus, amygdala, and the periaqueductal gray). They are found in close association with serotonin (5-HT) and neurons containing norepinephrine that are targeted by the currently used antidepressant drugs. The SP receptor promoter contains regions that are sensitive to cAMP, AP-1, AP-4, CEBPB, and epidermal growth factor. Because these regions are related to complexed signal transduction pathways mediated by cytokines, it has been proposed that cytokines and neurotropic factors can induce NK-1. Also, SP can induce the cytokines that are capable of inducing NK-1 transcription factors. Function The "P" in substance "P" [SP] is mistakenly thought to signify Pain or Psychiatric substance. Substance P ("P" standing for "Preparation" or "Powder") is a neuropeptide – but only nominally so, as it is ubiquitous. Its receptor – the neurokinin type 1 – is distributed over cytoplasmic and nuclear membranes of many cell types (neurons, glia, endothelia of capillaries and lymphatics, fibroblasts, stem cells, white blood cells) in many tissues and organs. SP amplifies or excites most cellular processes. Substance P is a key first responder to most noxious/extreme stimuli (stressors), i.e., those with a potential to compromise biological integrity. SP is thus regarded as an immediate defense, stress, repair, survival system. The molecule, which is rapidly inactivated (or at times further activated by peptidases) is rapidly released – repetitively and chronically, as warranted, in the presence of a stressor. Unique among biological processes, SP release (and expression of its NK1 Receptor (through autocrine, paracrine, and endocrine-like processes)) may not naturally subside in diseases marked by

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chronic inflammation (including cancer). The SP or its NK1R, as well as similar neuropeptides, appear to be vital targets capable of satisfying many unmet medical needs. The failure of clinical proof of concept studies, designed to confirm various preclinical predictions of efficacy, is currently a source of frustration and confusion among biomedical researchers. Vasodilation Substance P is a potent vasodilator. Substance P-induced vasodilatation is dependent on nitric oxide release. Substance P is involved in the axon reflex-mediated vasodilatation to local heating and wheal and flare reaction. It has been shown that vasodilatation to substance P is dependent on the NK1 receptor located on the endothelium. In contrast to other neuropeptides studied in human skin, substance P-induced vasodilatation has been found to decline during continuous infusion. This possibly suggests an internalization of neurokinin-1 (NK1). As is typical with many vasodilators, it also has bronchoconstrictive properties, administered through the non-adrenergic, non-cholinergic nervous system (branch of the vagal system). Inflammation SP initiates expression of almost all known immunological chemical messengers (cytokines). Also, most of the cytokines, in turn, induce SP and the NK1 receptor. SP is particularly excitatory to cell growth and multiplication. via usual, as well as oncogenic driver. SP is a trigger for nausea and emesis, Substance P and other sensory neuropeptides can be released from the peripheral terminals of sensory nerve fibers in the skin, muscle, and joints. It is proposed that this release is involved in neurogenic inflammation, which is a local inflammatory response to certain types of infection or injury. Pain Preclinical data support the notion that Substance P is an important element in pain perception. The sensory function of substance P is thought to be related to the transmission of pain information into the central nervous system. Substance P coexists with the excitatory neurotransmitter glutamate in primary afferents that respond to painful stimulation. Substance P and other sensory neuropeptides can be released from the peripheral terminals of sensory nerve


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fibers in the skin, muscle, and joints. It is proposed that this release is involved in neurogenic inflammation, which is a local inflammatory response to certain types of infection or injury. Unfortunately, the reasons why NK1RAs have failed as efficacious analgesics in well-conducted clinical proof of concept studies have not yet been persuasively elucidated. Mood, Anxiety, Learning Substance P has been associated with the regulation of mood disorders, anxiety, stress, reinforcement, neurogenesis, respiratory rhythm, neurotoxicity, pain, and nociception. In 2014, a role for substance P in male fruit fly aggression was identified. Vomiting The vomiting center in the medulla called the Area Postrema, contains high concentrations of substance P and its receptor, in addition to other neurotransmitters such as choline, histamine, dopamine, serotonin, and opioids. Their activation stimulates the vomiting reflex. Different emetic pathways exist, and substance P/NK1R appears to be within the final common pathway to regulate vomiting. Cell Growth, Proliferation, Angiogenesis, and Migration The above processes are part and parcel to tissue integrity and repair. Substance P has been known to stimulate cell growth in normal and cancer cell line cultures, and it was shown that substance P could promote wound healing of non-healing ulcers in humans. SP and its induced cytokines promote multiplication of cells required for repair or replacement, growth of new blood vessels, and "leg-like pods" on cells (including cancer cells) bestowing upon them mobility, and metastasis. It has been suggested that cancer exploits the SP-NK1R to progress and metastasize, and that NK1RAs may be useful in the treatment of several cancer types. Clinical Significance of the SP-NK1R Quantification in Disease Elevation of serum, plasma, or tissue SP and/or its receptor (NK1R) has been associated with many diseases: sickle cell crisis; inflammatory bowel disease;

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major depression and related disorders; fibromyalgia; rheumatological; and infections such as HIV/AIDS and respiratory syncytial virus, as well as in cancer. When assayed in the human, the observed variability of the SP concentrations are large, and in some cases the assay methodology is questionable. SP concentrations cannot yet be used to diagnose disease clinically or gauge disease severity. It is not yet known whether changes in concentration of SP or density of its receptors is the cause of any given disease, or an effect. Blockade for Diseases with a Chronic Immunological Component As increasingly documented, the SP-NK1R system induces or modulates many aspects of the immune response, including WBC production and activation, and cytokine expression, Reciprocally, cytokines may induce expression of SP and its NK1R. In this sense, for diseases in which a pro-inflammatory component has been identified or strongly suspected, and for which current treatments are absent or in need of improvement, abrogation of the SP-NK1 system continues to receive focus as a treatment strategy. Currently, the only completely developed method available in that regard is antagonism (blockade, inhibition) of the SP preferring receptor, i.e., by drugs known as neurokinin type 1 antagonists (also termed: SP antagonists, or tachykinin antagonists.) One such drug is aprepitant to prevent the nausea and vomiting that accompanies chemotherapy, typically for cancer. With the exception of chemotherapy-induced nausea and vomiting, the patho-physiological basis of many of the disease groups listed below, for which NK1RAs have been studied as a therapeutic intervention, are to varying extents hypothesized to be initiated or advanced by a chronic non-homeostatic inflammatory response. Infections: HIV-AIDS, Measles, RSV, others The role of SP in HIV-AIDS has been well-documented. Doses of aprepitant greater than those tested to date are required for demonstration of full efficacy. Respiratory syncytial and related viruses appear to upregulate SP receptors, and rat studies suggest that NK1RAs may be useful in treating or limiting long term sequelae from such infections.


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Entamoeba histolytica is a unicellular parasitic protozoan that infects the lower gastrointestinal tract of humans. The symptoms of infection are diarrhea, constipation, and abdominal pain. This protozoan was found to secrete serotonin as well as substance P and neurotensin. Inflammatory Bowel Disease (IBS)/cystitis Despite strong preclinical rationale, efforts to demonstrate efficacy of SP antagonists in inflammatory disease have been unproductive. A study in women with IBS confirmed that an NK1RAs antagonist was anxiolytic. Chemotherapy Induced Nausea and Vomiting In line with its role as a first line defense system, SP is released when toxicants or poisons come into contact with a range of receptors on cellular elements in the chemoreceptor trigger zone, located in the floor of the fourth ventricle of the brain, the (area postrema). Presumably, SP is released in or around the nucleus of the solitary tract upon integrated activity of dopamine, serotonin, opioid, and/or acetylcholine receptor signaling. NK1Rs are stimulated. In turn, a fairly complex reflex is triggered involving cranial nerves sub-serving respiration, retroperistalsis, and general autonomic discharge. The actions of aprepitant are said to be entirely central, thus requiring passage of the drug into the central nervous system. However, given that NK1Rs are unprotected by a blood brain barrier in the area postrema just adjacent to neuronal structures in the medulla, and the activity of sendide (the peptide based NK1RA) against cisplatin-induced emesis in the ferret. It is likely that some peripheral exposure contributes to antiemetic effects, even if through vagal terminals in the clinical setting. Other Findings Denervation Supersensitivity When the innervation to substance P nerve terminals is lost, post-synaptic cells compensate for the loss of adequate neurotransmitter by increasing the expression of post-synaptic receptors. This, ultimately, leads to a condition known as denervation supersensitivity as the post-synaptic nerves will become hypersensitive to any release of substance P into the synaptic cleft.

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Male Aggression A suggestion of a link to male aggression was made in 2014. One research team found a correlation in male fruit flies and discussed it as a possibility in other species, even humans. Clues found in the brains of fruit flies might lead to further research that reveals the role of substance P in similar behaviour in those other species. Dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is an organic chemical of the catecholamine and phenethylaminefamilies that plays several important roles in the brain and body. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons (nerve cells) to send signals to other nerve cells. The brain includes several distinct dopamine pathways, one of which plays a major role in reward-motivated behavior. Most types of rewards increase the level of dopamine in the brain, and many addictive drugs increase dopamine neuronal activity. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory. Outside the central nervous system, dopamine functions primarily as a local chemical messenger. In blood vessels, it inhibits norepinephrine release and acts as a vasodilator (at normal concentrations); in the kidneys, it increases sodium excretion and urine output; in the pancreas, it reduces insulin production; in the digestive system, it reduces gastrointestinal motility and protects intestinal mucosa; and in the immune system, it reduces the activity of lymphocytes. With the exception of the blood vessels, dopamine in each of these peripheral systems is synthesized locally and exerts its effects near the cells that release it. Several important diseases of the nervous system are associated with dysfunctions of the dopamine system, and some of the key medications used to


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treat them work by altering the effects of dopamine. Parkinson's disease, a degenerative condition causing tremor and motor impairment, is caused by a loss of dopamine-secreting neurons in an area of the midbrain called the substantia nigra. Its metabolic precursor L-DOPA can be manufactured, and in its pure form marketed as Levodopa is the most widely used treatment for the condition. There is evidence that schizophrenia involves altered levels of dopamine activity, and most antipsychotic drugs used to treat this are dopamine antagonists which reduce dopamine activity. Similar dopamine antagonist drugs are also some of the most effective anti-nausea agents. Restless legs syndrome and attention deficit hyperactivity disorder (ADHD) are associated with decreased dopamine activity. Dopaminergic stimulants can be addictive in high doses, but some are used at lower doses to treat ADHD. Dopamine itself is available as a manufactured medication for intravenous injection: although it cannot reach the brain from the bloodstream, its peripheral effects make it useful in the treatment of heart failure or shock, especially in newborn babies. Structure A dopamine molecule consists of a catechol structure (a benzene ring with two hydroxyl side groups) with one amine group attached via an ethyl chain. As such, dopamine is the simplest possible catecholamine, a family that also includes the neurotransmitters norepinephrine and epinephrine. The presence of a benzene ring with this amine attachment makes it a substituted phenethylamine, a family that includes numerous psychoactive drugs. Like most amines, dopamine is an organic base. As a base, it is generally protonated in acidic environments (in an acid-base reaction). The protonated form is highly water-soluble and relatively stable, but can become oxidized if exposed to oxygen or other oxidants. In basic environments, dopamine is not protonated. In this free base form, it is less water-soluble and also more highly reactive. Because of the increased stability and water-solubility of the protonated form, dopamine is supplied for chemical or pharmaceutical use as dopamine hydrochloride—that is, the hydrochloride salt that is created when dopamine is combined with hydrochloric acid. In dry form, dopamine hydrochloride is a fine colorless powder.

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Dopamine structure

Phenethylamine structure

Catechol structure

Biochemistry Biosynthetic pathways for catecholamines and trace amines in the human brain

In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid phenylalanine. It is well established that dopamine is produced from L-tyrosine via L-DOPA; however, recent evidence has shown that CYP2D6 is expressed in the human brain and catalyzes the biosynthesis of dopamine from L-tyrosine via p-tyramine


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Synthesis Dopamine is synthesized in a restricted set of cell types, mainly neurons and cells in the medulla of the adrenal glands. The primary and minor metabolic pathways respectively are: Primary: L-Phenylalanine → L-Tyrosine → L-DOPA → Dopamine Minor: L-Phenylalanine → L-Tyrosine → p-Tyramine → Dopamine Minor: L-Phenylalanine → m-Tyrosine → m-Tyramine → Dopamine The direct precursor of dopamine, L-DOPA, can be synthesized indirectly from the essential amino acid phenylalanine or directly from the non-essential amino acid tyrosine. These amino acids are found in nearly every protein and so are readily available in food, with tyrosine being the most common. Although dopamine is also found in many types of food, it is incapable of crossing the blood–brain barrier that surrounds and protects the brain. It must therefore be synthesized inside the brain to perform its neuronal activity. L-Phenylalanine is converted into L-tyrosine by the enzyme phenylalanine hydroxylase, with molecular oxygen (O2) and tetrahydrobiopterin as cofactors. L-Tyrosine is converted into L-DOPA by the enzyme tyrosine hydroxylase, with tetrahydrobiopterin, O2, and iron (Fe2+) as cofactors. L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase (also known as DOPA decarboxylase), with pyridoxal phosphate as the cofactor. Dopamine itself is used as precursor in the synthesis of the neurotransmitters norepinephrine and epinephrine. Dopamine is converted into norepinephrine by the enzyme dopamine β-hydroxylase, with O2 and L-ascorbic acid as cofactors. Norepinephrine is converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase with S-adenosyl-L-methionine as the cofactor. Some of the cofactors also require their own synthesis. Deficiency in any required amino acid or cofactor can impair the synthesis of dopamine, norepinephrine, and epinephrine. [14] Degradation Dopamine is broken down into inactive metabolites by a set of

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enzymes—monoamine oxidase (MAO), catechol-O-methyl transferase (COMT), and aldehyde dehydrogenase (ALDH), acting in sequence. Both isoforms of monoamine oxidase, MAO-Aand MAO-B, effectively metabolize dopamine. Different breakdown pathways exist but the main end-product is homovanillic acid (HVA), which has no known biological activity. From the bloodstream, homovanillic acid is filtered out by the kidneys and then excreted in the urine. The two primary metabolic routes that convert dopamine into HVA are: Dopamine → DOPAL → DOPAC → HVA – catalyzed by MAO, ALDH, and COMT respectively Dopamine → 3-Methoxytyramine → HVA – catalyzed by COMT and MAO+ALDH respectively In clinical research on schizophrenia, measurements of homovanillic acid in plasma have been used to estimate levels of dopamine activity in the brain. A difficulty in this approach however, is separating the high level of plasma homovanillic acid contributed by the metabolism of norepinephrine. Although dopamine is normally broken down by an oxidoreductase enzyme, it is also susceptible to oxidation by direct reaction with oxygen, yielding quinones plus various free radicals as products. The rate of oxidation can be increased by the presence of ferric iron or other factors. Quinones and free radicals produced by autoxidation of dopamine can poison cells, and there is evidence that this mechanism may contribute to the cell loss that occurs in Parkinson's disease and other conditions.


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Functions Cellular Effects

Primary targets of dopamine in the human brain Family Receptor

Gene

D1

DRD1

D5

DRD5

D2

DRD2

D3

DRD3

D4

DRD4

TAAR1

TAAR1

D1-like

D2-like

TAAR

Type

Mechanism

Increase intracellular levels of Gs-coupled. cAMP by activating adenylate cyclase.

Gi-coupled.

Decrease intracellular levels of cAMP by inhibiting adenylate cyclase.

Increase intracellular levels of Gs-coupled. cAMP and intracellular calcium Gq-coupled. concentration.

Dopamine exerts its effects by binding to and activating cell surface receptors. In humans, dopamine has a high binding affinity at dopamine receptors and trace amine-associated receptor 1 (TAAR1). In mammals, five subtypes of dopamine receptorshave been identified, labeled from D1 to D5. All of them function as metabotropic, G protein-coupled receptors, meaning that they exert their effects via a complex second messenger system. These receptors can be divided into two families, known as D1-likeand D2-like. For receptors located on neurons in the nervous system, the ultimate effect of D1-like activation (D1 and D5) can be excitation (via opening of sodium channels) or inhibition (via opening of potassium channels); the ultimate effect of D2-like activation (D2, D3, and D4) is usually inhibition of the target neuron. Consequently, it is incorrect to describe dopamine itself as either excitatory or inhibitory: its effect on a target neuron depends on which types of receptors are present on the membrane of that neuron and on the internal responses of that neuron to the second messenger cAMP. D1 receptors are the most numerous dopamine receptors in the human nervous system; D2 receptors are next; D3,

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D4, and D5 receptors are present at significantly lower levels. Storage, Release, and Reuptake

Dopamine processing in a synapse. After release dopamine can either be taken up again by the presynaptic terminal, or broken down by enzymes. TH: tyrosine hydroxylase DOPA: L-DOPA DAT: dopamine transporter DDC: DOPA decarboxylase VMAT: vesicular monoamine transporter 2 MAO: Monoamine oxidase COMT: Catechol-O-methyl transferase HVA: Homovanillic acid


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Inside the brain, dopamine functions as a neurotransmitter and neuromodulator, and is controlled by a set of mechanisms common to all monoamine neurotransmitters. After synthesis, dopamine is transported from the cytosol into synaptic vesicles by a solute carrier—a vesicular monoamine transporter, VMAT2. Dopamine is stored in these vesicles until it is ejected into the synaptic cleft. In most cases, the release of dopamine occurs through a process called exocytosis which is caused by action potentials, but it can also be caused by the activity of an intracellular trace amine-associated receptor, TAAR1. TAAR1 is a high-affinity receptor for dopamine, trace amines, and certain substituted amphetamines that is located along membranes in the intracellular milieu of the presynaptic cell; activation of the receptor can regulate dopamine signaling by inducing dopamine reuptake inhibition and efflux as well as by inhibiting neuronal firing through a diverse set of mechanisms. Once in the synapse, dopamine binds to and activates dopamine receptors. These can be postsynaptic dopamine receptors, which are located on dendrites (the postsynaptic neuron), or presynaptic autoreceptors (e.g., the D2sh and presynaptic D3 receptors), which are located on the membrane of an axon terminal (the presynaptic neuron). After the postsynaptic neuron elicits an action potential, dopamine molecules quickly become unbound from their receptors. They are then absorbed back into the presynaptic cell, via reuptakemediated either by the dopamine transporter or by the plasma membrane monoamine transporter. Once back in the cytosol, dopamine can either be broken down by a monoamine oxidase or repackaged into vesicles by VMAT2, making it available for future release. In the brain the level of extracellular dopamine is modulated by two mechanisms: phasic and tonic transmission. Phasic dopamine release, like most neurotransmitter release in the nervous system, is driven directly by action potentials in the dopamine-containing cells. [27] Tonic dopamine transmission occurs when small amounts of dopamine are released without being preceded by presynaptic action potentials. Tonic transmission is regulated by a variety of factors, including the activity of other neurons and neurotransmitter reuptake.

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Nervous System

Major dopamine pathways. As part of the reward pathway, dopamine is manufactured in nerve cell bodies located within the ventral tegmental area (VTA) and is released in the nucleus accumbens and the prefrontal cortex. The motor functions of dopamine are linked to a separate pathway, with cell bodies in the substantia nigra that manufacture and release dopamine into the dorsal striatum

Inside the brain, dopamine plays important roles in executive functions, motor control, motivation, arousal, reinforcement, and reward, as well as lower-level functions including lactation, sexual gratification, and nausea. The dopaminergic cell groups and pathways make up the dopamine system which is neuromodulatory. Dopaminergic neurons (dopamine-producing nerve cells) are comparatively few in number—a total of around 400,000 in the human brain —and their cell bodies are confined in groups to a few relatively small brain areas. However their axons project to many other brain areas, and they exert powerful effects on their targets. These dopaminergic cell groups were first mapped in 1964 by Annica Dahlström and Kjell Fuxe, who assigned them labels starting with the letter "A" (for "aminergic"). In their scheme, areas A1 through A7 contain the neurotransmitter norepinephrine, whereas A8 through A14 contain dopamine. The dopaminergic areas they identified are the substantia nigra (groups 8 and 9); the ventral tegmental area (group 10); the posterior hypothalamus (group 11); the arcuate nucleus (group 12); the zona incerta (group 13) and the periventricular nucleus (group 14). The substantia nigra is a small midbrain area that forms a component of the basal ganglia. This has two parts—an input area called the pars compacta and


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an output area the pars reticulata. The dopaminergic neurons are found mainly in the pars compacta (cell group A8) and nearby (group A9). In humans, the projection of dopaminergic neurons from the substantia nigra pars compacta to the dorsal striatum, termed the nigrostriatal pathway, plays a significant role in the control of motor function and in learning new motor skills. These neurons are especially vulnerable to damage, and when a large number of them die, the result is a parkinsonian syndrome. The ventral tegmental area (VTA) is another midbrain area. The most prominent group of VTA dopaminergic neurons projects to the prefrontal cortex via the mesocortical pathway and another smaller group projects to the nucleus accumbens via the mesolimbic pathway. Together, these two pathways are collectively termed the mesocorticolimbic projection. The VTA also sends dopaminergic projections to the amygdala, cingulate gyrus, hippocampus, and olfactory bulb. Mesocorticolimbic neurons play a central role in reward and other aspects of motivation. The posterior hypothalamus has dopamine neurons that project to the spinal cord, but their function is not well established. There is some evidence that pathology in this area plays a role in restless legs syndrome, a condition in which people have difficulty sleeping due to an overwhelming compulsion to constantly move parts of the body, especially the legs. The arcuate nucleus and the periventricular nucleus of the hypothalamus have dopamine neurons that form an important projection—the tuberoinfundibular pathway which goes to the pituitary gland, where it influences the secretion of the hormone prolactin. Dopamine is the primary neuroendocrine inhibitor of the secretion of prolactin from the anterior pituitary gland. Dopamine produced by neurons in the arcuate nucleus is secreted into the hypophyseal portal system of the median eminence, which supplies the pituitary gland. The prolactin cells that produce prolactin, in the absence of dopamine, secrete prolactin continuously; dopamine inhibits this secretion. In the context of regulating prolactin secretion, dopamine is occasionally called prolactin-inhibiting factor, prolactin-inhibiting hormone, or prolactostatin. The zona incerta, grouped between the arcuate and periventricular nuclei, projects to several areas of the hypothalamus, and participates in the control of

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gonadotropin-releasing hormone, which is necessary to activate the development of the male and female reproductive systems, following puberty. An additional group of dopamine-secreting neurons is found in the retina of the eye. [35] These neurons are amacrine cells, meaning that they have no axons. [35] They release dopamine into the extracellular medium, and are specifically active during daylight hours, becoming silent at night. This retinal dopamine acts to enhance the activity of cone cells in the retina while suppressing rod cells—the result is to increase sensitivity to color and contrast during bright light conditions, at the cost of reduced sensitivity when the light is dim. Basal Ganglia

Main circuits of the basal ganglia. The dopaminergic pathway from the substantia nigra pars compacta to the striatum is shown in light blue


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The largest and most important sources of dopamine in the vertebrate brain are the substantia nigra and ventral tegmental area. These structures are closely related to each other and functionally similar in many respects. Both are components of the basal ganglia, a complex network of structures located mainly at the base of the forebrain. The largest component of the basal ganglia is the striatum. The substantia nigra sends a dopaminergic projection to the dorsal striatum, while the ventral tegmental area sends a similar type of dopaminergic projection to the ventral striatum. Progress in understanding the functions of the basal ganglia has been slow. The most popular hypotheses, broadly stated, propose that the basal ganglia play a central role in action selection. The action selection theory in its simplest form proposes that when a person or animal is in a situation where several behaviors are possible, activity in the basal ganglia determines which of them is executed, by releasing that response from inhibition while continuing to inhibit other motor systems that if activated would generate competing behaviors. Thus the basal ganglia, in this concept, are responsible for initiating behaviors, but not for determining the details of how they are carried out. In other words, they essentially form a decision-making system. The basal ganglia can be divided into several sectors, and each is involved in controlling particular types of actions. The ventral sector of the basal ganglia (containing the ventral striatum and ventral tegmental area) operates at the highest level of the hierarchy, selecting actions at the whole-organism level. The dorsal sectors (containing the dorsal striatum and substantia nigra) operate at lower levels, selecting the specific muscles and movements that are used to implement a given behavior pattern. Dopamine contributes to the action selection process in at least two important ways. First, it sets the "threshold" for initiating actions. The higher the level of dopamine activity, the lower the impetus required to evoke a given behavior. As a consequence, high levels of dopamine lead to high levels of motor activity and impulsive behavior; low levels of dopamine lead to torpor and slowed reactions. Parkinson's disease, in which dopamine levels in the substantia nigra circuit are greatly reduced, is characterized by stiffness and difficulty initiating movement—however, when people with the disease are

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confronted with strong stimuli such as a serious threat, their reactions can be as vigorous as those of a healthy person. In the opposite direction, drugs that increase dopamine release, such as cocaine or amphetamine, can produce heightened levels of activity, including at the extreme, psychomotor agitation and stereotyped movements. The second important effect of dopamine is as a "teaching" signal. When an action is followed by an increase in dopamine activity, the basal ganglia circuit is altered in a way that makes the same response easier to evoke when similar situations arise in the future. This is a form of operant conditioning, in which dopamine plays the role of a reward signal. Reward In the reward system, reward is the attractive and motivational property of a stimulus that induces appetitive behavior (also known as approach behavior) – and consummatory behavior. [42] A rewarding stimulus is one that has the potential to cause an approach to it and a choice to be made to consume it or not. Pleasure, learning (e.g., classical and operant conditioning), and approach behavior are the three main functions of reward. As an aspect of reward, pleasure provides a definition of reward; however, while all pleasurable stimuli are rewarding, not all rewarding stimuli are pleasurable (e.g., extrinstic rewards like money). The motivational or desirable aspect of rewarding stimuli is reflected by the approach behavior that they induce, whereas the pleasurable component of intrinstic rewards is derived from the consummatory behavior that ensues upon acquiring them. A neuropsychological model which distinguishes these two components of an intrinsically rewarding stimulus is the incentive salience model, where "wanting" or desire (less commonly, "seeking" corresponds to appetitive or approach behavior while "liking" or pleasure corresponds to consummatory behavior. In human drug addicts, "wanting" becomes dissociated with "liking" as the desire to use an addictive drug increases, while the pleasure obtained from consuming it decreases due to drug tolerance. Within the brain, dopamine functions partly as a "global reward signal", where an initial phasic dopamine response to a rewarding stimulus encodes


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information about the salience, value, and context of a reward. In the context of reward-related learning, dopamine also functions as a reward prediction error signal, that is, the degree to which the value of a reward is unexpected. According to this hypothesis of Wolfram Schultz, rewards that are expected do not produce a second phasic dopamine response in certain dopaminergic cells, but rewards that are unexpected, or greater than expected, produce a short-lasting increase in synaptic dopamine, whereas the omission of an expected reward actually causes dopamine release to drop below its background level. The "prediction error" hypothesis has drawn particular interest from computational neuroscientists, because an influential computational-learning method known as temporal difference learning makes heavy use of a signal that encodes prediction error. This confluence of theory and data has led to a fertile interaction between neuroscientists and computer scientists interested in machine learning. Evidence from microelectrode recordings from the brains of animals shows that dopamine neurons in the ventral tegmental area (VTA) and substantia nigra are strongly activated by a wide variety of rewarding events. These reward-responsive dopamine neurons in the VTA and substantia nigra are crucial for reward-related cognition and serve as the central component of the reward system. The function of dopamine varies in each axonal projection from the VTA and substantia nigra; for example, the VTA–nucleus accumbens shell projection assigns incentive salience ("want") to rewarding stimuli and its associated cues, the VTA–orbitofrontal cortex projection updates the value of different goals in accordance with their incentive salience, the VTA–amygdala and VTA–hippocampus projections mediate the consolidation of reward-related memories, and both the VTA–nucleus accumbens core and substantia nigra–dorsal striatum pathways are involved in learning motor responses that facilitate the acquisition of rewarding stimuli. Some activity within the VTA dopaminergic projections appears to be associated with reward prediction as well. While dopamine has a central role in mediating "wanting" — associated with the appetitive or approach behavioral responses to rewarding stimuli, detailed studies have shown that dopamine cannot simply be equated with hedonic

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"liking" or pleasure, as reflected in the consummatory behavioral response. Dopamine neurotransmission is involved in some but not all aspects of pleasure-related cognition, since pleasure centers have been identified both within the dopamine system (i.e., nucleus accumbens shell) and outside the dopamine system (i.e., ventral pallidum and parabrachial nucleus). For example, direct electrical stimulation of dopamine pathways, using electrodes implanted in the brain, is experienced as pleasurable, and many types of animals are willing to work to obtain it. Antipsychotic drugs used to treat psychosis reduce dopamine levels and tend to cause anhedonia, a diminished ability to experience pleasure. Many types of pleasurable experiences—such as sex, enjoying food, or playing video games—increase dopamine release. All addictive drugs directly or indirectly affect dopamine neurotransmission in the nucleus accumbens; these drugs increase drug "wanting", leading to compulsive drug use, when repeatedly taken in high doses, presumably through the sensitization of incentive-salience. Drugs that increase synaptic dopamine concentrations include psychostimulants such as methamphetamine and cocaine. These produce increases in "wanting" behaviors, but do not greatly alter expressions of pleasure or change levels of satiation. However, opiate drugs such as heroin or morphine produce increases in expressions of "liking" and "wanting" behaviors. Moreover, animals in which the ventral tegmental dopamine system has been rendered inactive do not seek food, and will starve to death if left to themselves, but if food is placed in their mouths they will consume it and show expressions indicative of pleasure. Outside the Nervous System Dopamine does not cross the blood–brain barrier, so its synthesis and functions in peripheral areas are to a large degree independent of its synthesis and functions in the brain. A substantial amount of dopamine circulates in the bloodstream, but its functions there are not entirely clear. Dopamine is found in blood plasma at levels comparable to those of epinephrine, but in humans, over 95% of the dopamine in the plasma is in the form of dopamine sulfate, a conjugate produced by the enzyme sulfotransferase 1A3/1A4acting on free dopamine. The bulk of this dopamine sulfate is produced in the mesentery that


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surrounds parts of the digestive system. The production of dopamine sulfate is thought to be a mechanism for detoxifying dopamine that is ingested as food or produced by the digestive process—levels in the plasma typically rise more than fifty-fold after a meal. Dopamine sulfate has no known biological functions and is excreted in urine. The relatively small quantity of unconjugated dopamine in the bloodstream may be produced by the sympathetic nervous system, the digestive system, or possibly other organs. It may act on dopamine receptors in peripheral tissues, or be metabolized, or be converted to norepinephrine by the enzyme dopamine beta hydroxylase, which is released into the bloodstream by the adrenal medulla. Some dopamine receptors are located in the walls of arteries, where they act as a vasodilator and an inhibitor of norepinephrine release. These responses might be activated by dopamine released from the carotid body under conditions of low oxygen, but whether arterial dopamine receptors perform other biologically useful functions is not known. Beyond its role in modulating blood flow, there are several peripheral systems in which dopamine circulates within a limited area and performs an exocrine or paracrine function. The peripheral systems in which dopamine plays an important role include the immune system, the kidneys and the pancreas. In the immune system dopamine acts upon receptors present on immune cells, especially lymphocytes. Dopamine can also affect immune cells in the spleen, bone marrow, and circulatory system. In addition, dopamine can be synthesized and released by immune cells themselves. The main effect of dopamine on lymphocytes is to reduce their activation level. The functional significance of this system is unclear, but it affords a possible route for interactions between the nervous system and immune system, and may be relevant to some autoimmune disorders. The renal dopaminergic system is located in the cells of the nephron in the kidney, where all subtypes of dopamine receptors are present. Dopamine is also synthesized there, by tubule cells, and discharged into the tubular fluid. Its actions include increasing the blood supply to the kidneys, increasing the glomerular filtration rate, and increasing the excretion of sodium in the urine.

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Hence, defects in renal dopamine function can lead to reduced sodium excretion and consequently result in the development of high blood pressure. There is strong evidence that faults in the production of dopamine or in the receptors can result in a number of pathologies including oxidative stress, edema, and either genetic or essential hypertension. Oxidative stress can itself cause hypertension. Defects in the system can also be caused by genetic factors or high blood pressure. In the pancreas the role of dopamine is somewhat complex. The pancreas consists of two parts, an exocrine and an endocrine component. The exocrine part synthesizes and secretes digestive enzymes and other substances, including dopamine, into the small intestine. The function of this secreted dopamine after it enters the small intestine is not clearly established—the possibilities include protecting the intestinal mucosa from damage and reducing gastrointestinal motility (the rate at which content moves through the digestive system). The pancreatic islets make up the endocrine part of the pancreas, and synthesize and secrete hormones including insulin into the bloodstream. There is evidence that the beta cells in the islets that synthesize insulin contain dopamine receptors, and that dopamine acts to reduce the amount of insulin they release. The source of their dopamine input is not clearly established—it may come from dopamine that circulates in the bloodstream and derives from the sympathetic nervous system, or it may be synthesized locally by other types of pancreatic cells. Medical Uses Dopamine as a manufactured medication is sold under the trade names Intropin, Dopastat, and Revimine, among others. It is on the World Health Organization's List of Essential Medicines. It is most commonly used as a stimulant drug in the treatment of severe low blood pressure, slow heart rate, and cardiac arrest. It is especially important in treating these in newborn infants. It is given intravenously. Since the half-life of dopamine in plasma is very short—approximately one minute in adults, two minutes in newborn infants and up to five minutes in preterm infants—it is usually given in a continuous intravenous drip rather than a single injection.


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Its effects, depending on dosage, include an increase in sodium excretion by the kidneys, an increase in urine output, an increase in heart rate, and an increase in blood pressure. At low doses it acts through the sympathetic nervous system to increase heart muscle contraction force and heart rate, thereby increasing cardiac output and blood pressure. Higher doses also cause vasoconstriction that further increases blood pressure. Older literature also describes very low doses thought to improve kidney function without other consequences, but recent reviews have concluded that doses at such low levels are not effective and may sometimes be harmful. While some effects result from stimulation of dopamine receptors, the prominent cardiovascular effects result from dopamine acting at α1, β1, and β2 adrenergic receptors. Side effects of dopamine include negative effects on kidney function and irregular heartbeats. The LD50, or lethal dose which is expected to prove fatal in 50% of the population, has been found to be: 59 mg/kg (mouse; administered intravenously); 95 mg/kg (mouse; administered intraperitoneally); 163 mg/kg (rat; administered intraperitoneally); 79 mg/kg (dog; administered intravenously). A fluorinated form of L-DOPA known as fluorodopa is available for use in positron emission tomography to assess the function of the nigrostriatal pathway. Disease, Disorders, and Pharmacology The dopamine system plays a central role in several significant medical conditions, including Parkinson's disease, attention deficit hyperactivity disorder, schizophrenia, and addiction. Aside from dopamine itself, there are many other important drugs that act on dopamine systems in various parts of the brain or body. Some are used for medical or recreational purposes, but neurochemists have also developed a variety of research drugs, some of which bind with high affinity to specific types of dopamine receptors and either agonize or antagonize their effects, and many that affect other aspects of dopamine physiology, including dopamine transporter inhibitors, VMAT inhibitors, and enzyme inhibitors.

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Aging Brain A number of studies have reported an age-related decline in dopamine synthesis and dopamine receptor density (i.e., the number of receptors) in the brain. This decline has been shown to occur in the striatum and extrastriatal regions. Decreases in the D1, D2, and D3 receptors are well documented. The reduction of dopamine with aging is thought to be responsible for many neurological symptoms that increase in frequency with age, such as decreased arm swing and increased rigidity. Changes in dopamine levels may also cause age-related changes in cognitive flexibility. Other neurotransmitters, such as serotonin and glutamate also show a decline in output with aging. Parkinson's Disease Parkinson's disease is an age-related disorder characterized by movement disorders such as stiffness of the body, slowing of movement, and trembling of limbs when they are not in use. In advanced stages it progresses to dementia and eventually death. The main symptoms are caused by the loss of dopamine-secreting cells in the substantia nigra. These dopamine cells are especially vulnerable to damage, and a variety of insults, including encephalitis (as depicted in the book and movie "Awakenings"), repeated sports-related concussions, and some forms of chemical poisoning such as MPTP, can lead to substantial cell loss, producing a parkinsonian syndrome that is similar in its main features to Parkinson's disease. Most cases of Parkinson's disease, however, are idiopathic, meaning that the cause of cell death cannot be identified. The most widely used treatment for parkinsonism is administration of L-DOPA, the metabolic precursor for dopamine. L-DOPA is converted to dopamine in the brain and various parts of the body by the enzyme DOPA decarboxylase. L-DOPA is used rather than dopamine itself because, unlike dopamine, it is capable of crossing the blood-brain barrier. It is often co-administered with an enzyme inhibitor of peripheral decarboxylation such as carbidopa or benserazide, to reduce the amount converted to dopamine in the periphery and thereby increase the amount of L-DOPA that enters the brain.


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When L-DOPA is administered regularly over a long time period, a variety of unpleasant side effects such as dyskinesia often begin to appear; even so, it is considered the best available long-term treatment option for most cases of Parkinson's disease. L-DOPA treatment cannot restore the dopamine cells that have been lost, but it causes the remaining cells to produce more dopamine, thereby compensating for the loss to at least some degree. In advanced stages the treatment begins to fail because the cell loss is so severe that the remaining ones cannot produce enough dopamine regardless of L-DOPA levels. Other drugs that enhance dopamine function, such as bromocriptine and pergolide, are also sometimes used to treat Parkinsonism, but in most cases L-DOPA appears to give the best trade-off between positive effects and negative side-effects. Dopaminergic medications that are used to treat Parkinson's disease are sometimes associated with the development of a dopamine dysregulation syndrome, which involves the overuse of dopaminergic medication and medication-induced compulsive engagement in natural rewards like gambling and sexual activity. The latter behaviors are similar to those observed in individuals with a behavioral addiction. Drug Addiction and Psychostimulants

Cocaine increases dopamine levels by blocking dopamine transporters (DAT), which transport dopamine back into a synaptic terminal after it has been emitted

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Cocaine, substituted amphetamines (including methamphetamine), Adderall, methylphenidate (marketed as Ritalin or Concerta), MDMA (ecstasy) and other psychostimulants exert their effects primarily or partly by increasing dopamine levels in the brain by a variety of mechanisms. [84] Cocaine and methylphenidate are dopamine transporter blockers or reuptake inhibitors; they non-competitively inhibitdopamine reuptake, resulting in increased dopamine concentrations in the synaptic cleft. Like cocaine, substituted amphetamines and amphetamine also increase the concentration of dopamine in the synaptic cleft, but by different mechanisms. The effects of psychostimulants include increases in heart rate, body temperature, and sweating; improvements in alertness, attention, and endurance; increases in pleasure produced by rewarding events; but at higher doses agitation, anxiety, or even loss of contact with reality. Drugs in this group can have a high addiction potential, due to their activating effects on the dopamine-mediated reward system in the brain. However some can also be useful, at lower doses, for treating attention deficit hyperactivity disorder (ADHD) and narcolepsy. An important differentiating factor is the onset and duration of action. Cocaine can take effect in seconds if it is injected or inhaled in free base form; the effects last from 5 to 90 minutes. This rapid and brief action makes its effects easily perceived and consequently gives it high addiction potential. Methylphenidate taken in pill form, in contrast, can take two hours to reach peak levels in the bloodstream, and depending on formulation the effects can last for up to 12 hours. These slow and sustained actions reduce the potential for abuse and make it more useful for treating ADHD. A variety of addictive drugs produce an increase in reward-related dopamine activity. Stimulants such as nicotine, cocaine and methamphetamine promote increased levels of dopamine which appear to be the primary factor in causing addiction. For other addictive drugs such as the opioid heroin, the increased levels of dopamine in the reward system may only play a minor role in addiction. When people addicted to stimulants go through withdrawal, they do not experience the physical suffering associated with alcohol withdrawal or withdrawal from opiates; instead they experience craving, an intense desire for


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the drug characterized by irritability, restlessness, and other arousal symptoms, brought about by psychological dependence. The dopamine system plays a crucial role in several aspects of addiction. At the earliest stage, genetic differences that alter the expression of dopamine receptors in the brain can predict whether a person will find stimulants appealing or aversive. Consumption of stimulants produces increases in brain dopamine levels that last from minutes to hours. Finally, the chronic elevation in dopamine that comes with repetitive high-dose stimulant consumption triggers a wide-ranging set of structural changes in the brain that are responsible for the behavioral abnormalities which characterize an addiction. Treatment of stimulant addiction is very difficult, because even if consumption ceases, the craving that comes with psychological withdrawal does not. Even when the craving seems to be extinct, it may re-emerge when faced with stimuli that are associated with the drug, such as friends, locations and situations. Association networks in the brain are greatly interlinked. Psychosis and Antipsychotic Drugs Psychiatrists in the early 1950s discovered that a class of drugs known as typical antipsychotics (also known as major tranquilizers), were often effective at reducing the psychoticsymptoms of schizophrenia. The introduction of the first widely used antipsychotic, chlorpromazine (Thorazine), in the 1950s, led to the release of many patients with schizophrenia from institutions in the years that followed. By the 1970s researchers understood that these typical antipsychotics worked as antagonists on the D2 receptors. This realization led to the so-called dopamine hypothesis of schizophrenia, which postulates that schizophrenia is largely caused by hyperactivity of brain dopamine systems. The dopamine hypothesis drew additional support from the observation that psychotic symptoms were often intensified by dopamine-enhancing stimulantssuch as methamphetamine, and that these drugs could also produce psychosis in healthy people if taken in large enough doses. In the following decades other atypical antipsychotics that had fewer serious side effects were developed. Many of these newer drugs do not act directly on dopamine receptors, but instead produce alterations in dopamine activity indirectly. These

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drugs were also used to treat other psychoses. Antipsychotic drugs have a broadly suppressive effect on most types of active behavior, and particularly reduce the delusional and agitated behavior characteristic of overt psychosis. There remains substantial dispute, however, about how much of an improvement the patient experiences on these drugs. Later observations, however, have caused the dopamine hypothesis to lose popularity, at least in its simple original form. For one thing, patients with schizophrenia do not typically show measurably increased levels of brain dopamine activity. Also, other dissociative drugs, notably ketamine and phencyclidine that act on glutamate NMDA receptors (and not on dopamine receptors) can produce psychotic symptoms. Perhaps most importantly, those drugs that do reduce dopamine activity are a very imperfect treatment for schizophrenia: they only reduce a subset of symptoms, while producing severe short-term and long-term side effects. Even so, many psychiatrists and neuroscientists continue to believe that schizophrenia involves some sort of dopamine system dysfunction. As the "dopamine hypothesis" has evolved over time, however, the sorts of dysfunctions it postulates have tended to become increasingly subtle and complex. However, the widespread use of antipsychotic drugs has long been controversial. There are several reasons for this. First, antipsychotic drugs are perceived as very aversive by people who have to take them, because they produce a general dullness of thought and suppress the ability to experience pleasure. Second, it is difficult to show that they act specifically against psychotic behaviors rather than merely suppressing all types of active behavior. Third, they can produce a range of serious side effects, including weight gain, diabetes, fatigue, sexual dysfunction, hormonal changes, and a type of serious movement disorder known as tardive dyskinesia. Some of these side effects may continue long after the cessation of drug use, or even permanently. Attention Deficit Hyperactivity Disorder Altered dopamine neurotransmission is implicated in attention deficit hyperactivity disorder (ADHD), a condition associated with impaired cognitive control, in turn leading to problems with regulating attention (attentional


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control), inhibiting behaviors (inhibitory control), and forgetting things or missing details (working memory), among other problems. There are genetic links between dopamine receptors, the dopamine transporter, and ADHD, in addition to links to other neurotransmitter receptors and transporters. The most important relationship between dopamine and ADHD involves the drugs that are used to treat ADHD.[104] Some of the most effective therapeutic agents for ADHD are psychostimulants such as methylphenidate (Ritalin, Concerta) and amphetamine (Adderall, Dexedrine), drugs that increase both dopamine and norepinephrine levels in the brain. The clinical effects of these psychostimulants in treating ADHD are mediated through the indirect activation of dopamine and norepinephrine receptors, specifically dopamine receptor D1 and adrenoceptor A2, in the prefrontal cortex. Pain Dopamine plays a role in pain processing in multiple levels of the central nervous system including the spinal cord, periaqueductal gray, thalamus, basal ganglia, and cingulate cortex. Decreased levels of dopamine have been associated with painful symptoms that frequently occur in Parkinson's disease. Abnormalities in dopaminergic neurotransmission also occur in several painful clinical conditions, including burning mouth syndrome, fibromyalgia, and restless legs syndrome. Nausea Nausea and vomiting are largely determined by activity in the area postrema in the medulla of the brainstem, in a region known as the chemoreceptor trigger zone. This area contains a large population of type D2 dopamine receptors. Consequently, drugs that activate D2 receptors have a high potential to cause nausea. This group includes some medications that are administered for Parkinson's disease, as well as other dopamine agonists such as apomorphine. In some cases, D2-receptor antagonists such as metoclopramide are useful as anti-nausea drugs. Comparative Biology and Evolution Microorganisms

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There are no reports of dopamine in archaea, but it has been detected in some types of bacteria and in the protozoan called Tetrahymena. Perhaps more importantly, there are types of bacteria that contain homologs of all the enzymes that animals use to synthesize dopamine. It has been proposed that animals derived their dopamine-synthesizing machinery from bacteria, via horizontal gene transfer that may have occurred relatively late in evolutionary time, perhaps as a result of the symbiotic incorporation of bacteria into eukaryotic cells that gave rise to mitochondria. Animals Dopamine is used as a neurotransmitter in most multicellular animals. In sponges there is only a single report of the presence of dopamine, with no indication of its function; however, dopamine has been reported in the nervous systems of many other radially symmetric species, including the cnidarian jellyfish, hydra and some corals. This dates the emergence of dopamine as a neurotransmitter back to the earliest appearance of the nervous system, over 500 million years ago in the Cambrian era. Dopamine functions as a neurotransmitter in vertebrates, echinoderms, arthropods, molluscs, and several types of worm. In every type of animal that has been examined, dopamine has been seen to modify motor behavior. In the model organism, nematode Caenorhabditis elegans, it reduces locomotion and increases food-exploratory movements; in flatworms it produces "screw-like" movements; in leeches it inhibits swimming and promotes crawling. Across a wide range of vertebrates, dopamine has an "activating" effect on behavior-switching and response selection, comparable to its effect in mammals. Dopamine has also consistently been shown to play a role in reward learning, in all animal groups. As in all vertebrates – invertebrates such as roundworms, flatworms, molluscs and common fruit flies can all be trained to repeat an action if it is consistently followed by an increase in dopamine levels. It had long been believed that arthropods were an exception to this with dopamine being seen as having an adverse effect. Reward was seen to be mediated instead by octopamine, a neurotransmitter closely related to


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norepinephrine. More recent studies however have shown that dopamine does play a part in reward learning in fruit flies. Also it has been found that the rewarding effect of octopamine is due to its activating a set of dopaminergic neurons not previously accessed in the research. Plants Many plants, including a variety of food plants, synthesize dopamine to varying degrees. The highest concentrations have been observed in bananas—the fruit pulp of red and yellow bananas contains dopamine at levels of 40 to 50 parts per million by weight. Potatoes, avocados, broccoli, and Brussels sprouts may also contain dopamine at levels of 1 part per million or more; oranges, tomatoes, spinach, beans, and other plants contain measurable concentrations less than 1 part per million. The dopamine in plants is synthesized from the amino acid tyrosine, by biochemical mechanisms similar to those that animals use. It can be metabolized in a variety of ways, producing melanin and a variety of alkaloids as byproducts. The functions of plant catecholamines have not been clearly established, but there is evidence that they play a role in the response to stressors such as bacterial infection, act as growth-promoting factors in some situations, and modify the way that sugars are metabolized. The receptors that mediate these actions have not yet been identified, nor have the intracellular mechanisms that they activate. Dopamine consumed in food cannot act on the brain, because it cannot cross the blood–brain barrier. However, there are also a variety of plants that contain L-DOPA, the metabolic precursor of dopamine. [119] The highest concentrations are found in the leaves and bean pods of plants of the genus Mucuna, especially in Mucuna pruriens (velvet beans), which have been used as a source for L-DOPA as a drug. Another plant containing substantial amounts of L-DOPA is Vicia faba, the plant that produces fava beans (also known as "broad beans"). The level of L-DOPA in the beans, however, is much lower than in the pod shells and other parts of the plant. The seeds of Cassia and Bauhinia trees also contain substantial amounts of L-DOPA. In a species of marine green algae Ulvaria obscura, a major component of some algal blooms, dopamine is present in very high concentrations, estimated

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at 4.4% of dry weight. There is evidence that this dopamine functions as an anti-herbivore defense, reducing consumption by snails and isopods. As a Precursor for Melanin Melanins are a family of dark-pigmented substances found in a wide range of organisms. Chemically they are closely related to dopamine, and there is a type of melanin, known as dopamine-melanin, that can be synthesized by oxidation of dopamine via the enzyme tyrosinase. The melanin that darkens human skin is not of this type: it is synthesized by a pathway that uses L-DOPA as a precursor but not dopamine. However, there is substantial evidence that the neuromelanin that gives a dark color to the brain's substantia nigra is at least in part dopamine-melanin. Dopamine-derived melanin probably appears in at least some other biological systems as well. Some of the dopamine in plants is likely to be used as a precursor for dopamine-melanin. [125] The complex patterns that appear on butterfly wings, as well as black-and-white stripes on the bodies of insect larvae, are also thought to be caused by spatially structured accumulations of dopamine-melanin. History and Development Dopamine was first synthesized in 1910 by George Barger and James Ewens at Wellcome Laboratories in London, England and first identified in the human brain by Kathleen Montagu in 1957. It was named dopamine because it is a monoamine whose precursor in the Barger-Ewens synthesis is 3,4-dihydroxyphenylalanine (levodopa or L-DOPA). Dopamine's function as a neurotransmitter was first recognized in 1958 by Arvid Carlsson and Nils-Å ke Hillarp at the Laboratory for Chemical Pharmacology of the National Heart Institute of Sweden. Carlsson was awarded the 2000 Nobel Prize in Physiology or Medicine for showing that dopamine is not only a precursor of norepinephrine (noradrenaline) and epinephrine (adrenaline), but is also itself a neurotransmitter. Polydopamine Research motivated by adhesive polyphenolic proteins in mussels led to the discovery in 2007 that a wide variety of materials, if placed in a solution of


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dopamine at slightly basic pH, will become coated with a layer of polymerized dopamine, often referred to as polydopamine. This polymerized dopamine forms by a spontaneous oxidation reaction, and is formally a type of melanin. Synthesis usually involves reaction of dopamine hydrochloride with Tris as a base in water. The structure of polydopamine is unknown. Polydopamine coatings can form on objects ranging in size from nanoparticles to large surfaces. Polydopamine layers have chemical properties that have the potential to be extremely useful, and numerous studies have examined their possible applications. At the simplest level, they can be used for protection against damage by light, or to form capsules for drug delivery. At a more sophisticated level, their adhesive properties may make them useful as substrates for biosensors or other biologically active macromolecules. Cholecystokinin Cholecystokinin (CCK or CCK-PZ; from Greek chole, "bile"; cysto, "sac"; kinin, "move"; hence, move the bile-sac (gallbladder)) is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein. Cholecystokinin, previously called pancreozymin, is synthesized and secreted by enteroendocrine cells in the duodenum, the first segment of the small intestine. Its presence causes the release of digestive enzymes and bile from the pancreas and gallbladder, respectively, and also acts as a hunger suppressant. Structure The existence of CCK was first suggested in 1905 by the British physiologist Joy Simcha Cohen. It is a member of the gastrin/cholecystokinin family of peptide hormones and is very similar in structure to gastrin, another gastrointestinal hormone. CCK and gastrin share the same five C-terminal amino acids. CCK is composed of varying numbers of amino acids depending on post-translational modification of the 150-amino acid precursor, preprocholecystokinin. Thus, the CCK peptide hormone exists in several forms, each identified by the number of amino acids it contains, e.g., CCK58, CCK33, CCK22 and CCK8. CCK58 assumes a helix-turn-helix configuration. Biological activity resides in the C-terminus of the peptide. Most CCK peptides

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have a sulfate-group attached to a tyrosine located seven residues from the C-terminus. This modification is crucial for the ability of CCK to activate the cholecystokinin A receptor. Nonsulfated CCK peptides also occur, which consequently cannot activate the CCK-A receptor. Function CCK plays important physiologic roles both as a neuropeptide in the central nervous system and as a peptide hormone in the gut. It participates in a number of physiological processes such as digestion, satiety and anxiety. Gastrointestinal CCK is synthesized and released by enteroendocrine cells in the mucosal lining of the small intestine (mostly in the duodenum and jejunum), called I cells, neurons of the enteric nervous system, and neurons in the brain. It is released rapidly into the circulation in response to a meal. The greatest stimulator of CCK release is the presence of fatty acids and/or certain amino acids in the chyme entering the duodenum. In addition, release of CCK is stimulated by monitor peptide (released by pancreatic acinar cells), CCK-releasing protein (via paracrine signalling mediated by enterocytes in the gastric and intestinal mucosa), and acetylcholine (released by the parasympathetic nerve fibers of the vagus nerve). Once in the circulatory system, CCK has a relatively short half-life. Digestion CCK mediates digestion in the small intestine by inhibiting gastric emptying. It stimulates the acinar cells of the pancreas to release a juice rich in pancreatic digestive enzymes (hence an alternate name, pancreozymin) that catalyze the digestion of fat, protein, and carbohydrates. Thus, as the levels of the substances that stimulated the release of CCK drop, the concentration of the hormone drops as well. The release of CCK is also inhibited by somatostatin and pancreatic peptide. Trypsin, a protease released by pancreatic acinar cells, hydrolyzes CCK-releasing peptide and monitor peptide, in effect turning off the additional signals to secrete CCK. CCK also causes the increased production of hepatic bile, and stimulates the contraction of the gall bladder and the relaxation of the sphincter of Oddi


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(Glisson's sphincter), resulting in the delivery of bile into the duodenal part of the small intestine. Bile salts form amphipathic lipids, micelles that emulsify fats, aiding in their digestion and absorption. Satiety As a peptide hormone, CCK mediates satiety by acting on the CCK receptors distributed widely throughout the central nervous system. The mechanism for hunger suppression is thought to be a decrease in the rate of gastric emptying. CCK also has stimulatory effects on the vagus nerve, effects that can be inhibited by capsaicin. The stimulatory effects of CCK oppose those of ghrelin, which has been shown to inhibit the vagus nerve. The effects of CCK vary between individuals. For example, in rats, CCK administration significantly reduces hunger in adult males, but is slightly less effective in younger subjects, and even slightly less effective in females. The hunger-suppressive effects of CCK also are reduced in obese rats. Neurological CCK is found extensively throughout the central nervous system, with high concentrations found in the limbic system. CCK is synthesized as a 115 amino acid preprohormone, that is then converted into multiple isoforms. The predominant form of CCK in the central nervous system is the sulfated octapeptide, CCK-8S. Anxiogenic In both humans and rodents, studies clearly indicate that elevated CCK levels causes increased anxiety. The site of the anxiety-inducing effects of CCK seems to be central with specific targets being the basolateral amygdala, hippocampus, hypothalamus, peraqueductal grey, and cortical regions. Panicogenic The CCK tetrapeptide fragment CCK-4 (Trp-Met-Asp-Phe-NH2) reliably causes anxiety and panic attacks (panicogenic effect) when administered to humans and is commonly used in scientific research for this purpose of in order to test new anxiolytic drugs. Positron emission tomography visualization of regional cerebral blood flow in patients undergoing CCK-4 induced panic

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attacks show changes in the anterior cingulate claustrum-insular-amygdala region, and cerebellar vermis.

gyrus,

the

Hallucinogenic Several studies have implicated CCK as a cause of visual hallucinations in Parkinson’s disease. Mutations in CCK receptors in combination with mutated CCK genes potentiate this association. These studies also uncovered potential racial/ethnic differences in the distribution of mutated CCK genes. Interactions CCK has been shown to interact with the Cholecystokinin A receptor located mainly on pancreatic acinar cells and Cholecystokinin B receptor mostly in the brain and stomach. CCKB receptor also binds gastrin, a gastrointestinal hormone involved in stimulating gastric acid release and growth of the gastric mucosa. CCK has also been shown to interact with calcineurin in the pancreas. Calcineurin will go on to activate the transcription factors NFAT 1–3, which will stimulate hypertrophy and growth of the pancreas. CCK can be stimulated by a diet high in protein, or by protease inhibitors. CCK has been shown to interact with orexin neurons, which control appetite and wakefulness (sleep). CCK can have indirect effects on sleep regulation. CCK in the body cannot cross the blood-brain barrier, but certain parts of the hypothalamus and brainstem are not protected by the barrier. Neurotensin Neurotensin is a 13 amino acid neuropeptide that is implicated in the regulation of luteinizing hormone and prolactinrelease and has significant interaction with the dopaminergic system. Neurotensin was first isolated from extracts of bovinehypothalamus based on its ability to cause a visible vasodilation in the exposed cutaneous regions of anesthetized rats. Neurotensin is distributed throughout the central nervous system, with highest levels in the hypothalamus, amygdala and nucleus accumbens. It induces a variety of effects, including analgesia, hypothermia and increased locomotor activity. It is also involved in regulation of dopamine pathways. In the periphery, neurotensin is found in enteroendocrine cells of the small intestine, where it leads to secretion and smooth muscle contraction.


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Sequence and Biosynthesis Neurotensin shares significant sequence similarity in its 6 C-terminal amino acids with several other neuropeptides, including neuromedin N (which is derived from the same precursor). This C-terminal region is responsible for the full biological activity, the N-terminal portion having a modulatory role. The neurotensin/neuromedin N precursor can also be processed to produce large 125–138 amino acid peptides with the neurotensin or neuromedin N sequence at their C terminus. These large peptides appear to be less potent than their smaller counterparts, but are also less sensitive to degradation and may represent endogenous, long-lasting activators in a number of pathophysiological situations. The sequence of bovine neurotensin was determined to be pyroGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu-OH. Neurotensin is synthesized as part of a 169 or 170 amino acid precursor protein that also contains the related neuropeptide neuromedin N. The peptide coding domains are located in tandem near the carboxyl terminal end of the precursor and are bounded and separated by paired basic amino acid (lysine-arginine) processing sites. Clinical Significance Neurotensin is a potent mitogen for colorectal cancer. Neurotensin has been implicated in the modulation of dopamine signaling, and produces a spectrum of pharmacological effects resembling those of antipsychotic drugs, leading to the suggestion that neurotensin may be an endogenous neuroleptic. Neurotensin-deficient mice display defects in responses to several antipsychotic drugs consistent with the idea that neurotensin signaling is a key component underlying at least some antipsychotic drug actions. These mice exhibit modest defects in prepulse inhibition (PPI) of the startle reflex, a model that has been widely used to investigate antipsychotic drug action in animals. Antipsychotic drug administration augments PPI under certain conditions. Comparisons between normal and neurotensin-deficient mice revealed striking differences in the ability of different antipsychotic drugs to augment PPI. While the atypical

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antipsychotic drug clozapine augmented PPI normally in neurotensin-deficient mice, the conventional antipsychotic haloperidol and the newer atypical antipsychotic quetiapine were ineffective in these mice, in contrast to normal mice where these drugs significantly augmented PPI. These results suggest that certain antipsychotic drugs require neurotensin for at least some of their effects. Neurotensin-deficient mice also display defects in striatal activation following haloperidol, but not clozapine administration in comparison to normal wild type mice, indicating that striatal neurotensin is required for the full spectrum of neuronal responses to a subset of antipsychotic drugs. Neurotensin is an endogenous neuropeptide involved in thermoregulation that can induce hypothermia and neuroprotection in experimental models of cerebral ischemia. The neurotensin receptors are transmembrane receptors that bind the neurotransmitter neurotensin. Two of the receptors encoded by the NTSR1 and NTSR2 genes contain seven transmembrane helices and are G protein coupled. The third receptor has a single transmembrane domain and is encoded by the SORT1 gene. Glucagon-like Peptide-1 Glucagon-like peptide-1 (GLP-1) is a 30 amino acid long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon gene. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and proteolytic cleavage which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1 composes two α-helicesfrom amino acid position 13–20 and 24–35 separated by a linker region. Alongside glucose-dependent insulinotropic peptide (GIP), GLP-1 is the only known incretin describing its ability to decrease blood sugar levels in a glucose-dependent manner by enhancing the secretion of insulin. Beside the insulinotropic effects, GLP-1 has been associated with numerous regulatory and protective effects. Unlike GIP, the action of GLP-1 is preserved in patients


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with type 2 diabetes and substantial pharmaceutical research has therefore been directed towards the development of GLP-1-based treatment.

Figure 4. GLP-1 and diabetes

However, endogenous GLP-1 is rapidly degraded primarily by dipeptidyl peptidase-4 (DPP-4), but also neutral endopeptidase 24.11 (NEP 24.11) and renal clearance, resulting in a half-life of approximately 2 minutes. Consequently, only 10–15 % of GLP-1 reaches circulation intact leading to fasting plasma levels of only 0–15 pmol/L. To overcome this, GLP-1 receptor agonists and DPP-4 inhibitors have been developed to resist and reduce this activity, respectively. As opposed to common treatment agents such as insulin and sulphonylurea, GLP-1-based treatment has been associated with weight loss and lower hypoglycemia risks, two very important aspects of a life with type 2 diabetes. Gene Expression The proglucagon gene is expressed in several organs including the pancreas (α-cells of the islets of Langerhans), gut (intestinal enteroendocrine L-cells) and brain (caudal brainstem and hypothalamus). Pancreatic proglucagon gene expression is promoted upon fasting and hypoglycaemia induction and inhibited by insulin. Conversely, intestinal proglucagon gene expression is reduced during fasting and stimulated upon food consumption. In mammals, the transcription gives rise to identical mRNA in all three cell types, which is

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further translated to the 180 amino acid precursor called proglucagon. However, as a result of tissue-specific posttranslational processing mechanisms, different peptides are produced in the different cells.

Proglucagon Expression

In the pancreas (α-cells of the islets of Langerhans), proglucagon is cleaved by prohormone convertase (PC) 2 producing glicentin-related pancreatic peptide (GRPP), glucagon, intervening peptide-1 (IP-1) and major proglucagon fragment (MPGF). In the gut and brain, proglucagon is catalysed by PC 1/3 giving rise to glicentin, which may be further processed to GRPP and oxyntomodulin, GLP-1, intervening peptide-2 (IP-2) and glucagon-like peptide-2 (GLP-2). Initially, GLP-1 was thought to correspond to proglucagon (72–108) suitable with the N-terminal of the MGPF, but sequencing experiments of endogenous GLP-1 revealed a structure corresponding to proglucagon (78–107) from which two discoveries were found. Firstly, the full-length GLP-1 (1–37) was found to be catalysed by endopeptidase to the biologically active GLP-1 (7–37). Secondly, the glycine corresponding to proglucagon (108) was found to serve as a substrate for amidation of the C-terminal arginine resulting in the equally potent GLP-1 (7–36) amide. In humans, almost all (>80%) secreted GLP-1 is amidated, whereas a considerable part remains GLP-1 (7–37) in other species.


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Secretion GLP-1 is packaged in secretory granules and secreted into the hepatic portal system by the intestinal L-cells located primarily in the distal ileum and colon but also found in the jejunum and duodenum. The L-cells are open-type triangular epithelial cells directly in contact with the lumen and neuro-vascular tissue and are accordingly stimulated by various nutrient, neural and endocrine factors. GLP-1 is released in a biphasic pattern with an early phase after 10–15 minutes followed by a longer second phase after 30–60 minutes upon meal ingestion. As the majority of L-cells are located in the distal ileum and colon, the early phase is likely explained by neural signalling, gut peptides or neurotransmitters. Other evidence suggest that the amount of L-cells located in the proximal jejunum is sufficient to account for the early phase secretion through direct contact with luminal nutrients. Less controversially, the second phase is likely caused by direct stimulation of L-cells by digested nutrients. The rate of gastric emptying is therefore an important aspect to consider, as it regulates the entry of nutrients into the small intestines where the direct stimulation occurs. Interestingly, one of the actions of GLP-1 is to inhibit gastric emptying, thus slowing down its own secretion upon postprandial activation. Fasting plasma concentration of biologically active GLP-1 range between 0 and 15 pmol/L in humans and is increased 2- to 3-fold upon food consumption depending on meal size and nutrient composition. Individual nutrients, such as fatty acids, essential amino acids and dietary fibre have also shown to stimulate GLP-1 secretion. Sugars have been associated with various signalling pathways, which initiate depolarisation of the L-cell membrane causing an elevated concentration of cytosolic Ca2+ which in turn induce GLP-1 secretion. Fatty acids have been associated with the mobilisation of intracellular Ca2+ stores and subsequently release of Ca2+ into the cytosol. The mechanisms of protein-triggered GLP-1 secretion are less clear, but the amino acid proportion and composition appear important to the stimulatory effect.

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Degradation Once secreted, GLP-1 is extremely susceptible to the catalytic activity of the proteolytic enzyme dipeptidyl peptidase-4 (DPP-4). Specifically, DPP-4 cleaves the peptide bondbetween Ala8-Glu9 resulting in the abundant GLP-1 (9–36) amide constituting 60–80 % of total GLP-1 in circulation. DPP-4 is widely expressed in multiple tissues and cell types and exists in both a membrane-anchored and soluble circulating form. Notably, DPP-4 is expressed on the surface of endothelial cells, including those located directly adjacent to GLP-1 secretion sites. Consequently, less than 25% of secreted GLP-1 is estimated to leave the gut intact. Additionally, presumably due to the high concentration of DPP-4found on hepatocytes, 40–50% of the remaining active GLP-1 is degraded across the liver. Conclusively, only 10–15% of secreted GLP-1 reaches circulation intact due to the activity of DPP-4. Neutral endopeptidase 24.11 (NEP 24.11) is a membrane-bound zinc metallopeptidase widely expressed in several tissues, but found in particularly high concentrations in the kidneys, which is also identified accountable for the rapid degradation of GLP-1. It primarily cleaves peptides at the N-terminal side of aromatic amino acids or hydrophobic amino acids and is estimated to contribute by up to 50% of the GLP-1 degradation. However, the activity only becomes apparent once the degradation of DPP-4 has been prevented, as the majority of GLP-1 reaching the kidneys have already been processed by DPP-4. Similarly, renal clearance appear more significant for the elimination of already inactivated GLP-1. The resulting half-life of active GLP-1 is approximately 2 minutes, which is however sufficient to activate GLP-1 receptors. Physiological Functions GLP-1 possesses several physiological properties making it (and its functional analogs) a subject of intensive investigation as a potential treatment of diabetes mellitus, as these actions induce long-term improvements along with the immediate effects. Although reduced GLP-1 secretion has previously been associated with attenuated incretin effect in patients with type 2 diabetes, it is now granted that GLP-1 secretion in patients with type 2 diabetes does not


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differ from healthy subjects. The most noteworthy effect of GLP-1 is its ability to promote insulin secretion in a glucose-dependent manner. As GLP-1 binds to GLP-1 receptors expressed on the pancreatic β cells, the receptors couples to G-protein subunits and activates adenylate cyclase that increases the production of cAMP from ATP. Subsequently, activation of secondary pathways, including PKA and Epac2, alters the ion channel activity causing elevated levels of cytosolic Ca2+ that enhances exocytosis of insulin-containing granules. During the process, influx of glucose ensures sufficient ATP to sustain the stimulatory effect. Additionally, GLP-1 ensures the β cell insulin stores are replenished to prevent exhaustion during secretion by promoting insulin gene transcription, mRNA stability and biosynthesis. GLP-1 evidently also in creases β cell mass by promoting proliferation and neogenesis while inhibiting apoptosis. As both type 1 and 2 diabetes are associated with reduction of functional β cells, this effect is highly interesting regarding diabetes treatment. Considered almost as important to the insulin secretion effects, GLP-1 has shown to inhibit glucagon secretion at glucose levels above fasting levels. Critically, this does not affect the glucagon response to hypoglycaemia as this effect is also glucose-dependent. The inhibitory effect is presumably mediated indirectly through somatostatin secretion, but a direct effect cannot be completely excluded. In the brain, GLP-1 receptor activation has been linked with neurotrophic effects including neurogenesis and neuroprotective effects including reduced necrotic and apoptotic signalling and cell death. In the diseased brain, GLP-1 receptor agonist treatment is associated with protection against a range of experimental disease models such as Parkinson's Disease, Alzheimer's Disease, Stroke, Traumatic Brain Injury, and Multiple Sclerosis. In accordance with the expression of GLP-1 receptor on brainstem and hypothalamus, GLP-1 has shown to promote satiety and thereby reduce food and water intake. Consequently, diabetic subjects treated with GLP-1 receptor agonists often experience weight loss as opposed to the weight gain commonly induced with other treatment agents. In the stomach, GLP-1 inhibits gastric emptying, acid secretion and motility

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collectively decreasing appetite. By decelerating gastric emptying GLP-1 reduce postprandial glucose excursion which is another attractive property regarding diabetes treatment. However, these gastrointestinal activities are also the reason why subjects treated with GLP-1-based agents occasionally experience nausea. GLP-1 has also shown signs of carrying out protective and regulatory effects in numerous other tissues, including heart, tongue, adipose, muscles, bones, kidneys, liver and lungs. The glucagon-like peptide 1 receptor (GLP1R) is a receptor protein found on beta cells of the pancreas. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of G protein-coupled receptors. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, [8] and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism. Epinephrine Epinephrine, also known as adrenalin or adrenaline, is a hormone, neurotransmitter, and medication. Epinephrine is normally produced by both the adrenal glands and certain neurons. It plays an important role in the fight-or-flight response by increasing blood flow to muscles, output of the heart, pupil dilation, and blood sugar. It does this by binding to alpha and beta receptors. It is found in many animals and some single cell organisms. Napoleon Cybulski first isolated epinephrine in 1895.

As a medication, it is used to treat a number of conditions including anaphylaxis, cardiac arrest, and superficial bleeding. Inhaledepinephrine may be used to improve the symptoms of croup. It may also be used for asthma


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when other treatments are not effective. It is given intravenously, by injection into a muscle, by inhalation, or by injection just under the skin. Common side effects include shakiness, anxiety, and sweating. A fast heart rate and high blood pressure may occur. Occasionally it may result in an abnormal heart rhythm. While the safety of its use during pregnancy and breastfeeding is unclear, the benefits to the mother must be taken into account. Physiological Effects The adrenal medulla is a minor contributor to total circulating catecholamines (L-DOPA is at a higher concentration in the plasma), [11] though it contributes over 90% of circulating epinephrine. Little epinephrine is found in other tissues, mostly in scattered chromaffin cells. Following adrenalectomy, epinephrine disappears below the detection limit in the blood stream. The adrenals contribute about 7% of circulating norepinephrine, most of which is a spill over from neurotransmission with little activity as a hormone. Pharmacological doses of epinephrine stimulate α1, α2, β1, β2, and β3 adrenoceptors of the sympathetic nervous system. Sympathetic nerve receptors are classified as adrenergic, based on their responsiveness to adrenaline. The term "adrenergic" is often misinterpreted in that the main sympathetic neurotransmitter is norepinephrine (noradrenaline), rather than epinephrine, as discovered by Ulf von Euler in 1946. Epinephrine does have a β2 adrenoceptor-mediated effect on metabolism and the airway, there being no direct neural connection from the sympathetic ganglia to the airway. The concept of the adrenal medulla and the sympathetic nervous system being involved in the flight, fight and fright response was originally proposed by Cannon. But the adrenal medulla, in contrast to the adrenal cortex, is not required for survival. In adrenalectomized patients hemodynamic and metabolic responses to stimuli such as hypoglycemia and exercise remain normal. Exercise One physiological stimulus to epinephrine secretion is exercise. This was

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first demonstrated using the denervated pupil of a cat as an assay, later confirmed using a biological assay on urine samples. Biochemical methods for measuring catecholamines in plasma were published from 1950 onwards. Although much valuable work has been published using fluorimetric assays to measure total catecholamine concentrations, the method is too non-specific and insensitive to accurately determine the very small quantities of epinephrine in plasma. The development of extraction methods and enzyme-isotope derivate radio-enzymatic assays (REA) transformed the analysis down to a sensitivity of 1 pg for epinephrine. Early REA plasma assays indicated that epinephrine and total catecholamines rise late in exercise, mostly when anaerobic metabolism commences. During exercise the epinephrine blood concentration rises partially from increased secretion from the adrenal medulla and partly from decreased metabolism because of reduced hepatic blood flow. Infusion of epinephrine to reproduce exercise circulating concentrations of epinephrine in subjects at rest has little haemodynamic effect, other than a small β2-mediated fall in diastolic blood pressure. Infusion of epinephrine well within the physiological range suppresses human airway hyper-reactivity sufficiently to antagonize the constrictor effects of inhaled histamine. A link between what we now know as the sympathetic system and the lung was shown in 1887 when Grossman showed that stimulation of cardiac accelerator nerves reversed muscarine induced airway constriction. In elegant experiments in the dog, where the sympathetic chain was cut at the level of the diaphragm, Jackson showed that there was no direct sympathetic innervation to the lung, but that bronchoconstriction was reversed by release of epinephrine from the adrenal medulla. An increased incidence of asthma has not been reported for adrenalectomized patients; those with a predisposition to asthma will have some protection from airway hyper-reactivity from their corticosteroid replacement therapy. Exercise induces progressive airway dilation in normal subjects that correlates with work load and is not prevented by beta blockade. The progressive dilation of the airway with increasing exercise is mediated by a progressive reduction in resting vagal tone. Beta blockade with propranolol causes a rebound in airway resistance after exercise


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in normal subjects over the same time course as the bronchoconstriction seen with exercise induced asthma. The reduction in airway resistance during exercise reduces the work of breathing. Emotional Response Every emotional response has a behavioral component, an autonomic component, and a hormonal component. The hormonal component includes the release of epinephrine, an adrenomedullary response that occurs in response to stress and that is controlled by the sympathetic nervous system. The major emotion studied in relation to epinephrine is fear. In an experiment, subjects who were injected with epinephrine expressed more negative and fewer positive facial expressions to fear films compared to a control group. These subjects also reported a more intense fear from the films and greater mean intensity of negative memories than control subjects. The findings from this study demonstrate that there are learned associations between negative feelings and levels of epinephrine. Overall, the greater amount of epinephrine is positively correlated with an arousal state of negative feelings. These findings can be an effect in part that epinephrine elicits physiological sympathetic responses including an increased heart rate and knee shaking, which can be attributed to the feeling of fear regardless of the actual level of fear elicited from the video. Although studies have found a definite relation between epinephrine and fear, other emotions have not had such results. In the same study, subjects did not express a greater amusement to an amusement film nor greater anger to an anger film. Similar findings were also supported in a study that involved rodent subjects that either were able or unable to produce epinephrine. Findings support the idea that epinephrine does have a role in facilitating the encoding of emotionally arousing events, contributing to higher levels of arousal due to fear. Memory It has been found that adrenergic hormones, such as epinephrine, can produce retrograde enhancement of long-term memory in humans. The release of epinephrine due to emotionally stressful events, which is endogenous epinephrine, can modulate memory consolidation of the events, ensuring

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memory strength that is proportional to memory importance. Post-learning epinephrine activity also interacts with the degree of arousal associated with the initial coding. There is evidence that suggests epinephrine does have a role in long-term stress adaptation and emotional memory encoding specifically. Epinephrine may also play a role in elevating arousal and fear memory under particular pathological conditions including post-traumatic stress disorder. Overall, "Extensive evidence indicates that epinephrine (EPI) modulates memory consolidation for emotionally arousing tasks in animals and human subjects.” Studies have also found that recognition memory involving epinephrine depends on a mechanism that depends on β adrenoceptors. Epinephrine does not readily cross the blood–brain barrier, so its effects on memory consolidation are at least partly initiated by β adrenoceptors in the periphery. Studies have found that sotalol, a β adrenoceptor antagonist that also does not readily enter the brain, blocks the enhancing effects of peripherally administered epinephrine on memory. These findings suggest that β adrenoceptors are necessary for epinephrine to have an effect on memory consolidation. For noradrenaline to be acted upon by PNMT in the cytosol, it must first be shipped out of granules of the chromaffin cells. This may occur via the catecholamine-H+ exchanger VMAT1. VMAT1 is also responsible for transporting newly synthesized adrenaline from the cytosol back into chromaffin granules in preparation for release. In liver cells, adrenaline binds to the β adrenergic receptor, which changes conformation and helps Gs, a G protein, exchange GDP to GTP. This trimeric G protein dissociates to Gs alpha and Gs beta/gamma subunits. Gs alpha binds to adenyl cyclase, thus converting ATP into cyclic AMP. Cyclic AMP binds to the regulatory subunit of protein kinase A: Protein kinase A phosphorylates phosphorylase kinase. Meanwhile, Gs beta/gamma binds to the calcium channel and allows calcium ions to enter the cytoplasm. Calcium ions bind to calmodulin proteins, a protein present in all eukaryotic cells, which then binds to phosphorylase kinase and finishes its activation. Phosphorylase kinase phosphorylates glycogen phosphorylase, which then phosphorylates glycogen and converts it to glucose-6-phosphate.


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Pathology Increased epinephrine secretion is observed in pheochromocytoma, hypoglycemia, myocardial infarction and to a lesser degree in benign essential familial tremor. A general increase in sympathetic neural activity is usually accompanied by increased adrenaline secretion, but there is selectivity during hypoxia and hypoglycaemia, when the ratio of adrenaline to noradrenaline is considerably increased. Therefore, there must be some autonomy of the adrenal medulla from the rest of the sympathetic system. Myocardial infarction is associated with high levels of circulating epinephrine and norepinephrine, particularly in cardiogenic shock. Benign familial tremor (BFT) is responsive to peripheral β adrenergic blockers and β2-stimulation is known to cause tremor. Patients with BFT were found to have increased plasma epinephrine, but not norepinephrine. Low, or absent, concentrations of epinephrine can be seen in autonomic neuropathy or following adrenalectomy. Failure of the adrenal cortex, as with Addisons disease, can suppress epinephrine secretion as the activity of the synthesing enzyme, phenylethanolamine-N-methyltransferase, depends on the high concentration of cortisol that drains from the cortex to the medulla. Terminology Epinephrine is the pharmaceutical's United States Adopted Name and International Nonproprietary Name, though the name adrenaline is frequently used. The term epinephrinewas coined by the pharmacologist John Abel (from the Greek for "on top of the kidneys"), who used the name to describe the extracts he prepared from the adrenal glands as early as 1897. In 1901, Jokichi Takamine patented a purified adrenal extract, and called it "adrenalin" (from the Latin for "on top of the kidneys"), which was trademarked by Parke, Davis & Co in the U.S. In the belief that Abel's extract was the same as Takamine's, a belief since disputed, epinephrine became the generic name in the U.S. The British Approved Name and European Pharmacopoeia term for this drug is adrenaline and is indeed now one of the few differences between the INN and BAN systems of names. Among American health professionals and scientists, the term epinephrine is

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used over adrenaline. However, pharmaceuticals that mimic the effects of epinephrine are often called adrenergics, and receptors for epinephrine are called adrenergic receptors or adrenoceptors. Mechanism of Action Physiologic responses to epinephrine by organ Organ

Effects

Heart

Increases heart rate; contractility; conduction across AV node

Lungs

Increases respiratory rate; bronchodilation

Systemic Liver

Vasoconstriction and vasodilation Stimulates glycogenolysis

Systemic

Triggers lipolysis

Systemic

Muscle contraction

As a hormone, epinephrine acts on nearly all body tissues. Its actions vary by tissue type and tissue expression of adrenergic receptors. For example, high levels of epinephrine causes smooth musclerelaxation in the airways but causes contraction of the smooth muscle that lines most arterioles. Epinephrine acts by binding to a variety of adrenergic receptors. Epinephrine is a nonselective agonist of all adrenergic receptors, including the major subtypes α1, α2, β1, β2, and β3 Epinephrine's binding to these receptors triggers a number of metabolic changes. Binding to α-adrenergic receptors inhibits insulin secretion by the pancreas, stimulates glycogenolysis in the liverand muscle, and stimulates glycolysis and inhibits insulin-mediated glycogenesis in muscle. β adrenergic receptor binding triggers glucagon secretion in the pancreas, increased adrenocorticotropic hormone (ACTH) secretion by the pituitary gland, and increased lipolysis by adipose tissue. Together, these effects lead to increased blood glucose and fatty acids, providing substrates for energy production within cells throughout the body. Its actions are to increase peripheral resistance via α1 receptor-dependent vasoconstriction and to increase cardiac output via its binding to β1 receptors.


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The goal of reducing peripheral circulation is to increase coronary and cerebral perfusion pressures and therefore increase oxygen exchange at the cellular level. While epinephrine does increase aortic, cerebral, and carotid circulation pressure, it lowers carotid blood flow and end-tidal CO2 or ETCO2 levels. It appears that epinephrine may be improving macrocirculation at the expense of the capillary beds where actual perfusion is taking place. Measurement in Biological Fluids Epinephrine may be quantified in blood, plasma or serum as a diagnostic aid, to monitor therapeutic administration, or to identify the causative agent in a potential poisoning victim. Endogenous plasma epinephrine concentrations in resting adults are normally less than 10 ng/L, but may increase by 10-fold during exercise and by 50-fold or more during times of stress. Pheochromocytoma patients often have plasma adrenaline levels of 1000–10,000 ng/L. Parenteral administration of epinephrine to acute-care cardiac patients can produce plasma concentrations of 10,000 to 100,000 ng/L. Biosynthesis and Regulation In chemical terms, epinephrine is one of a group of monoamines called the catecholamines. It is produced in some neurons of the central nervous system, and in the chromaffin cells of the adrenal medulla from the amino acids phenylalanine and tyrosine Epinephrine is synthesized in the medulla of the adrenal gland in an enzymatic pathway that converts the amino acid tyrosine into a series of intermediates and, ultimately, epinephrine. Tyrosine is first oxidized to L-DOPA, which is subsequently decarboxylated to give dopamine. Oxidation gives norepinephrine. The final step in epinephrine biosynthesis is the methylation of the primary amine of norepinephrine. This reaction is catalyzed by the enzyme phenylethanolamine N-methyltransferase (PNMT) which utilizes S-adenosyl methionine (SAMe) as the methyl donor. While PNMT is found primarily in the cytosol of the endocrine cells of the adrenal medulla (also known as chromaffin cells), it has been detected at low levels in both the heart and brain.

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The biosynthesis of adrenaline involves a series of enzymatic reactions


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Biosynthetic pathways for catecholamines and trace amines in the human brain

Epinephrine is produced in a small group of neurons in the human brain via the metabolic pathway shown above

Regulation The major physiologic triggers of adrenaline release center upon stresses, such as physical threat, excitement, noise, bright lights, and high ambient temperature. All of these stimuli are processed in the central nervous system. Adrenocorticotropic hormone (ACTH) and the sympathetic nervous system stimulate the synthesis of adrenaline precursors by enhancing the activity of

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tyrosine hydroxylase and dopamine β-hydroxylase, two key enzymes involved in catecholamine synthesis. ACTH also stimulates the adrenal cortex to release cortisol, which increases the expression of PNMT in chromaffin cells, enhancing adrenaline synthesis. This is most often done in response to stress. The sympathetic nervous system, acting via splanchnic nerves to the adrenal medulla, stimulates the release of adrenaline. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and, thus, the release of adrenaline (and noradrenaline) into the bloodstream. Unlike many other hormones adrenaline (as with other catecholamines) does not exert negative feedback to down-regulate its own synthesis.[75] Abnormally elevated levels of adrenaline can occur in a variety of conditions, such as surreptitious epinephrine administration, pheochromocytoma, and other tumors of the sympathetic ganglia. Its action is terminated with reuptake into nerve terminal endings, some minute dilution, and metabolism by monoamine oxidase and catechol-O-methyl transferase. Extracts of the adrenal gland were first obtained by Polish physiologist Napoleon Cybulski in 1895. These extracts, which he called nadnerczyna ("adrenalin"), contained adrenaline and other catecholamines. American ophthalmologist William H. Bates discovered adrenaline's usage for eye surgeries prior to 20 April 1896 Japanese chemist Jokichi Takamine and his assistant Keizo Uenaka independently discovered adrenaline in 1900. In 1901, Takamine successfully isolated and purified the hormone from the adrenal glands of sheep and oxen. Adrenaline was first synthesized in the laboratory by Friedrich Stolz and Henry Drysdale Dakin, independently, in 1904. Society and Culture Adrenaline Junkie An adrenaline junkie is somebody who engages in sensation-seeking behavior through "the pursuit of novel and intense experiences without regard


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for physical, social, legal or financial risk". Such activities include extreme and risky sports, substance abuse, unsafe sex, and crime. The term relates to the increase in circulating levels of adrenaline during physiological stress. Such an increase in the circulating concentration of adrenaline is secondary to activation of the sympathetic nerves innervating the adrenal medulla, as it is rapid and not present in animals where the adrenal gland has been removed. Although such stress triggers adrenaline release, it also activates many other responses within the central nervous system reward system which drives behavioral responses, so while the circulating adrenaline concentration is present, it may not drive behavior. Nevertheless, adrenaline infusion alone does increase alertness and has roles in the brain including the augmentation of memory consolidation. Strength Adrenaline has been implicated in feats of great strength, often occurring in times of crisis. For example, there are stories of a parent lifting part of a car when their child is trapped underneath. Serotonin Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract (GI tract), blood platelets, and the central nervous system (CNS) of animals, including humans. It is popularly thought to be a contributor to feelings of well-being and happiness.

Approximately 90% of the human body's total serotonin is located in the enterochromaffin cells in the GI tract, where it is used to regulate intestinal movements. The serotonin is secreted luminally and basolaterally which leads to increased serotonin uptake by circulating platelets and activation after stimulation, which gives increased stimulation of myenteric neurons and gastrointestinal motility. The remainder is synthesized in serotonergic neurons

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of the CNS, where it has various functions. These include the regulation of mood, appetite, and sleep. Serotonin also has some cognitive functions, including memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants. Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they release serotonin, where it can serve as a vasoconstrictorand/or a vasodilator while regulating hemostasis and blood clotting. In high concentrations, serotonin acts as a vasoconstrictor by contracting endothelial smooth muscle directly or by potentiating the effects of other vasoconstrictors (e.g. angiotensin II, norepinephrine). The vasoconstrictive property is mostly seen in pathologic states affecting the endothelium such as atherosclerosis or chronic hypertension. In physiologic states, vasodilation occurs through the serotonin mediated release of nitric oxide from endothelial cells. Additionally, it inhibits the release of norepinephrine from adrenergic nerves. Serotonin is also a growth factor for some types of cells, which may give it a role in wound healing. There are various serotonin receptors. Serotonin is metabolized mainly to 5-HIAA, chiefly by the liver. Metabolism involves first oxidation by monoamine oxidase to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase to 5-HIAA, the indole acetic acid derivative. The latter is then excreted by the kidneys. Aside from mammals it is found in all bilateral animals including worms and insects, as well as in fungi and plants. Serotonin's presence in insect venoms and plant spines serves to cause pain, which is a side-effect of serotonin injection. Serotonin is produced by pathogenic amoebae, and its effect in the human gut is diarrhea. Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds. Functions Serotonin is a neurotransmitter and is found in all bilateral animals including insects. [18] Serotonin is also present in plants (phytoserotonin).


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Perception of Resource Availability Serotonin mediates the animal's perceptions of resource; In less complex animals, such as some invertebrates, resources simply mean food availability. In plants serotonin synthesis seems to be associated with stress signals. In more complex animals, such as arthropods and vertebrates, resources also can mean social dominance. In response to the perceived abundance or scarcity of resources, an animal's growth, reproduction or mood may be elevated or lowered. This may somewhat depend on how much serotonin the organism has at its disposal. Cellular Effects Receptors The 5-HT receptors, the receptors for serotonin, are located on the cell membrane of nerve cells and other cell types in animals, and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and hallucinogenic drugs. Except for the 5-HT3 receptor, a ligand-gated ion channel, all other 5-HT receptors are G-protein-coupled receptors (also called seven-transmembrane, or heptahelical receptors) that activate an intracellular second messenger cascade. Termination Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is accomplished through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake, including cocaine, dextromethorphan (an antitussive), tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). A 2006 study conducted by the University of Washington suggested that a newly discovered monoamine transporter, known as PMAT, may account for "a significant percentage of 5-HT clearance". Contrasting with the high-affinity SERT, the PMAT has been identified as a low-affinity transporter, with an apparent Km of 114 micromoles/l for serotonin; approximately 230 times higher than that of SERT. However, the PMAT, despite its relatively low serotonergic affinity, has a considerably higher transport 'capacity' than SERT, "resulting in roughly comparable uptake

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efficiencies to SERT in heterologous expression systems." The study also suggests some SSRIs, such as fluoxetine and sertraline anti-depressants, inhibit PMAT but at IC50 values which surpass the therapeutic plasma concentrations by up to four orders of magnitude. Therefore, SSRI monotherapy is "ineffective" in PMAT inhibition. At present, no known pharmaceuticals are known to appreciably inhibit PMAT at normal therapeutic doses. The PMAT also suggestively transports dopamine and norepinephrine, albeit at Km values even higher than that of 5-HT (330–15,000 μmoles/L). Serotonylation Serotonin can also signal through a nonreceptor mechanism called serotonylation, in which serotonin modifies proteins. This process underlies serotonin's effects upon platelet-forming cells (thrombocytes) in which it links to the modification of signaling enzymes called GTPases that then trigger the release of vesicle contents by exocytosis. A similar process underlies the pancreatic release of insulin. The effects of serotonin upon vascular smooth muscle tone (this is the biological function from which serotonin originally got its name) depend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells. Binding profile of serotonin Receptor Ki(nM)

Receptor function

5-HT1 receptor family signals via Gi/o inhibition of adenylyl cyclase.

5-HT1A

3.17

Memory (agonists ↓); learning (agonists ↓); anxiety (agonists ↓); depression (agonists ↓); positive, negative, and cognitive symptoms of schizophrenia (partial agonists ↓); analgesia (agonists ↑); aggression (agonists ↓); dopamine release in the prefrontal cortex (agonists ↑); serotonin release and synthesis (agonists ↓)

5-HT1B

4.32

Vasoconstriction (agonists ↑); aggression (agonists ↓); bone mass (↓). Serotonin autoreceptor.


5-HT1D

5.03

5-HT1E

7.53

5-HT1F

10

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Vasoconstriction (agonists ↑)

5-HT2 receptor family signals via Gq activation of phospholipase C.

5-HT2A

11.55

Psychedelia (agonists ↑); depression (agonists & antagonists ↓); anxiety (antagonists ↓); positive and negative symptoms of schizophrenia (antagonists ↓); norepinephrine release from the locus coeruleus (antagonists ↑); glutamate release in the prefrontal cortex (agonists ↑); urinary bladder contractions (agonists ↑)

5-HT2B

8.71

Cardiovascular functioning (agonists increase risk of pulmonary hypertension), empathy (via the spindle neurons or Von Economo neurons)

5.02

Dopamine release into the mesocorticolimbic pathway (agonists ↓); acetylcholine release in the prefrontal cortex (agonists ↑); appetite (agonists ↓); antipsychotic effects (agonists ↑); antidepressant effects (agonists & antagonists ↑)

5-HT2C

Other 5-HT receptors 5-HT3

593

Emesis (agonists ↑); anxiolysis (antagonists ↑).

5-HT4

125.89

Movement of food across the GI tract (agonists ↑); memory & learning (agonists ↑); antidepressant effects (agonists ↑). Signalling via Gαs activation of adenylyl cyclase.

5-HT5A

251.2

Memory consolidation. Signals via Gi/o inhibition of adenylyl cyclase.

5-HT6

98.41

Cognition (antagonists ↑); antidepressant effects (agonists & antagonists ↑); anxiogenic effects (antagonists). Gs signalling via activating adenylyl cyclase.

5-HT7

8.11

Cognition (antagonists ↑); antidepressant effects (antagonists ↑). Acts by Gs signalling via activating adenylyl cyclase.

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Nervous System The neurons of the raphe nuclei are the principal source of 5-HT release in the brain. There are nine raphe nuclei, designated B1-B9, which contain the majority of serotonin-containing neurons (some scientists chose to group the nuclei raphes lineares into one nucleus), all of which are located along the midline of the brainstem, and centered on the reticular formation. Axons from the neurons of the raphe nuclei form a neurotransmitter system reaching almost every part of the central nervous system. Axons of neurons in the lower raphe nuclei terminate in the cerebellum and spinal cord, while the axons of the higher nuclei spread out in the entire brain. Ultrastructure and Function The serotonin nuclei may also be divided into two main groups, the rostral and caudal containing three and four nuclei respectively. The rostral group consists of the caudal linear nuclei (B8), the dorsal raphe nuclei (B6 and B7) and the median raphe nuclei (B5, B8 and B9), that project into multiple cortical and subcortical structures. The caudal group consists of the nucleus raphe magnus (B3), raphe obscurus nucleus (B2), raphe pallidus nucleus (B1), and lateral medullary reticular formation, that project into the brainstem. Serotonergic pathway are involved in sensorimotor function, with pathways projecting both into cortical (Dorsal and Median Raphe Nuclei), subcortical, and spinal areas involved in motor activity. Pharmacological manipulation suggest that serotonergic activity increases with motor activity, while firing rates of serotonergic neurons increase with intense visual stimuli. The descending projections form a pathway that inhibits pain called the "descending inhibitory pathway" that may be relevant to disorder such as fibromyalgia, migraine and other pain disorders, and the efficacy of antidepressants in them. Serotonergic projections from the caudal nuclei are involved in regulating mood, emotion and hypo or hyperserotonergic states may be involved in depression and sickness behavior. Microanatomy Serotonin is released into the synapse, or space between neurons, and


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diffuses over a relatively wide gap (>20 µm) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons. When humans smell food, dopamine is released to increase the appetite. But, unlike in worms, serotonin does not increase anticipatory behaviour in humans; instead, the serotonin released while consuming activates 5-HT2C receptors on dopamine-producing cells. This halts their dopamine release, and thereby serotonin decreases appetite. Drugs that block 5-HT2C receptors make the body unable to recognize when it is no longer hungry or otherwise in need of nutrients, and are associated with weight gain, especially in people with a low number of receptors. The expression of 5-HT2C receptors in the hippocampus follows a diurnal rhythm, just as the serotonin release in the ventromedial nucleus, which is characterised by a peak at morning when the motivation to eat is strongest. The amount of food that an animal acquires depends not only on food availability but also on the animal's ability to compete with others. This is especially true for social animals, where the stronger individuals might steal food from the weaker (this is not to say some non-social animals do not concern themselves with the needs of others or steal food from others). Thus, serotonin is involved not only in the perception of food availability but also in social rank. In macaques, alpha males have twice the level of serotonin released in the brain than subordinate males and females (as measured by the levels of 5-Hydroxyindoleacetic acid (5-HIAA) in the cerebro-spinal fluid). Dominance status and cerebro-serotonin levels appear to be positively correlated. When dominant males were removed from such groups, subordinate males begin competing for dominance. Once new dominance hierarchies were established, serotonin levels of the new dominant individuals also increased to double those in subordinate males and females. The reason why serotonin levels are only high in dominant males but not dominant females has not yet been established. In humans, levels of 5-HT1A receptor activation in the brain show negative correlation with aggression, and a mutation in the gene that codes for the 5-HT2A receptor may double the risk of suicide for those with that genotype. Serotonin in the brain is not usually degraded after use, but is collected by

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serotonergic neurons by serotonin transporters on their cell surfaces. Studies have revealed nearly 10% of total variance in anxiety-related personality depends on variations in the description of where, when and how many serotonin transporters the neurons should deploy. Psychological Influences Serotonin has been implicated in cognition, mood, anxiety and psychosis, but strong clarity has not been achieved. Outside the Nervous System In the Digestive Tract (emetic) The gut is surrounded by enterochromaffin cells, which release serotonin in response to food in the lumen. This makes the gut contract around the food. Platelets in the veins draining the gut collect excess serotonin. If irritants are present in the food, the enterochromaffin cells release more serotonin to make the gut move faster, i.e., to cause diarrhea, so the gut is emptied of the noxious substance. If serotonin is released in the blood faster than the platelets can absorb it, the level of free serotonin in the blood is increased. This activates 5-HT3 receptors in the chemoreceptor trigger zone that stimulate vomiting. The enterochromaffin cells not only react to bad food but are also very sensitive to irradiation and cancer chemotherapy. Drugs that block 5HT3 are very effective in controlling the nausea and vomiting produced by cancer treatment, and are considered the gold standard for this purpose. Bone Metabolism In mice and humans, alterations in serotonin levels and signalling have been shown to regulate bone mass. Mice that lack brain serotonin have osteopenia, while mice that lack gut serotonin have high bone density. In humans, increased blood serotonin levels have been shown to be significant negative predictor of low bone density. Serotonin can also be synthesized, albeit at very low levels, in the bone cells. It mediates its actions on bone cells using three different receptors. Through 5-HT1B receptors, it negatively regulates bone mass, while it does so positively through 5-HT2B receptors and 5-HT2C receptors. There is very delicate balance between physiological role of gut


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serotonin and its pathology. Increase in the extracellular content of serotonin results in a complex relay of signals in the osteoblasts culminating in FoxO1/ Creb and ATF4 dependent transcriptional events. These studies have opened a new area of research in bone metabolism that can be potentially harnessed to treat bone mass disorders. Organ Development Since serotonin signals resource availability it is not surprising that it affects organ development. Many human and animal studies have shown that nutrition in early life can influence, in adulthood, such things as body fatness, blood lipids, blood pressure, atherosclerosis, behavior, learning and longevity. Rodent experiment shows that neonatal exposure to SSRI's makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes, which are reversed by treatment with antidepressants. By treating normal and knockout mice lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period. Human serotonin can also act as a growth factor directly. Liver damage increases cellular expression of 5-HT2A and 5-HT2B receptors, mediating liver compensatory regrowth (see Liver § Regeneration and transplantation) Serotonin present in the blood then stimulates cellular growth to repair liver damage. 5HT2B receptors also activate osteocytes, which build up bone. However, serotonin also inhibits osteoblasts, through 5-HT1B receptors. Cardiovascular Growth Factor Serotonin, in addition, evokes endothelial nitric oxide synthase activation and stimulates, through a 5-HT1B receptor-mediated mechanism, the phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures. In blood, serotonin is collected from plasma by platelets, which store it. It is thus active wherever platelets bind in damaged tissue, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic (growth factor), to aid healing.

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Pharmacology Several classes of drugs target the 5-HT system, including some antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs, as well as the psychedelic drugsand empathogens. Psychedelic Drugs The psychedelic drugs psilocin/psilocybin, DMT, mescaline, psychedelic mushroom and LSD are agonists, primarily at 5HT2A/2C receptors. The empathogen-entactogenMDMA releases serotonin from synaptic vesicles of neurons. Antidepressants Drugs that alter serotonin levels are used in treating depression, generalized anxiety disorder and social phobia. Monoamine oxidase inhibitors (MAOIs) prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive emergency triggered by foods with high tyramine content, and certain drugs. Some drugs inhibit the re-uptake of serotonin, making it stay in the synaptic cleft longer. The tricyclic antidepressants (TCAs) inhibit the reuptake of both serotonin and norepinephrine. The newer selective serotonin reuptake inhibitors (SSRIs) have fewer side-effects and fewer interactions with other drugs. Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases. The 5-HTTLPR gene codes for the number of serotonin transporters in the brain, with more serotonin transporters causing decreased duration and magnitude of serotonergic signaling. The 5-HTTLPR polymorphism (l/l) causing more serotonin transporters to be formed is also found to be more resilient against depression and anxiety. Serotonin Syndrome Extremely high levels of serotonin can cause a condition known as serotonin syndrome, with toxic and potentially fatal effects. In practice, such toxic levels


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are essentially impossible to reach through an overdose of a single antidepressant drug, but require a combination of serotonergic agents, such as an SSRI with an MAOI. The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at nontoxic levels. Antiemetics Some 5-HT3 antagonists, such as ondansetron, granisetron, and tropisetron, are important antiemetic agents. They are particularly important in treating the nausea and vomitingthat occur during anticancer chemotherapy using cytotoxic drugs. Another application is in the treatment of postoperative nausea and vomiting.Some serotonergic agonist drugs cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis, as well as cardiac valve fibrosis. In the past, three groups of serotonergic drugs have been epidemiologically linked with these syndromes. These are the serotonergic vasoconstrictive antimigraine drugs (ergotamine and methysergide), the serotonergic appetite suppressant drugs (fenfluramine, chlorphentermine, and aminorex), and certain anti-Parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include pergolide and cabergoline, but not the more dopamine-specific lisuride. As with fenfluramine, some of these drugs have been withdrawn from the market after groups taking them showed a statistical increase of one or more of the side effects described. An example is pergolide. The drug was declining in use since it was reported in 2003 to be associated with cardiac fibrosis. Two independent studies published in the New England Journal of Medicine in January 2007, implicated pergolide, along with cabergoline, in causing valvular heart disease. As a result of this, the FDA removed pergolide from the United States market in March 2007. [87] (Since cabergoline is not approved in the United States for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease).

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Methyl-tryptamines and Hallucinogens Several plants contain serotonin together with a family of related tryptamines that are methylated at the amino (NH2) and (OH) groups, are N-oxides, or miss the OH group. These compounds do reach the brain, although some portion of them are metabolized by monoamine oxidase enzymes (mainly MAO-A) in the liver. Examples are plants from the Anadenanthera genus that are used in the hallucinogenic yopo snuff. These compounds are widely present in the leaves of many plants, and may serve as deterrents for animal ingestion. Serotonin occurs in several mushrooms of the genus Panaeolus. Comparative Biology and Evolution Unicellular Organisms Serotonin is used by a variety of single-cell organisms for various purposes. SSRIs have been found to be toxic to algae. The gastrointestinal parasite Entamoeba histolyticasecretes serotonin, causing a sustained secretory diarrhea in some people. Patients infected with E. histolytica have been found to have highly elevated serum serotonin levels, which returned to normal following resolution of the infection. E. histolytica also responds to the presence of serotonin by becoming more virulent. This means serotonin secretion not only serves to increase the spread of enteamoebas by giving the host diarrhea but also serves to coordinate their behaviour according to their population density, a phenomenon known as quorum sensing. Outside the gut of a host, there is nothing that the entoamoebas provoke to release serotonin, hence the serotonin concentration is very low. Low serotonin signals to the entoamoebas they are outside a host and they become less virulent to conserve energy. When they enter a new host, they multiply in the gut, and become more virulent as the enterochromaffine cells get provoked by them and the serotonin concentration increases. Plants In drying seeds, serotonin production is a way to get rid of the buildup of poisonous ammonia. The ammonia is collected and placed in the indole part of L-tryptophan, which is then decarboxylated by tryptophan decarboxylase to give tryptamine, which is then hydroxylated by a cytochrome P450


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monooxygenase, yielding serotonin. However, since serotonin is a major gastrointestinal tract modulator, it may be produced by plants in fruits as a way of speeding the passage of seeds through the digestive tract, in the same way as many well-known seed and fruit associated laxatives. Serotonin is found in mushrooms, fruits and vegetables. The highest values of 25–400 mg/kg have been found in nuts of the walnut (Juglans) and hickory (Carya) genera. Serotonin concentrations of 3–30 mg/kg have been found in plantains, pineapples, banana, kiwifruit, plums, and tomatoes. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables. Serotonin is one compound of the poison contained in stinging nettles (Urtica dioica), where it causes pain on injection in the same manner as its presence in insect venoms (see below). It is also naturally found in Paramuricea clavata, or the Red Sea Fan. Serotonin and tryptophan have been found in chocolate with varying cocoa contents. The highest serotonin content (2.93 µg/g) was found in chocolate with 85% cocoa, and the highest tryptophan content (13.27–13.34 µg/g) was found in 70–85% cocoa. The intermediate in the synthesis from tryptophan to serotonin, 5-hydroxytryptophan, was not found. Invertebrates Serotonin functions as a neurotransmitter in the nervous systems of most animals. For example, in the roundworm Caenorhabditis elegans, which feeds on bacteria, serotonin is released as a signal in response to positive events, such as finding a new source of food or in male animals finding a female with which to mate. [97] When a well-fed worm feels bacteria on its cuticle, dopamine is released, which slows it down; if it is starved, serotonin also is released, which slows the animal down further. This mechanism increases the amount of time animals spend in the presence of food. The released serotonin activates the muscles used for feeding, while octopamine suppresses them. Serotonin diffuses to serotonin-sensitive neurons, which control the animal's perception of nutrient availability. If lobsters are injected with serotonin, they behave like dominant individuals

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whereas octopamine causes subordinate behavior. A crayfish that is frightened may flip its tail to flee, and the effect of serotonin on this behavior depends largely on the animal's social status. Serotonin inhibits the fleeing reaction in subordinates, but enhances it in socially dominant or isolated individuals. The reason for this is social experience alters the proportion between serotonin receptors (5-HT receptors) that have opposing effects on the fight-or-flight response. The effect of 5-HT1 receptors predominates in subordinate animals, while 5-HT2 receptors predominates in dominants. Insects Serotonin is evolutionary conserved and appears across the animal kingdom. It is seen in insect processes in roles similar to in the human central nervous system, such as memory, appetite, sleep, and behavior. Locust swarming is mediated by serotonin, by transforming social preference from aversion to a gregarious state that enables coherent groups. Learning in flies and honeybees is affected by the presence of serotonin. Insect 5-HT receptors have similar sequences to the vertebrate versions, but pharmacological differences have been seen. Invertebrate drug response has been far less characterized than mammalian pharmacology and the potential for species selective insecticides has been discussed. Wasps and hornets have serotonin in their venom, [106] which causes pain and inflammation. [15] as do scorpions. If flies are fed serotonin, they are more aggressive; flies depleted of serotonin still exhibit aggression, but they do so much less frequently. Growth and Reproduction In the nematode C. elegans, artificial depletion of serotonin or the increase of octopamine cues behavior typical of a low-food environment: C. elegans becomes more active, and mating and egg-laying are suppressed, while the opposite occurs if serotonin is increased or octopamine is decreased in this animal. Serotonin is necessary for normal nematode male mating behavior, and the inclination to leave food to search for a mate. The serotonergic signaling used to adapt the worm's behaviour to fast changes in the environment affects insulin-like signaling and the TGF beta signaling pathway, which control


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long-term adaption. In the fruit fly insulin both regulates blood sugar as well as acting as a growth factor. Thus, in the fruit fly, serotonergic neurons regulate the adult body size by affecting insulin secretion. Serotonin has also been identified as the trigger for swarm behavior in locusts. In humans, though insulin regulates blood sugar and IGF regulates growth, serotonin controls the release of both hormones, modulating insulin release from the beta cells in the pancreas through serotonylation of GTPase signaling proteins. Exposure to SSRIs during Pregnancy reduces fetal growth. Genetically altered C. elegans worms that lack serotonin have an increased reproductive lifespan, may become obese, and sometimes present with arrested development at a dormant larval state. Aging and Age-related Phenotypes Serotonin is known to regulate aging, learning and memory. The first evidence comes from the study of longevity in C. elegans. During early phase of aging, the level of serotonin increases, which alters locomotory behaviors and associative memory. The effect is restored by mutations and drugs (including mianserin and methiothepin) that inhibit serotonin receptors. The observation does not contradict with the notion that the serotonin level goes down in mammals and humans, which is typically seen in late but not early phase of aging. Biochemical Mechanisms Biosynthesis

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The pathway for the synthesis of serotonin from tryptophan

In animals including humans, serotonin is synthesized from the amino acid L-tryptophan by a short metabolic pathwayconsisting of three enzymes:


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tryptophan hydroxylase (TPH), aromatic amino acid decarboxylase (DDC) and pyridoxal phosphate. The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a neuron-specific isoform. Serotonin can be synthesized from tryptophan in the lab using Aspergillus niger and Psilocybe coprophila as catalysts. The first phase to 5-hydroxytryptophan would require letting tryptophan sit in ethanol and water for 7 days, then mixing in enough HCl (or other acid) to bring the pH to 3, and then adding NaOH to make a pH of 13 for 1 hour. Asperigillus niger would be the catalyst for this first phase. The second phase to synthesizing tryptophan itself from the 5-hydroxytryptophan intermediate would require adding ethanol and water, and letting sit for 30 days this time. The next two steps would be the same as the first phase: adding HCl to make the pH = 3, and then adding NaOH to make the pH very basic at 13 for 1 hour. This phase uses the Psilocybe coprophila as the catalyst for the reaction. Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system, because it does not cross the blood–brain barrier. However, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, does cross the blood–brain barrier. These agents are available as dietary supplements, and may be effective serotonergic agents. One product of serotonin breakdown is 5-hydroxyindoleacetic acid (5-HIAA), which is excreted in the urine. Serotonin and 5-HIAA are sometimes produced in excess amounts by certain tumors or cancers, and levels of these substances may be measured in the urine to test for these tumors. Effects of Food Content Consuming purified tryptophan increases brain serotonin whereas eating foods containing tryptophan does not. This is because the transport system which brings tryptophan across the blood-brain barrier is also selective for the other amino acids contained in protein sources. High plasma levels of other large neutral amino acids compete for transport and prevent the elevated plasma tryptophan from increasing serotonin synthesis. In 1935, Italian Vittorio Erspamer showed an extract from enterochromaffin

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cells made intestines contract. Some believed it contained adrenaline, but two years later, Erspamer was able to show it was a previously unknown amine, which he named "enteramine". In 1948, Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinicdiscovered a vasoconstrictor substance in blood serum, and since it was a serum agent affecting vascular tone, they named it serotonin. In 1952, enteramine was shown to be the same substance as serotonin, and as the broad range of physiological roles was elucidated, the abbreviation 5-HT of the proper chemical name 5-hydroxytryptamine became the preferred name in the pharmacological field. Synonyms of serotonin include: 5-hydroxytriptamine, thrombotin, enteramin, substance DS, and 3-(β-Aminoethyl)-5-hydroxyindole. In 1953, Betty Twarog and Page discovered serotonin in the central nervous system. Serotonin 5-HT2 receptors are stimulated by monoamine neurotransmitters including serotonin, dopamine and norepinephrine. 5-HT2 receptor stimulation causes a buildup of intracellular inositol triphosphate and thereby an increase of cytosolic Ca2+. 5-HT2C receptor agonists are attractive drug targets that have potential use in the treatment of a number of conditions including obesity, psychiatric disorders, sexual dysfunction and urinary incontinence. The 5-HT2C receptors are one of three subtypes that belong to the serotonin 5-HT2 receptor subfamily along with 5-HT2A and 5-HT2B receptors. The development of 5-HT2Cagonists has been a major obstacle, because of severe side effects due to a lack of selectivity over 5-HT2A and 5-HT2B receptors. Activation of 5-HT2A receptors can induce hallucinations, and the activation of 5-HT2B receptors has been implicated in cardiac valvular insufficiency and possibly in pulmonary hypertension. Mechanism of Action The 5-HT2C receptors are G protein–coupled receptors that are coupled to phospholipase C(PLC) via Gαq, phospholipase A2 (PLA2), and possibly Gα13. PLC metabolizes phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-triphosphate (IP3), which regulates cellular Ca2+ flux by binding to IP3 receptors, thereby inducing the release of Ca2+. In addition, the activation of


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PLA2 also results in recruitment of a RhoA/PLD pathway through RhoA, an enzyme that regulates a wide spectrum of cellular functions through PLD (phospholipase D) target protein. The 5-HT2C receptors can also stimulate the extracellular signal-regulated kinase (ERK) pathway which is activated by neurotrophins and other neuroactive chemicals. Production of these chemicals effects neuronal differentiation, survival, regeneration, and structural and functional plasticity. Early studies of the ERK pathway showed that mood stabilizers for the treatment of manic-depressive illness stimulated the pathway. This led to the understanding that stimulation of the 5-HT2C receptors could regulate manic-depressive conditions in a manner similar to mood stabilizers.

Figure 5. Mechanism of action. A hypothetical model for the agonist activation of 5-HT2C receptor. Activation leads to accumulation of inositol phosphate and increase in intracellular Ca2+. Receptor activation also stimulates the ERK pathway and RhoA/PLD pathway

5-HT2C receptors are located only within the CNS, where they can be found in several locations. The highest density of receptor expression is within the choroid plexus. Other brain locations include the nucleus of the solitary tract, dorsomedial hypothalamus, paraventricular hypothalamic nucleus and the amygdala, all of which are associated with regulation of food intake. This distribution pattern may explain the effect they have in integral function in the control of many physiological and behavioral responses, such as feeding,

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anxiety, temperature regulation, locomotion, sexual behavior, and the occurrence of seizures. Binding The 5-HT2C Receptors and Ligand Binding

Figure 6. A schematic representation of the two state-model in which the 5-HT2C receptor are in equilibrium between an active state (R*) and an inactive state (R)

5-HT2 receptors are G protein-coupled receptors that can regulate cellular signaling in the absence of a ligand. This can be explained by a two-state model (Figure 6) where the receptor is in equilibrium between two states, an active state (R*) and an inactive state (R). Basal effector activity is defined, in part, by the absolute level of (R*), which will increase along with increasing receptor density. Ligands that preferentially bind to and stabilize the R state are termed inverse agonists and reduce the effector activity. Agonists preferentially bind to and stabilize the R* state, thereby increasing effector activity. Neutral antagonists show equal affinity for both conformations and do not alter the equilibrium between the two states, however they occupy the receptor and can block the effect of both agonists and inverse agonists. 5-HT2C and 5-HT2A receptors have a similar amino acid sequence homology, with ~50% overall sequence identity and ~80% within the TM domains, resulting in a similar pharmacological profile for the two receptors. Both receptors couple the same cellular signal transduction pathways, PLC and PLA2, that lead to an accumulation of inositol phosphate and Ca2+ within the


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postsynaptic cell. The 5-HT2C receptors are the only G-protein coupled receptors known to undergo a post-transcriptional process of RNA editing. The 5-HT2C receptor gene is found on the X-chromosome, Xq24. This gene product undergoes an RNA editing process leading to a decrease in agonist binding affinity, however antagonist binding remains unaltered. This process of RNA editing generates 14 unique receptor isoforms of the 5-HT2C receptor that differ in three amino acids in the second intracellular loop. Serotonin Binding to 5-HT2C

Figure 7. Outline of the 5-HT2C receptor. The most important contacts when serotonin binds are with residues in TM helixes 3, 5, and 6

Serotonin is an endogenous non-selective agonist for the 5-HT2C receptor with a binding constant of Ki = 16.0 nM. When serotonin binds to the receptors, the most important contacts are in TM helixes 3, 5 and 6 (Figure 7), while the other four TM helixes do not interact directly with the serotonin compound. When binding of serotonin takes place, the protonated primary amine site

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forms a salt bridge with D134 residue in TM 3, as well as forming a hydrogen bond with residue S138 in TM 3. The aromatic indole ring forms a strong Van der Waals interaction with residues F223 in TM 5 and F328 in TM 6. The ring falls tight into the receptor pocket, stacked between two phenylalanines. Amine of the indole group forms a hydrogen bond with S219 residue in TM 5 and hydroxide substituent of the indole forms hydrogen bonds both with residue S131 in TM 3 and I332 in TM 6. There is also a strong Van der Waals interaction between the indole and I332 in TM 6. Pharmacophore

Figure 8. The best fit mapped with the four features of the pharmacophore

In the drug discovery process of a 5-HT2C agonist, a pharmacophore module has been used to discover novel 5-HT2C receptor ligands. The pharmacophore has four features; one aromatic ring, two hydrophobic features and one positive ionizable feature. Figure 8 shows an example of a compound that fits the agonist pharmacophore perfectly. The nitrogen atom of piperazine fits the positive ionizable feature, the benzofuran part fits the aromatic ring and one hydrophobic, and the trifluoromethane part fits another hydrophobic feature of the pharmacophore. Structure-activity Relationships In a virtual screen for novel agonists, a structure-activity relationship was determined from the most potent compounds ('hits') identified. These hits contained a pyrazolo[3,4-d]pyrimidine core (shown in figure 9), which is


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important for potency toward the 5-HT2C receptors. Compounds with maximum potency featured two substituents linked to the core structure. The first substituent is a piperazine ring, containing a small hydrophobic group; the second substituent is a phenyl part containing a halogen- and/or oxygen-containing side chain (electronegative groups), see derivatives 1 and 2 in figure 9. Addition of aromatic groups to the piperazine ring reduces potency (derivative 4 in figure 9) and the absence of the piperazine ring or substitution with other aliphatic- or cyclic groups reduces potency as well (derivatives 5 and 6 in figure 9).

Pyrazolo[3,4-d]pyrimidine core

Derivative 1

Derivative 2

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Derivative 3

Derivative 4

Derivative 5 Figure 9. Pyrazolo[3,4-d]pyrimidine derivatives

Figure 10. Lorcaserin ((1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine)


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mCPP (meta-chlorophenylpiperazine)

A potent mCPP derivative (4-(3-chlorophenyl)-1,2,3,6-tetrahydropyridine) Figure 11. mCPP and a potent derivative

A series of 3-benzazepine derivatives, such as Lorcaserin (Figure 10) have been evaluated for their potency and selectivity for the 5-HT2C receptors. Lorcaserin is a very potent agonist, but the potency is dependent on the presence of a chloro substituent in position 8. Arylpiperazine-containing compounds such as mCPP (Figure 11), show good potency toward the 5-HT2C receptors, but do not have sufficient selectivity for the 5-HT2C receptors over the other two receptor subtypes. Many derivatives have been examined in an attempt to increase the selectivity. Derivatives lacking the arylpiperazine core, such as 4-aryl-1,2,3,6-tetrahydropyridinum chlorine analogues, are more favorable for potency and selectivity over the other two receptors (Figure 11). Functional Selectivity In 2016 the discovery of novel G protein biased 5-HT2C receptor agonists was published. Drug Development Obesity is a global epidemic health problem and has received considerable attention as a major public hazard. Obesity is a chronic pathological and costly disease of abnormal or excessive fat accumulation in the body. Studies indicate that 5-HT2C receptor activation will regulate appetite and food consumption, most likely by promoting satiety through appetite

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suppression by activation of 5-HT2C. Consequently, selective agents with high affinity for this receptor over 5-HT2B and 5-HT22A are being developed for the treatment of obesity. Lorcaserin Lorcaserin is the only agent that has completed phase III clinical trials, and achieved US Food and Drug Administration (FDA) approval. Previously approved agents were subsequently removed from the US market. Lorcaserin is a full agonist for 5-HT2C and 5-HT2B receptors and partial agonist for 5-HT2A receptors (75% of the maximal response elicited by serotonin). Lorcaserin is a potent and selective 5-HT2C agonist with rapid oral absorption that shows dose-dependent decrease in food intake and body weight. Lorcaserin affects body weight by producing a negative energy balance through reduced food intake (energy intake) without alterations in energy expenditure and substrate oxidation. Lorcaserin has a high affinity for the 5-HT2C receptors, with 18-fold selectivity over 5-HT2A receptors and 104-fold over 5-HT2B receptors. The predicted blood concentration to stimulate 2A and 2B receptors is approximately 1400-fold for 2B and 250-fold for 2A, above the blood concentration that is required to stimulate the 2C receptors. This functional selectivity is critical to prevent potential side effects and suggests that the theoretical risk of cardiac valvulopathy is very low. Clinical trials have supported this theory since they have not revealed any side effects on heart valves or pulmonary artery pressure like the former obesity drugs. Lorcaserin is well tolerated in general, but the most frequent adverse effect are headache, nausea and dizziness. Psychiatric Disorders Serotonin plays an important role in numerous physiological conditions. 5-HT2 receptor antagonists have long been known, but recently 5-HT2 receptor agonists are becoming promising agents in the development for new antipsychotic drugs. Historically, most pharmacological research on antipsychotic drugs have concentrated on the 5-HT2A receptor subtype. However, recent studies show that agonist activity on 5-HT2A receptors can cause hallucination. Comparison of SSRIs and the 5-HT2C receptor agonists


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showed that the agonists decreased immobility time and increased swimming time in the FST (forced swim test) in rats in a manner comparable to SSRIs. In the 1990s 5-HT2C receptors have received more attention as many studies have shown that selective 5-HT2C receptor agonists may be more suited in the treatment for psychotic indications. A 5-HT2C agonist may be expected to reduce positive symptoms of schizophrenia by reducing dopamine release in the mesolimbic dopamine pathway. Vabicaserin (SCA-136) is a 5-HT2C agonist that has shown promise in preliminary testing for the treatment of schizophrenia. Vabicaserin and Aripiprazole Vabicaserin has a high affinity for 5-HT2C receptors and low affinity for 5-HT2B and 5-HT2A receptors. Vabicaserin is a full agonist with approximately 4-fold greater selectivity for 5-HT2C over these related receptors, in terms of binding affinity. Vabicacserin is a full agonist in stimulating the 5-HT2C receptor; it was discovered when a class of tetrahydroquinoline-fused diazepines were being researched as possible potent 5-HT2C receptor agonists. As of 2012, vabicaserin is in clinical trials for the treatment of schizophrenia. Long-term administration of vabicaserin significantly decreased the number of spontaneously active mesocorticolimbic dopamine neurons without affecting nigrostriatal dopamine neurons, consistent with effects of atypical antipsychotic agents. The outcome of clinical studies for vabicaserin may reveal whether 5-HT2C receptors can be possible targets for the treatment of schizophrenia. Aripiprazole is also a mild partial agonist of 5HT2C receptor. Sexual Dysfunction Activation of 5-HT2C receptor subtype has been reported to mediate numerous effects, such as penile erection. Based on multiple studies, results show that several 5-HT2C receptor agonists, including mCPP and YM348 induce penile erections in rats, but mCPP seems to mimic both vasodilation and vasoconstriction. The vasodilator action is mediated by 5-HT1D receptors, whereas the vasoconstriction effect involves 5-HT2 receptor activation. YM-348 is a highly selective 5-HT2C agonist and results show that YM348 can

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induce penile erections and hypolocomotion (induced at a high dose) in rats, as did other 5-HT2C receptor agonists. These effects were completely inhibited by a selective 5-HT2C receptor antagonist, SB-242,084. Therefore, results suggest that YM348 is a potent and orally active 5-HT2C receptor agonist. Urinary Incontinence Serotonin plays a key role in mechanisms involved in micturition and continence. Many potent compounds with high selectivity for 5-HT2C receptors have been synthesized and are promising candidates for further development for the treatment of stress urinary incontinence (SUI). Current Status Many exogenous agents have been developed since the discovery of 5-HT2C receptors. Thus far a small number of agonists, with sufficient selectivity for the 5-HT2C receptors over the other subtypes have been studied in clinical trials. A variety of other 5-HT2C receptor agonists remain in pre-clinical developments, like Ro60-0175, WAY-163,909 and the inverse agonist SB-243,213. Evidence supports a therapeutic potential of 5-HT2C receptor modulation in the treatment of a variety of pathological conditions, including schizophrenia, obesity, urinary incontinence and sexual dysfunction.

Compound name

Chemical name

Mode of action

Company

Phase of developme nt

Indication

PRX-00933

N/A

5-HT2C agonist

Proximager

Phase III (2011)

Obesity and diabetes

Vabicaserin

(9aR,12aS)-4,5,6,7,9,9a ,10,11,12,12adecahydrocyclopenta[c] [1,4]diazepino[6,7, 1-ij]quinoline

5-HT2C agonist

Pfizer

Phase I (February, 28th, 2012)

Schizophre nia

Lorcaserin

1R)-8-chloro-2,3,4,5-tet rahydro-1-methyl1H-3-benzazepine

5-HT2C agonist

Arena Pharmaceuti cals

FDA approved (2012)

Obesity


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Thyrotropin-Releasing Hormone Thyrotropin-releasing hormone (TRH), also called thyrotropin-releasing factor (TRF) or thyroliberin, is a releasing hormone, produced by the hypothalamus, that stimulates the release of thyrotropin (thyroid-stimulating hormone or TSH) and prolactin from the anterior pituitary. It is a tropic, tripeptidal hormone.

TRH has been used clinically for the treatment of spinocerebellar degeneration and disturbance of consciousness in humans. [1] Its pharmaceutical form is called protirelin (INN) (/proʊtaɪrɪlɪn/).

Synthesis

The system of the thyroid hormones T3and T4

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TRH is produced by the globe in medial neurons of the paraventricular nucleus. [3] At the beginning, it is synthesized as a 242-amino acid precursor polypeptide that contains 6 copies of the sequence -Gln-His-Pro-Gly-, flanked by Lys-Arg or Arg-Arg sequences. To produce the mature form, a series of enzymes are required. First, a protease cleaves to the C-terminal side of the flanking Lys-Arg or Arg-Arg. Second, a carboxypeptidase removes the Lys/Arg residues leaving Gly as the C-terminal residue. Then, this Gly is converted into an amide residue by a series of enzymes collectively known as peptidylglycine-alpha-amidating monooxygenase. Concurrently with these processing steps, the N-terminal Gln (glutamine) is converted into pyroglutamate (a cyclic residue). These multiple steps produce 6 copies of the mature TRH molecule per precursor molecule for human TRH (5 for mouse TRH). Following secretion, TRH travels across the median eminence to the anterior pituitary gland via the hypophyseal portal system where it stimulates the release of thyroid-stimulating hormone from cells called thyrotropes. TRH can also be detected in other areas of the body including the gastrointestinal system and pancreatic islets, as well as in the brain. The seleke of TRH was first determined, and the hormone synthesized, by Roger Guillemin and Andrew V. Schally in 1969. Both parties insisted their labs determined the sequence first: Schally first suggested the possibility in 1966, but abandoned it after Guillemin proposed TRH was not actually a peptide. Guillemin's chemist began concurring with these results in 1969, as NIH threatened to cut off funding for the project, leading both parties to return to work on synthesis. Schally and Guillemin shared the 1977 Nobel Prize in Medicine "for their discoveries concerning the peptide hormone production of the brain." [8] News accounts of their work often focused on their "fierce competition" and use of a very large amount of sheep and pig brains to locate the hormone. Chemical Properties Its molecular weight is 359.5 Da. Its tripeptide (pyro)Glu-His-Pro-NH2. Its logp octanol/water is -2.46.

structure

is:


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Clinical Significance TRH is used clinically by intravenous injection (brand name Relefact TRH) to test the response of the anterior pituitary gland; this procedure is known as a TRH test. This is done as diagnostic test of thyroid disorders such as secondary hypothyroidism and in acromegaly. TRH has anti-depressant and anti-suicidal properties, and in 2012 the U.S. Army awarded a research grant to develop a TRH nasal spray in order to prevent suicide amongst its ranks. TRH has been shown in mice to be an anti-aging agent with a broad spectrum of activities that, because of their actions, suggest that TRH has a fundamental role in the regulation of metabolic and hormonal functions. Side Effects Side effects after intravenous TRH administration are minimal. Nausea, flushing, urinary urgency, and mild rise in blood pressure have been reported. After intrathecaladministration, shaking, sweating, shivering, restlessness, and mild rise in blood pressure were observed. Related Peptides Thyrotropin-releasing hormone (TRH) Identifiers Symbol

TRH

Pfam

PF05438

InterPro

IPR008857


TRH belongs to a family of several thyrotropin-releasing hormones. The thyrotropin-releasing hormone receptor (TRHR) is a G protein-coupled receptor which binds the tripeptide thyrotropin releasing hormone. The TRHR are found in the brain and when bound by TRH act (through

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phospholipase C) to increase intracellular inositol trisphosphate. Рецептор тиреотропин-рилизинг-гормона (TRHR) представляет собой рецептор, связанный с белком G, который связывает трипептидный тиреотропин-высвобождающий гормон. TRHR обнаружены в головном мозге и, когда они связаны действием TRH (через фосфолипазу C), увеличивают внутрисосудистый трифосфат инозита. Opioid Peptides Opioid peptides are peptides that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Such peptides may be produced by the body itself, for example endorphins. The effects of these peptides vary, but they all resemble those of opiates. Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, and the control of food intake. Opioid-like peptides may also be absorbed from partially digested food (casomorphins, exorphins, and rubiscolins). The opioid food peptides have lengths of typically 4–8 amino acids. The body's own opioids are generally much longer.

Figure 12. Structural correlation between met-enkephalin, an opioid peptide, (left) and morphine, an opiate drug, (right)


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Opioid peptides are released by post-translational proteolytic cleavage of precursor proteins. The precursors consist of the following components: a signal sequence that precedes a conserved region of about 50 residues; a variable-length region; and the sequence of the neuropeptides themselves. Sequence analysis reveals that the conserved N-terminal region of the precursors contains 6 cysteines, which are probably involved in disulfide bond formation. It is speculated that this region might be important for neuropeptide processing. Neurohormones A neurohormone is any hormone produced and released by neuroendocrine cells (also called neurosecretory cells) into the blood. By definition of being hormones, they are secreted into the circulation for systemic effect, but they can also have a role of neurotransmitter or other roles such as autocrine (self) or paracrine (local) messenger. The hypothalamus produces releasing hormones and neurohypophysial hormones in specialized hypothalamic neurons which extend to the median eminence and posterior pituitary. The adrenal medulla produces adrenomedullary hormones in chromaffin cells, cells which are very similar in structure to post-synaptic sympathetic neurons, even though they are not neurons they are derivatives of the neural crest. Enterochromaffin and enterochromaffin-like cells, both being enteroendocrine cells, are also considered neuroendocrine cells due to their structural and functional similarity to chromaffin cells, although they are not derivatives of the neural crest. [5] Other neuroendocrine cells are scattered throughout the body. Releasing Hormones Releasing hormones also known as hypophysiotropic or hypothalamic hormones are synthesized by different kinds of specialized neurons in the hypothalamus. They are then transported along neuronal axons to their axon terminals forming the bulk of the median eminence, where they are stored and released into the hypophyseal portal system. They then rapidly reach the anterior pituitary where they exert their hormonal action. The residual

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hormones pass into the systemic circulation where they are diluted, degraded and have comparatively little effects. The synthesis, control, and release of those hormones is co-regulated by hormonal, local and synaptic signals (neurotransmitters). The neurons secreting various hormones have been found to discharge impulses in burst, causing a pulsatile release which is more efficient than a continuous release. [8] Hypophysiotropic hormones include:  Thyrotropin-releasing hormone  Corticotropin-releasing hormone  Growth hormone-releasing hormone  Somatostatin  Gonadotropin-releasing hormone  Dopamine  Neurotensin Neurohypophysial Hormones Neurohypophysial hormones are synthesized in the magnocellular secretory neurons of the hypothalamus. They are then transported along neuronal axons within the infundibular stalk to their axon terminals forming the pars nervosa of the posterior pituitary, where they are stored and released into the systemic circulation. The synthesis, control, and release of those hormones is co-regulated by hormonal, local and synaptic signals. Neurohypophysial hormones include:  Oxytocin  Vasopressin This is through this pathway that the vast majority of oxytocin and vasopressin hormones reach the systemic circulation. Adrenomedullary Hormones Adrenomedullary hormones are catecholamines secreted from the adrenal medulla by chromaffin cells, neurosecretory cells connected to the central nervous system. The synthesis, storage (in chromaffin cells) and release of catecholamines is co-regulated by synaptic input from their respective pre-synaptic sympathetic neurons, as well as hormonal and local inputs. The adrenomedullary hormones are:


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 Epinephrine  Norepinephrine  Dopamine Enteric Neurohormones Enterochromaffin cells in the epithelia lining the lumen of the digestive tract secrete serotonin, while enterochromaffin-like cells at the stomach glands secrete histamine. Their synthesis, storage, and release of hormones is co-regulated by hormonal, local and nervous inputs. REFERENCES [1] Purves WK, Sadava D, Orians GH, Heller HC (2001). Life: The Science of Biology (6th ed.). Massachusetts: Sinauer Associates. p. 718. [2]

Unsicker K, Huber K, Schütz G, Kalcheim C (Jun–Jul 2005). "The chromaffin cell and its development". Neurochemical Research. 30 (6–7): 921–5.

[3]

Andrew A (June 1974). "Further evidence that enterochromaffin cells are not derived from the neural crest". Journal of Embryology and Experimental Morphology. 31 (3): 589–98.

[4]

Meites J, Sonntag WE (April 1981). "Hypothalamic hypophysiotropic hormones and neurotransmitter regulation: current views". Annual Review of Pharmacology and Toxicology. 21: 295–322.

[5]

Nillni EA (April 2010). "Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs". Frontiers in Neuroendocrinology. 31(2): 134–56.

[6]

Brown AG (2001). Nerve cells and nervous systems: an introduction to neuroscience. London: Springer. p. 200.

[7]

Burbach JP, Luckman SM, Murphy D, Gainer H (July 2001). "Gene regulation in the magnocellular hypothalamo-neurohypophysial system". Physiological Reviews. 81 (3): 1197–267.

[8]

Chung KF, Sicard F, Vukicevic V, Hermann A, Storch A, Huttner WB, Bornstein SR, Ehrhart-Bornstein M (October 2009). "Isolation of neural crest derived chromaffin progenitors from adult adrenal medulla". Stem Cells. 27 (10): 2602–13.

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[9]


Gasman S, Chasserot-Golaz S, Bader MF, Vitale N (October 2003). "Regulation of exocytosis in adrenal chromaffin cells: focus on ARF and Rho GTPases". Cellular Signalling. 15 (10): 893–9.

[10] Bornstein SR, Ehrhart-Bornstein M (December 1992). "Ultrastructural evidence for a paracrine regulation of the rat adrenal cortex mediated by the local release of catecholamines from chromaffin cells". Endocrinology. 131 (6): 3126–8. [11] Prinz C, Zanner R, Gerhard M, Mahr S, Neumayer N, Höhne-Zell B, Gratzl M (November 1999). "The mechanism of histamine secretion from gastric enterochromaffin-like cells". The American Journal of Physiology. 277 (5 Pt 1): C845–55. [12] Rhee SH, Pothoulakis C, Mayer EA (May 2009). "Principles and clinical implications of the brain-gut-enteric microbiota axis". Nature Reviews. Gastroenterology & Hepatology. 6 (5): 306–14. [13] Haas HL, Sergeeva OA, Selbach O (July 2008). "Histamine in the nervous system". Physiological Reviews. 88 (3): 1183–241. [14] Rodriguez-Diaz R, Dando R, Jacques-Silva MC, Fachado A, Molina J, Abdulreda MH, Ricordi C, Roper SD, Berggren PO, Caicedo A (June 2011). "Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans". Nature Medicine. 17 (7): 888–92. [15] Sandor A, Kidd M, Lawton GP, Miu K, Tang LH, Modlin IM (April 1996). "Neurohormonal modulation of rat enterochromaffin-like cell histamine secretion". Gastroenterology. 110 (4): 1084–92.


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Neuromodulators Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. This is in contrast to classical synaptic transmission, in which one presynaptic neuron directly influences a single postsynaptic partner. Neuromodulators secreted by a small group of neurons diffuse through large areas of the nervous system, affecting multiple neurons. Major neuromodulators in the central nervous system include dopamine, serotonin, acetylcholine, histamine, and norepinephrine. A neuromodulator can be conceptualized as a neurotransmitter that is not reabsorbed by the pre-synaptic neuron or broken down into a metabolite. Such neuromodulators end up spending a significant amount of time in the cerebrospinal fluid (CSF), influencing (or "modulating") the activity of several other neurons in the brain. For this reason, some neurotransmitters are also considered to be neuromodulators, such as serotonin and acetylcholine. [1] Neuromodulation is often contrasted with classical fast synaptic transmission. In both cases the transmitter acts on local postsynaptic receptors, but in neuromodulation, the receptors are typically G-protein coupled receptors while in classical chemical neurotransmission, they are ligand-gated ion channels. Neurotransmission that involves metabotropic receptors (like G-protein linked receptors) often also involves voltage-gated ion channels, and is relatively slow. Conversely, neurotransmission that involves exclusively ligand-gated ion channels is much faster. A related distinction is also sometimes drawn between modulator and driver synaptic inputs to a neuron, but here the emphasis is on modulating ongoing neuronal spiking versus causing that spiking. Neuromuscular Systems Neuromodulators may alter the output of a physiological system by acting on the associated inputs (for instance, central pattern generators). However, modeling work suggests that this alone is insufficient, [2] because the neuromuscular transformation from neural input to muscular output may be tuned for particular ranges of input. Stern et al. (2007) suggest that

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neuromodulators must act not only on the input system but must change the transformation itself to produce the proper contractions of muscles as output. Volume Transmission Neurotransmitter systems are systems of neurons in the brain expressing certain types of neurotransmitters, and thus form distinct systems. Activation of the system causes effects in large volumes of the brain, called volume transmission. Volume transmission is the diffusion of neurotransmitters through the brain extracellular fluid released at points that may be remote from the target cells with the resulting activation of extrasynaptic receptors, and with a longer time course than for transmission at a single synapse. Neurotransmitter Systems The major neurotransmitter systems are the noradrenaline (norepinephrine) system, the dopamine system, the serotonin system and the cholinergic system. Drugs targeting the neurotransmitter of such systems affects the whole system, and explains the mode of action of many drugs. Most other neurotransmitters, on the other hand, e.g. glutamate, GABA and glycine, are used very generally throughout the central nervous system. Comparison Neuromodulator systems System

Origin

Locus coeruleus

adrenergic receptors in:  spinal cord  thalamus  hypothalamus  striatum  neocortex  cingulate gyrus  cingulum  hippocampus  amygdala

Lateral tegmental field

 hypothalamus

dopamine pathways:

Dopamine receptors at

Noradrenaline system

Dopamine

Targets

Effects

 arousal (Arousal is a physiological and psychological state of being awake or reactive to stimuli)  reward system

motor system,


system

 mesocortical pathway  mesolimbic pathway  nigrostriatal pathway  tuberoinfundibular pathway caudal dorsal raphe nucleus

Serotonin receptors in:  deep cerebellar nuclei  cerebellar cortex  spinal cord

rostral dorsal raphe nucleus

Serotonin receptors in:  thalamus  striatum  hypothalamus  nucleus accumbens  neocortex  cingulate gyrus  cingulum  hippocampus  amygdala

Pedunculopontine nucleus and dorsolateral tegmental nuclei(pontomesenc ephalotegmental complex)

(mainly) M1 receptors in:  brainstem  deep cerebellar nuclei  pontine nuclei  locus ceruleus  raphe nucleus  lateral reticular nucleus  inferior olive  thalamus  tectum  basal ganglia  basal forebrain

basal optic nucleus of Meynert

(mainly) M1 receptors in:  neocortex

medial septal nucleus

(mainly) M1 receptors in:  hippocampus  neocortex

Serotonin system

Cholinergic system

pathway terminations.

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reward system, cognition, endocrine, nausea

Increase (introversion), mood, satiety, body temperature and sleep, while decreasing nociception.

 muscle and motor control system  learning  short-term memory  arousal  reward

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Noradrenaline System The noradrenaline system consists of just 1500 neurons on each side of the brain, primarily in the locus coeruleus. This is diminutive compared to the more than 100 billion neurons in the brain. As with dopaminergic neurons in the substantia nigra, neurons in the locus coeruleus tend to be melanin-pigmented. Noradrenaline is released from the neurons, and acts on adrenergic receptors. Noradrenaline is often released steadily so that it can prepare the supporting glial cells for calibrated responses. Despite containing a relatively small number of neurons, when activated, the noradrenaline system plays major roles in the brain including involvement in suppression of the neuroinflammatory response, stimulation of neuronal plasticity through LTP, regulation of glutamate uptake by astrocytes and LTD, and consolidation of memory. Dopamine System The dopamine or dopaminergic system consists of several pathways, originating from the ventral tegmentum or substantia nigra as examples. It acts on dopamine receptors. Parkinson's disease is at least in part related to dropping out of dopaminergic cells in deep-brain nuclei, primarily the melanin-pigmented neurons in the substantia nigra but secondarily the noradrenergic neurons of the locus coeruleus. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success. Dopamine Pharmacology  Cocaine, for example, blocks the reuptake of dopamine, leaving these neurotransmitters in the synaptic gap longer.  AMPT prevents the conversion of tyrosine to L-DOPA, the precursor to dopamine; reserpine prevents dopamine storage within vesicles; and deprenyl inhibits monoamine oxidase (MAO)-B and thus increases dopamine levels. Serotonin System The serotonin created by the brain comprises around 10% of total body serotonin. The majority (80-90%) is found in the gastrointestinal (GI) tract. It travels around the brain along the medial forebrain bundle and acts on serotonin


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receptors. In the peripheral nervous system (such as in the gut wall) serotonin regulates vascular tone. Serotonin Pharmacology  Selective serotonin reuptake inhibitors (SSRIs) such as Prozac (fluoxetine) are widely used antidepressants that specifically block the reuptake of serotonin with less effect on other transmitters.  Tricyclic antidepressants also block reuptake of biogenic amines from the synapse, but may primarily effect serotonin or norepinephrine or both. They typically take 4 to 6 weeks to alleviate any symptoms of depression. They are considered to have immediate and long-term effects.  Monoamine oxidase inhibitors allow reuptake of biogenic amine neurotransmitters from the synapse, but inhibit an enzyme which normally destroys (metabolizes) some of the transmitters after their reuptake. More of the neurotransmitters (especially serotonin, noradrenaline and dopamine) are available for release into synapses. MAOIs take several weeks to alleviate the symptoms of depression. Although changes in neurochemistry are found immediately after taking these antidepressants, symptoms may not begin to improve until several weeks after administration. Increased transmitter levels in the synapse alone does not relieve the depression or anxiety. Cholinergic System The cholinergic system consists of projection neurons from the pedunculopontine nucleus, laterodorsal tegmental nucleus, and basal forebrain and interneurons from the striatum and nucleus accumbens. It is not yet clear whether acetylcholine as a neuromodulator acts through volume transmission or classical synaptic transmission, as there is evidence to support both theories. Acetylcholine binds to both metabotropic muscarinic receptors (mAChR) and the ionotropic nicotinic receptors (nAChR). The cholinergic system has been found to be involved in responding to cues related to the reward pathway, enhancing signal detection and sensory attention, regulating homeostasis, mediating the stress response, and encoding the formation of memories.

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GABA Gamma-aminobutyric acid (GABA) has an inhibitory effect on brain and spinal cord activity. Neuropeptides Opioid peptides – a large family of endogenous neuropeptides that are widely distributed throughout the central and peripheral nervous system. Opiate drugs such as heroinand morphine act at the receptors of these neurotransmitters. 1. Endorphins 2. Enkephalins 3. Dynorphins  Oxytocin  Substance P

Neuromodulation also refers to an emerging class of medical therapies that target the nervous system for restoration of function (such as in cochlear implants), relief of pain, or control of symptoms, such as tremor seen in movement disorders like Parkinson's disease. The therapies consist primarily of targeted electrical stimulation, or infusion of medications into the cerebrospinal fluid using intrathecal drug delivery, such as baclofen for spasticity. Electrical stimulation devices include deep brain stimulation systems (DBS), colloquially referred to as "brain pacemakers", spinal cord stimulators (SCS) and vagus nerve stimulators (VNS), which are implanted using minimally invasive procedures, or transcutaneous electrical nerve stimulation devices, which are fully external, among others. Neurophylosophy Empirical (not transcendental) neurophilosophy or philosophy of neuroscience is the interdisciplinary study of neuroscience and philosophy that explores the relevance of neuroscientific studies to the arguments traditionally categorized as philosophy of mind. The philosophy of neuroscience attempts to clarify neuroscientific methods and results using the conceptual rigor and methods of philosophy of science. While the issue of brain-mind is still open for debate, from the perspective of


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neurophilosophy, an understanding of the philosophical applications of neuroscience discoveries is nevertheless relevant. Even if neuroscience eventually found that there is no causal relationship between brain and mind, the mind would still remain associated with the brain, some would argue an epiphenomenon, and as such neuroscience would still be relevant for the philosophy of the mind. At the other end of the spectrum, if neuroscience will eventually demonstrate a perfect overlap between brain and mind phenomena, neuroscience would become indispensable for the study of the mind. Clearly, regardless of the status of the brain-mind debate, the study of neuroscience is relevant for philosophy. Specific Issues Below is a list of specific issues important to Philosophy of neuroscience:  "The indirectness of studies of mind and brain"  "Computational or representational analysis of brain processing"  "Relations between psychological and neuroscientific inquiries"  Modularity of mind  What constitutes adequate explanation in Neuroscience?  "Location of Cognitive function" The Indirectness of Studies of Mind and Brain Many of the methods and techniques central to neuroscientific discovery rely on assumptions that can limit the interpretation of the data. Philosophers of Neuroscience have discussed such assumptions in the use of functional Magnetic Resonance Imaging, Dissociation in Cognitive Neuropsychology, single unit recording, and computational neuroscience. Following are descriptions of many of the current controversies and debates about the methods employed in neuroscience. fMRI Many fMRI studies rely heavily on the assumption of "localization of function" (same as functional specialization). Localization of function means that many cognitive functions can be localized to specific brain regions. A good example of functional localization comes from studies of the motor cortex. There seem to be different groups of cells in the motor cortex responsible for

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controlling different groups of muscles. Many philosophers of neuroscience criticize fMRI for relying too heavily on this assumption. Michael Anderson points out that subtraction method fMRI misses a lot of brain information that is important to the cognitive processes. Subtraction fMRI only shows the differences between the task activation and the control activation, but many of the brain areas activated in the control are obviously important for the task as well. Some philosophers entirely reject any notion of localization of function and thus believe fMRI studies to be profoundly misguided. These philosophers maintain that brain processing acts holistically, that large sections of the brain are involved in processing most cognitive tasks (see holism in neurology and the modularity section below). One way to understand their objection to the idea of localization of function is the radio repair man thought experiment. In this thought experiment, a radio repair man opens up a radio and rips out a tube. The radio begins whistling loudly and the radio repair man declares that he must have ripped out the anti-whistling tube. There is not really any anti-whistling tube in the radio and it is obvious that the radio repair man has confounded function with effect. This criticism was originally targeted at the logic used by neuropsychological brain lesion experiments, but the criticism is still applicable to neuroimaging. These considerations are similar to Van Orden's and Paap's criticism of circularity in neuroimaging logic. According to them, neuroimagers assume that their theory of cognitive component parcellation is correct and that these components divide cleanly into feed-forward modules. These assumptions are necessary to justify their inference of brain localization. The logic is circular if the researcher then use the appearance of brain region activation as proof of the correctness of their cognitive theories. A different problematic methodological assumption within fMRI research is the use of reverse inference A reverse inference is when the activation of a brain region is used to infer the presence of a given cognitive process. Poldrack points out that the strength of this inference depends critically on the likelihood that a given task employs a given cognitive process and the likelihood of that pattern of brain activation given that cognitive process. In other words, the


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strength of reverse inference is based upon the selectivity of the task used as well as the selectivity of the brain region activation. A 2011 article published in the NY times has been heavily criticized for misusing reverse inference. In the study, participants were shown pictures of their iPhones and the researchers measured activation of the insula. The researches took insula activation as evidence of feelings of love and concluded that people loved their iPhones. Critics were quick to point out that the insula is not a very selective piece of cortex, and therefore not amenable to reverse inference. The Neuropsychologist Max Coltheart took the problems with reverse inference a step further and challenged neuroimagers to give one instance in which neuroimaging had informed psychological theory Coltheart takes the burden of proof to be an instance where the brain imaging data is consistent with one theory but inconsistent with another theory. Roskies maintains that Coltheart's ultra cognitive position makes his challenge unwinnable. Since Coltheart maintains that the implementation of a cognitive state has no bearing on the function of that cognitive state, then it is impossible to find neuroimaging data that will be able to comment on psychological theories in the way Coltheart demands. Neuroimaging data will always be relegated to the lower level of implementation and be unable to selectively determine one or another cognitive theory. In an 2006 article, Richard Henson suggests that forward inference can be used to infer dissociation of function at the psychological level. He suggests that these kinds of inferences can be made when there is crossing activations between two task types in two brain regions and there is no change in activation in a mutual control region. One final assumption worth mentioning is the assumption of pure insertion in fMRI. The assumption of pure insertion is the assumption that a single cognitive process can be inserted into another set of cognitive process without effecting the functioning of the rest. For example, if you wanted to find the reading comprehension area of the brain, you might scan participants while they were presented with a word and while they were presented with a non-word (e.g. "Floob"). If you infer that the resulting difference in brain pattern represents the regions of the brain involved in reading comprehension, you have assumed that these changes are not reflective of changes in task

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difficulty or differential recruitment between tasks. The term pure insertion was coined by Donders as a criticism of reaction time methods. Recently, researchers have begun using a new functional imaging technique called resting state functional connectivity MRI. Subjects' brains are scanned while the subject sits idly in the scanner. By looking at the natural fluctuations in the bold pattern while the subject is at rest, the researchers can see which brain regions co-vary in activation together. They can use the patterns of covariance to construct maps of functionally linked brain areas. It is worth noting that the name "functional connectivity" is somewhat misleading since the data only indicates co-variation. Still, this is a powerful method for studying large networks throughout the brain. There are a couple of important methodological issues that need to be addressed. Firstly, there are many different possible brain mappings that could be used to define the brain regions for the network. The results could vary significantly depending on the brain region chosen. Secondly, what mathematical techniques are best about to characterize these brain regions? The brain regions of interest are somewhat constrained by the size of the voxels. Rs-fcMRI uses voxels that are few millimeters cubed so the brain regions will have to be defined on a larger scale. Two of the statistical methods that are commonly applied to network analysis can work on the single voxel spatial scale, but graph theory methods are extremely sensitive to the way nodes are defined. Brains regions can be divided according to their cellular architectural, according to their connectivity, or according to physiological measures. Alternatively, you could take a theory neutral approach and randomly divide the cortex into partitions of the size of your choosing. As mentioned earlier, there are several approaches to network analysis once the your brain regions have been defined. Seed based analysis begins with an a priori defined seed region and finds all of the regions that are functionally connected to that region. Wig et al. caution that the resulting network structure will not give any information concerning the inter-connectivity of the identified regions or the relations of those regions to regions other than the seed region. Another approach is to use independent component analysis to create spatio-temporal component maps and the components are sorted by


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components that carry information of interest and those that are caused by noise. Wigs et al. once again warns that inference of functional brain region communities is difficult under ICA. ICA also has the issue of imposing orthogonality on the data. Graph theory uses a matrix to characterize covariance between regions which is then transformed into a network map. The problem with graph theory analysis is that network mapping is heavily influenced by a priori brain region and connectivity (nodes and edges), thus the researcher is at risk for cherry picking regions and connections according to their own theories. However, graph theory analysis is extremely valuable since it is the only method that gives pair-wise relationships between nodes. ICA has the added advantage of being a fairly principled method. It seems that using both methods will be important in uncovering the network connectivity of the brain. Mumford et al. hoped to avoid these issues and use a principled approach that could determine pair-wise relationships using a statistical technique adopted from analysis of gene co-expression networks. Dissociation in Cognitive Neuropsychology Cognitive Neuropsychology studies brain damaged patients and uses the patterns of selective impairment in order to make inferences on the underlying cognitive structure. Dissociation between cognitive functions is taken to be evidence that these functions are independent. Theorists have identified several key assumptions that are needed to justify these inferences: 1) Functional Modularity- the mind is organized into functionally separate cognitive modules. 2). Anatomical Modularity- the brain is organized into functionally separate modules. This assumption is very similar to the assumption of functional localization. These assumptions differ from the assumption of functional modularity, because it is possible to have separable cognitive modules that are implemented by diffuse patterns of brain activation. 3) Universality- The basic organization of functional and anatomical modularity is the same for all normal humans. This assumption is needed if we are to make any claim about functional organization based on dissociation that extrapolates from the instance of a case study to the population. 4) Transparency / Subtractivity- the mind does not undergo substantial reorganization following brain damage. It is

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possible to remove one functional module without significantly altering the overall structure of the system. This assumption is necessary in order to justify using brain damaged patients in order to make inferences about the cognitive architecture of healthy people. There are three principal types of evidence in cognitive neuropsychology: association, single dissociation and double dissociation. Association inferences observe that certain deficits are likely to co-occur. For example, there are many cases who have deficits in both abstract and concrete word comprehension following brain damage. Association studies are considered the weakest form of evidence, because the results could be accounted for by damage to neighboring brain regions and not damage to a single cognitive system. Single Dissociation inferences observe that one cognitive faculty can be spared while another can be damaged following brain damage. This pattern indicates that a) the two tasks employ different cognitive systems b) the two tasks occupy the same system and the damaged task is downstream from the spared task or c) that the spared task requires fewer cognitive resources than the damaged task. The "gold standard" for cognitive neuropsychology is the double dissociation. Double dissociation occurs when brain damage impairs task A in Patient1 but spares task B and brain damage spares task A in Patient 2 but damages task B. It is assumed that one instance of double dissociation is sufficient proof to infer separate cognitive modules in the performance of the tasks. Many theorists criticize cognitive neuropsychology for its dependence on double dissociations. In one widely cited study, Joula and Plunkett used a model connectionist system to demonstrate that double dissociation behavioral patterns can occur through random lesions of a single module. They created a multilayer connectionist system trained to pronounce words. They repeatedly simulated random destruction of nodes and connections in the system and plotted the resulting performance on a scatter plot. The results showed deficits in irregular noun pronunciation with spared regular verb pronunciation in some cases and deficits in regular verb pronunciation with spared irregular noun pronunciation. These results suggest that a single instance of double dissociation is insufficient to justify inference to multiple systems. Charter offers a theoretical case in which double dissociation logic can be


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faulty. If two tasks, task A and task B, use almost all of the same systems but differ by one mutually exclusive module apiece, then the selective lesioning of those two modules would seem to indicate that A and B use different systems. Charter uses the example of someone who is allergic to peanuts but not shrimp and someone who is allergic to shrimp and not peanuts. He argues that double dissociation logic leads one to infer that peanuts and shrimp are digested by different systems. John Dunn offers another objection to double dissociation. He claims that it is easy to demonstrate the existence of a true deficit but difficult to show that another function is truly spared. As more data is accumulated, the value of your results will converge on an effect size of zero, but there will always be a positive value greater than zero that has more statistical power than zero. Therefore, it is impossible to be fully confident that a given double dissociation actually exists. On a different note, Alphonso Caramazza has given a principled reason for rejecting the use of group studies in cognitive neuropsychology. Studies of brain damaged patients can either take the form of a single case study, in which an individual's behavior is characterized and used as evidence, or group studies, in which a group of patients displaying the same deficit have their behavior characterized and averaged. In order to justify grouping a set of patient data together, the researcher must know that the group is homogenous, that their behavior is equivalent in every theoretically meaningful way. In brain damaged patients, this can only be accomplished a posteriori by analyzing the behavior patterns of all the individuals in the group. Thus according to Caramazza, any group study is either the equivalent of a set of single case studies or is theoretically unjustified. Newcombe and Marshall pointed out that there are some cases (they use Geschwind's syndrome as an example) and that group studies might still serve as a useful heuristic in cognitive neuropsychological studies. It is commonly understood in neuroscience that information is encoded in the brain by the firing patterns of neurons. Many of the philosophical questions surrounding the neural code are related to questions about representation and computation that are discussed below. There are other methodological questions including whether neurons represent information through an average

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firing rate or whether there is information represented by the temporal dynamics. There are similar questions about whether neurons represent information individually or as a population. Many of the philosophical controversies surrounding computational neuroscience involve the role of simulation and modeling as explanation. Carl Craver has been especially vocal about such interpretations. Jones and Love wrote an especially critical article targeted at Bayesian behavioral modeling that did not constrain the modeling parameters by psychological or neurological considerations Eric Winsberg has written about the role of computer modeling and simulation in science generally, but his characterization is applicable to computational neuroscience. The computational theory of mind has been widespread in neuroscience since the cognitive revolution in the 1960s. This section will begin with a historical overview of computational neuroscience and then discuss various competing theories and controversies within the field. Computational neuroscience began in the 1930s and 1940s with two groups of researchers. The first group consisted of Alan Turing, Alonzo Church and Otto Von Newman, who were working to develop computing machines and the mathematical underpinnings of computer science. This work culminated in the theoretical development of so-called Turing machines and the Church–Turing thesis, which formalized the mathematics underlying computability theory. The second group consisted of Warren McChulloch and Walter Pitts who were working to develop the first artificial neural networks. McCulloch and Pitts were the first to hypothesize that neurons could be used to implement a logical calculus that could explain cognition. They used their toy neurons to develop logic gates that could make computations. However these developments failed to take hold in the psychological sciences and neuroscience until the mid-1950s and 1960s. Behaviorism had dominated the psychology until the 1950s when new developments in a variety of fields overturned behaviorist theory in favor of a cognitive theory. From the beginning of the cognitive revolution, computational theory played a major role in theoretical developments. Minsky and McCarthy's work in artificial intelligence, Newell and Simon's computer simulations, and Noam Chomsky's importation of information theory into


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linguistics were all heavily reliant on computational assumptions. By the early 1960s, Hilary Putnam was arguing in favor of machine functionalism in which the brain instantiated Turing machines. By this point computational theories were firmly fixed in psychology and neuroscience. By the mid-1980s, a group of researchers began using multilayer feed-forward analog neural networks that could be trained to perform a variety of tasks. The work by researchers like Sejnowski, Rosenberg, Rumelhart, and McClelland were labeled as connectionism, and the discipline has continued since then. The connectionist mindset was embraced by Paul and Patricia Churchland who then developed their "state space semantics" using concepts from connectionist theory. Connectionism was also condemned by researchers such as Fodor, Pylyshyn, and Pinker. The tension between the connectionists and the classicists is still being debated today. One of the reasons that computational theories are appealing is that computers have the ability to manipulate representations to give meaningful output. Digital computers use strings of 1s and 0s in order to represent the content such as this Wikipedia page. Most cognitive scientists posit that our brains use some form of representational code that is carried in the firing patterns of neurons. Computational accounts seem to offer an easy way of explaining how our brains carry and manipulate the perceptions, thoughts, feelings, and actions that make up our everyday experience. While most theorists maintain that representation is an important part of cognition, the exact nature of that representation is highly debated. The two main arguments come from advocates of symbolic representations and advocates of associationist representations. Symbolic representational accounts have been famously championed by Fodor and Pinker. Symbolic representation means that the objects are represented by symbols and are processed through rule governed manipulations that are sensation to the constitutive structure. The fact that symbolic representation is sensitive to the structure of the representations is a major part of its appeal. Fodor proposed the Language of Thought Hypothesis in which mental representations manipulated in the same way that language is syntactically manipulated in order to produce thought. According to Fodor, the

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language of thought hypothesis explains the systematicity and productivity seen in both language and thought. Associativist representations are most often described with connectionist systems. In connectionist systems, representations are distributed across all the nodes and connection weights of the system and thus are said to be sub symbolic. It is worth noting that a connectionist system is capable of implementing a symbolic system. There are several important aspects of neural nets that suggest that distributed parallel processing provides a better basis for cognitive functions than symbolic processing. Firstly, the inspiration for these systems came from the brain itself indicating biological relevance. Secondly, these systems are capable of storing content addressable memory, which is far more efficient than memory searches in symbolic systems. Thirdly, neural nets are resilient to damage while even minor damage can disable a symbolic system. Lastly, soft constraints and generalization when processing novel stimuli allow nets to behave more flexibly than symbolic systems. The Churchlands described representation in a connectionist system in terms of state space. The content of the system is represented by an n-dimensional vector where the n= the number of nodes in the system and the direction of the vector is determined by the activation pattern of the nodes. Fodor rejected this method of representation on the grounds that two different connectionist systems could not have the same content. Further mathematical analysis of connectionist system relieved that connectionist systems that could contain similar content could be mapped graphically to reveal clusters of nodes that were important to representing the content. Unfortunately for the Churchlands, state space vector comparison was not amenable to this type of analysis. Recently, Nicholas Shea has offered his own account for content within connectionist systems that employs the concepts developed through cluster analysis. Computational neuroscience is committed to the position that the brain is some sort of computer, but what does it mean to be a computer? The definition of a computation must be narrow enough so that we limit the number of objects that can be called computers. For example, it might seem problematic to have a definition wide enough to allow stomachs and weather systems to be involved


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in computations. However, it is also necessary to have a definition broad enough to allow all of the wide varieties of computational systems to compute. For example, if the definition of computation is limited to syntactic manipulation of symbolic representations, then most connectionist systems would not be able to compute. [48] Rick Grush distinguishes between computation as a tool for simulation and computation as a theoretical stance in cognitive neuroscience. For the former, anything that can be computationally modeled counts as computing. In the latter case, the brain is a computing function that is distinct from systems like fluid dynamic systems and the planetary orbits in this regard. The challenge for any computational definition is to keep the two senses distinct. Alternatively, some theorists choose to accept a narrow or wide definition for theoretical reasons. Pancomputationalism is the position that everything can be said to compute. This view has been criticized by Piccinini on the grounds that such a definition makes computation trivial to the point where it is robbed of its explanatory value. The simplest definition of computations is that a system can be said to be computing when a computational description can be mapped onto the physical description. This is an extremely broad definition of computation and it ends up endorsing a form of pancomputationalism. Putnam and Searle, who are often credited with this view, maintain that computation is observer-related. In other words, if you want to view a system as computing then you can say that it is computing. Piccinini points out that, in this view, not only is everything computing, but also everything is computing in an indefinite number of ways. Since it is possible to apply an indefinite number of computational descriptions to a given system, the system ends up computing an indefinite number of tasks. The most common view of computation is the semantic account of computation. Semantic approaches use a similar notion of computation as the mapping approaches with the added constraint that the system must manipulate representations with semantic content. Note from the earlier discussion of representation that both the Churchlands' connectionist systems and Fodor's symbolic systems use this notion of computation. In fact, Fodor is famously credited as saying "No computation without representation".Computational

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states can be individuated by an externalized appeal to content in a broad sense (i.e. the object in the external world) or by internalist appeal to the narrow sense content (content defined by the properties of the system). In order to fix the content of the representation, it is often necessary to appeal to the information contained within the system. Grush provides a criticism of the semantic account. He points out that appeal to the informational content of a system to demonstrate representation by the system. He uses his coffee cup as an example of a system that contains information, such as the heat conductance of the coffee cup and the time since the coffee was poured, but is too mundane to compute in any robust sense. Semantic computationalists try to escape this criticism by appealing to the evolutionary history of system. This is called the biosemantic account. Grush uses the example of his feet, saying that by this account his feet would not be computing the amount of food he had eaten because their structure had not been evolutionarily selected for that purpose. Grush replies to the appeal to biosemantics with a thought experiment. Imagine that lightning strikes a swamp somewhere and creates an exact copy of you. According to the biosemantic account, this swamp-you would be incapable of computation because there is no evolutionary history with which to justify assigning representational content. The idea that for two physically identical structures one can be said to be computing while the other is not should be disturbing to any physicalist. There are also syntactic or structural accounts for computation. These accounts do not need to rely on representation. However, it is possible to use both structure and representation as constrains on computational mapping. Shagrir identifies several philosophers of neuroscience who espouse structural accounts. According to him, Fodor and Pylyshyn require some sort of syntactic constraint on their theory of computation. This is consistent with their rejection of connectionist systems on the grounds of systematicity. He also identifies Piccinini as a structuralist quoting his 2008 paper: "the generation of output strings of digits from input strings of digits in accordance with a general rule that depends on the properties of the strings and (possibly) on the internal state of the system".Though Piccinini undoubtedly espouses structuralist views in that paper, he claims that mechanistic accounts of computation avoid reference


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to either syntax or representation. It is possible that Piccinini thinks that there are differences between syntactic and structural accounts of computation that Shagrir does not respect. In his view of mechanistic computation, Piccinini asserts that functional mechanisms process vehicles in a manner sensitive to the differences between different portions of the vehicle, and thus can be said to generically compute. He claims that these vehicles are medium-independent, meaning that the mapping function will be the same regardless of the physical implementation. Computing systems can be differentiated based upon the vehicle structure and the mechanistic perspective can account for errors in computation. Dynamical systems theory presents itself as an alternative to computational explanations of cognition. These theories are staunchly anti-computational and anti-representational. Dynamical systems are defined as systems that change over time in accordance with a mathematical equation. Dynamical systems theory claims that human cognition is a dynamical model in the same sense computationalists claim that the human mind is a computer. A common objection leveled at dynamical systems theory is that dynamical systems are computable and therefore a subset of computationalism. Van Gelder is quick to point out that there is a big difference between being a computer and being computable. Making the definition of computing wide enough to incorporate dynamical models would effectively embrace pancomputationalism. Explanation in Neuroscience Mechanistic Explanation Smith wants to know why the dishwasher is not working. Jones tells him that the basement lights have to be on before the dishwasher will work. Smith doesn't understand the connection between the functioning of the dishwasher and the status of the basement lights, so Jones explains that the dishwasher is connected to the basement lights in a series circuit. This is an example of mechanistic explanation. In order to explain the phenomenon of the malfunctioning dishwasher, Jones has to appeal to the lower-level components of the circuit process, like a light switch and the wiring. Jones has to appeal to the organization of those components, i.e. the serial organization of the circuit.

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Jones also has to appeal to a causal aspect, the light switch being on completes the circuit, and thus allows power to flow to the dishwasher. After Jones explains those aspects of the mechanism, Smith is able to understand the connection between the dishwasher and the basement lights. This example, though imperfect, does help to illustrate mechanistic explanation. Mechanistic explanation works by appealing to the causal structure of some system or process. It attempts to demonstrate how constituent parts and their activities interact causally to explain the capacities of a given phenomenon. Understanding the mechanisms that give rise to a phenomenon are, according to a mechanistic explanation, necessary to explain the phenomenon. There are four important aspects of mechanisms: phenomenal, componential, causal, and organizational aspects. The phenomenal aspect involves the mechanism having to do something. The componential aspect involves the need for the mechanism to be able to be broken down into its component parts. The causal aspect involves the component parts of the mechanism needing to causally interact with one another. Finally, the organizational aspect involves the components' need to be spatially and temporally organized in a proper way in order to create some phenomenon. Because the present-day causal-mechanistic view of explanation was abetted by Wesley C. Salmon and Salmon emphasized an ontic view of explanation, mechanistic explanation is sometimes connected to the ontic conception. The ontic conception contains three important contentions. Firstly, the causal structures identified with the explanandum phenomenon form the basis of objective explanations. Secondly, explanations just are these structures. Thirdly, the ontic sense of explanation is fundamental to all other forms. The ontic conception construes mechanistic explanations as the real phenomena described by explanatory "texts," even if the explanation is not precise enough or contains inaccurate information. The ontic conception is opposed by the epistemic conception of Jan Faye, William Bechtel, Cory Wright, Dingmar van Eck, Marie Kaiser, and many others. According to the epistemic conception, explanations are operations on explanatory knowledge. Both the ontic and epistemic conceptions agree that philosophical progress among theories of explanation will characterize the norms of explanation. Carl Craver developed


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Salmon's mechanistic conception of causality. Salmon viewed causality as an exchange of conserved quantities at world-line intersections. Craver views causality from a manipulationist perspective. From this perspective, causal relevance in a mechanism involves seeing changes in the behavior of module X when module Y is intervened upon. This view of causation is very amenable to scientific discovery, since the entire goal of experimentation is to alter the values of an independent variable and measuring the changes in the dependent variable. Dynamical Systems Theory Proponents of dynamical system theory claim that dynamical systems are not amenable to mechanistic explanations. These theorists measure behavioral patterns and fit the results to a mathematical equation. The explanatory strength of these results come from the ability of the model to predict future patterns of behavior and thus resemble covering law explanations. [60] Mechanistic philosophers criticize predictivist explanations on the grounds that mathematical models are not satisfactory explanations, because they cannot distinguish between how the system could possibly work and how the system actually works. There are many different physical systems that could give the same behavioral results. By relying on models as the basis for explanation, the theory will never be able to identify the system that actually instantiates the mathematical results. REFERENCES [1] Craver, "Explaining the Brain: Mechanisms and Mosaic Unity of Neuroscience" 2007, Oxford University Press, citation: preface vii. [2]

Bickle, John, Mandik, Peter and Landreth, Anthony, "The Philosophy of Neuroscience", The Stanford Encyclopedia of Philosophy (Summer 2010 Edition), Edward N. Zalta (ed.).

[3]

Poldrack (2010) "Subtraction and Beyond" in Hanson and Bunzl, Human Brain Mapping. pp. 147–160.

[4]

Klein C. (2010) "Philosophical Issues in Neuroimaging" Philosophy Compass 5(2) pp. 186–198.

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[5]

Dunn (2003) "The Elusive Dissociation" cortex 39 no. 1 pp. 21–37.

[6]

Dunn and Kirsner. (2003). What can we infer from double dissociations?

[7]

deCharms and Zandor (2000) "Neural Representation and the temporal code" Annual Reviews of Neuroscience 23: pp. 613–47.

[8]

Winsberg (2003) "Simulated Experiments: a Methodology for the Virtual World" Philosophy of Science.vol 70 no 1 105–125.

[9]

Huettel, Song and McCarthy Functional Magnetic Resonance Imaging 2009 Sinauer Associates pp. 1.

[10] Passingham, R. E. Stephan, K. E. Kotter, R. "The anatomical basis of functional localization in the cortex", Nature Reviews Neuroscience. 2002, VOL 3; PART 8, pages 606–616. [11] Anderson. (2007) "The Massive Redeployment Hypothesis and Functional Topography of the Brain" Philosophical Psychology Vol20 no 2 pp.144–149. [12] The Massive Redeployment Hypothesis and Functional Topography of the Brain" Philosophical Psychology Vol20 no 2 pp.149–152. [13] Bunzel, Hanson, and Poldrack "An Exchange about Localization of Function" Human Brain Mapping. pp.50. [14] Van Orden, G and Paap, K "Functional Neuroimaging fails to discover Pieces of the Mind" Philosophy of science. 64 pp. S85-S94. [15]

Poldrack (2006) "Can Cognitive Processes be inferred from Neuroimaging Data" Trends in Cognitive science. vol 10 no 2.

[16] Coltheart, M (2006b), "What Has Functional Neuroimaging Told Us about the Mind (So Far)?", Cortex 42: 323–331. [17] Rooskies, A. (2009) "Brain-Mind and Structure-Function Relations: A methodological Response to Coltheart" Philosophy of Science. vol 76. [18] Henson, R (2006) "Forward Inference Using Functional Neuroimaging: Dissociations vs Associations" Trends in Cognitive Science vol 10 no 2. [19] Poldrack "Subtraction and Beyond" in Hanson and Bunzl Human Brain Mapping pp. 147–160.


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[20] Wig, Schlaggar, and Peterson (2011) "Concepts and Principals in the Analysis of Brain Networks" Annals of the New York Academy of Sciences 1224. [21] Mumford et al (2010) "Detecting network modules in fMRI time series: A weighted network analysis approach" Neuroimage. 52. [22] Coltheart, M "Assumptions and Methods in Cognitive Neuropsychology" in The Handbook of Cognitive Neuropsychology. 2001. [23] Patterson, K and Plaut, D (2009) "Shallow Droughts Intoxicate the Brain: Lessons from Cognitive Science for Cognitive Neuropsychology". [24] Davies, M (2010) "Double Dissociation: Understanding its Role in Cognitive Neuropsychology" Mind & Language vol 25 no 5 pp500-540. [25] Joula and Plunkett (1998) "Why Double Dissociations Don't Mean Much" Proceedings of the Cognitive Science Society. [26] Keren, G and Schuly (2003) "Two is not Always Better than One: a Critical Evaluation of Two System Theories" Perspectives on Psychological Science Vol 4 no 6. [27]

Charter, N (2003) "How Much Can We Learn from Double Dissociations" Cortex 39 pp.176–179.

[28] Dunn, J (2003) "The elusive Dissociation" Cortex 39 no 1 21–37. [29] Caramazza, A (1986) "On Drawing Inferences about the Structure of Normal Cognitive Systems From the Analysis of Patterns of Impaired Performance: the Case for Single Case Studies". [30] Newcombe and Marshall (1988) "Idealization Meets Psychometrics. The case for the Right Groups and the Right Individuals" Human Cognitive Neuropsychology edited by Ellis and Young. [31] deCharms and Zandor (2000) "Neural Representations and the Cortical Code" Annual Review of Neuroscience 23:613–647. [32] Craver, Carl Explaining the Brain. Oxford University Press New York, New York. 2007. [33] Jones and Love (2011) "Bayesian Fundemantalism or Enlightenment? on the explanatory status and theoretical contribution of Bayesian models of cognition"

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Brain and Behavioral Sciences vol 34 no 4. [34] Winberg, E (2003) "Simulated Experiments: Methodology for a Virtual World" Philosophy of Science.vol 70 no 1. [35] Horst, Steven, "The Computational Theory of Mind", The Stanford Encyclopedia of Philosophy (Spring 2011 Edition), Edward N. Zalta (ed.). [36] Piccini, G (2009) "Computationalism in the Philosophy of Mind" Philosophical Compass vol 4. [37] Miller, G (2003) "The Cognitive Revolution: a Historical Perspective" Trends in Cognitive Science. vol 7 no 3. [38] Garson, James, "Connectionism", The Stanford Encyclopedia of Philosophy (Winter 2010 Edition), Edward N. Zalta (ed.). [39] Pitt, David, "Mental Representation", The Stanford Encyclopedia of Philosophy (Fall 2008 Edition), Edward N. Zalta (ed.). [40] Aydede, Murat, "The Language of Thought Hypothesis", The Stanford Encyclopedia of Philosophy (Fall 2010 Edition), Edward N. Zalta (ed.). [41] Bechtel and Abrahamsen. Connectionism and the Mind. 2nd ed. Malden, Mass: Blackwell, 2002. [42] Shea, N. "Content and its Vehicles in Connectionist Systems" Mind and Language. 2007. [43] Laakso, Aarre & Cottrell, Garrison W. (2000). Content and cluster analysis: Assessing representational similarity in neural systems. Philosophical Psychology 13 (1):47–76. [44] Shagrir (2010) "Computation San Diego Style" Philosophy of science vol 77. [45] Grush, R (2001) "The semantic Challenge to Computational Neuroscience"In Peter K. Machamer, Peter McLaughlin & Rick Grush (eds.), Theory and Method in the Neurosciences. University of Pittsburgh Press. [46] Piccinini, G. (2010). "The Mind as Neural Software? Understanding Functionalism, Computationalism, and Computational Functionalism." Philosophy and Phenomenological Research. [47] Piccinini, G. (2010b). "The Mind as Neural Software? Understanding


Functionalism, Computationalism, and Computational Philosophy and Phenomenological Research 81.

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Functionalism."

[48] Piccinini, G (2009) "Computation in the Philosophy of Mind" Philosophical Compass. vol 4. [49] Piccinini, Gualtiero, "Computation in Physical Systems", The Stanford Encyclopedia of Philosophy (Fall 2010 Edition), Edward N. Zalta (ed.). [50] Piccinini (2008) "Computation without Representation" Philosophical Studies vol 137 no 2. [51] van Gelder, T. J. (1998). The dynamical hypothesis in cognitive science. Behavioral and Brain Sciences 21, 1–14. [52] Bechtel and Craver (2006) "Mechanism" In S. Sarkar & J. Pfeifer (eds.), Philosophy of science: an encyclopedia (pp. 469–478). New York: Routledge. [53] Salmon, Wesley C. (1998) "Causality and Explanation" New York: Oxford University Press. [54] Wright, C. (2012). Mechanistic explanation without the ontic conception. European Journal of Philosophy of Science, 2: 375–394. [55] van Eck, D. (2015). Reconciling ontic and epistemic constraints on mechanistic explanation, epistemically. Axiomathes, 25(1): 5–22. [56] Steep Chimero and Turvey (2011) "Philosophy for the rest of cognitive science" Topics in cognitive science 3. [57] Bechtel, W.; Mandik, P.; Mundale, J. (2001). "Philosophy meets the neurosciences.". In Bechtel, W.; Mandik, P.; Mundale, J.; et al. Philosophy and the Neurosciences: A Reader. Malden, MA, USA: Blackwell. [58] Clark, Andy (2000). Mindware: An Introduction to the Philosophy of Cognitive Science. New York: Oxford University Press. [59] Churchland, Patricia Smith (2002). Brain-Wise: Studies in Neurophilosophy. The MIT Press. [60] Churchland, Patricia Smith (1989). Neurophilosophy: Toward a Unified Science of the Mind-Brain. [61] Craver, Carl (2007). Explaining the brain: mechanisms and the mosaic unity of

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neuroscience. Oxford University Press. [62] Northoff, Georg (2004). Philosophy of the Brain: The brain problem. John Benjamins. [63] Walter, Henrik (2001). Neurophilosophy of Free Will: From Libertarian Illusions to a Concept of Natural Autonomy.


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Neurochemical Mechanisms of Memory, Visual and Auditory Perception, Vestibular Sensitivity, Chemoreception, Skin Sensitivity Neurochemical Mechanisms of Memory Constant storage of information is associated with chemical or structural changes in the brain. Memorization is carried out by means of electrical activity, i.e. Chemical or structural changes in the brain should somehow affect the electrical activity. If memory systems are the result of electrical activity, then, consequently, we are dealing with nerve circuits that can realize memory traces. The simplest chain providing memory is a closed loop. Excitation follows the whole circle and starts a new one. This process is called reverberation. The incoming sensor signal triggers a sequence of electrical pulses that persists indefinitely after the signal ceases. Selective electrical activation of a specific nerve loop provides a short-term memory. How can we imagine a long-term memory in such a scheme? According to one popular theory, multiple electrical activity in neural circuits causes chemical or structural changes in the neurons themselves, which leads to the emergence of new neural circuits. This change in the chain is called consolidation. Consolidation of the trace occurs in the continuation of a long time. The basis of long-term memory is the constancy of the structure of neural circuits. Thus, short-term and long-term memory can be associated with the same nerve elements, with the difference that short-term memory is the temporary electrical activity of certain neurons, and long-term memory is a constant structure of the same neurons. There are 2 hypotheses regarding consolidation mechanisms: The first assumes that the long-term memory is contained in the structure of protein molecules in each synapse. And the nervous information passes through the synaptic cleft by chemical means. According to another view, long-term memory can be the result of the

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emergence of new synapses. This means that whenever a new material is memorized, physical changes occur in the brain. After the chemical processes underlying heredity were discovered, the idea arose that the same mechanisms could participate in the memorization processes. Since DNA contains genetic memory for every individual organism, it is logical to assume that it or RNA can also transmit and acquire experience. Instructions for protein synthesis carried by an RNA molecule are enclosed in a specific sequence of organic bases attached to the backbone of the molecule, namely they serve as matrices for the synthesis of proteins. A different sequence leads to the synthesis of different proteins. It can be assumed that this sequence changes as a result of the experience acquired by animals in training. Molecular Mechanisms of Long-term Memory (gene expression) Effector proteins determine the storage of information in the body. Regulatory proteins - by joining DNA or separating from it, control the expression of genes. External action leads to a change in the extracellular environment, causes a cascade reaction in the genome, in which two phases are distinguished: 1. Activation phase: corresponds to the induction of specific regulatory genes from the class of early genes. About 100 early genes are known. The majority of them are regulatory proteins. The activity of these proteins occurs 15-30 minutes after exposure, is short-term (from 1 to 3 hours) - this process corresponds to short-term and intermediate memory (consolidation). Early genes control the transcription of late genes, which are targets for them. Regulatory proteins (products of early genes) produce expression of late genes - morphoregulatory. These genes determine the second phase of the synthesis of RNA and proteins. 2. The second phase of synthesis of RNA and proteins - causes the growth and alteration of cellular bonds in the structures of the brain. The second wave of activity appears 3 hours after exposure and lasts about 5 hours. Includes the synthesis of 4 new proteins, after 24 hours - 2 more proteins.


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Long-term memory is formed after the expression of late genes and depends on the induction of new genes through secondary mediators. It is suggested that early effector genes are responsible for the synthesis of proteins that retain information for days. Late effector genes support information for weeks and months. The formation of a new experiment requires the expression of genes in the brain. The main step in understanding the biological mechanisms of memory consolidation was the discovery of the 1960s, which showed that the transition of memory from short-term to long-term requires synthesis of new RNA and protein molecules, i.e. Gene expression. It was found that the wave of synthesis of new proteins in cells when memorizing information coincides with the period of memory consolidation, and the chemical blockade of gene expression during this period disrupts the formation of long-term memory. It turned out that the "critical window" of the amnestic action of gene expression blockers is universal for a variety of types of learning and various organisms, from invertebrates to humans. This assumption was also in good agreement with the hypothesis of the involvement of cell growth and changes in the morphology of synapses in long-term memory. Thus, the notion of long-term memory was gradually transformed from the conventional symbol of the relative duration of the phenomenon, into a component of the biological concept linking learning and experience with morphogenesis and development. The critical link in this concept was the molecular mechanism of memory consolidation, identified with the activation of gene transcription in nerve cells in learning. When learning in the brain, genes of transcription factors are activated. The first genes, activation of which was found in the brain during training, were the so-called "immediate early genes", which encode transcription factors. "Immediate early genes" were first discovered when studying the mechanisms of the genomic response to the action of growth factors that trigger the processes of the cell cycle. The induction of their transcription occurred despite the addition of inhibitors of protein synthesis, that is, it was built on mechanisms ready in advance for the perception of extracellular stimuli. The

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first of the identified products of the genes of this family turned out to be nuclear proteins that bind to DNA and regulate the transcription of other genes. By these properties, these genes resembled the group of "immediate early genes" of bacteriophages and eukaryotic DNA viruses, therefore, by analogy with viral genes, this group of rapidly activating genes was called "cellular immediate early genes." This family is often referred to as "primary response genes," "early response genes," or simply "early" genes. One of the first in this group was the cloned c-fos gene. Its structure and properties are well studied, and it can serve as a prototype of the genes of this family. It was originally established that during embryonic development, c-fos plays an important role in regulating the processes of cell growth and proliferation. Genes whose expression is under the control of induced transcription factors have been named, by analogy with viral systems, "late" genes, "late response genes" or "effector" genes, and the entire two-phase transcriptional regulation mechanism involving these two classes of genes is one of the most universal methods of ensuring the processes of cell division and growth in development. Gene expression is a process in which hereditary information from a gene (a sequence of DNA nucleotides) is converted into a functional product - RNA or protein. At the molecular-genetic level, learning constitutes a single continuum with development. Thus, when learning in nerve cells, the following sequence of molecular genetic processes is observed: First, the mismatch of the current situation with the available experience triggers activation of the cascade of "early" regulatory genes in the groups of cells that mediate these processes. Products of "early" genes induce, in turn, the expression of "late" genes, including the genes of morphoregulatory molecules, which are key participants in the processes of morphogenesis in embryonic development. These and other effector genes stabilize the participation of neurons in the new functional system that has developed in the learning outcome. At the same time, the basic molecular-genetic elements and stages of the molecular cascade of cell differentiation turn out to be extremely similar in learning and development. In a certain sense, we can say that at the molecular


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level, learning is an ongoing process of development. However, the mechanisms of regulation of gene expression in learning have one extremely important difference from similar processes in development. At the systemic level, the activity of genes in the brain during learning passes under cognitive control. It was mentioned above that the question of whether or not any behavioral situation will cause the expression of "early" genes in brain cells depends critically on the content of the past individual experience of the animal and is determined by the factor of subjective novelty of this event. This is clearly seen from the following experiment. Consequently, the relationship between the processes of development of the nervous system and learning requires description at two different levels. At the level of regulation of gene expression, learning really makes up with the development of the brain a single continuum. In both cases, the differentiation of nerve cells depends on the activation of certain transcription factors in them. Some of these proteins are encoded by a family of "early" genes. Activation of these genes in the developing and learning brain is carried out through growth factors, mediators and hormones. Following the expression of transcription factors, a second wave of activation of "late" or effector genes. Белковые продукты этих генов, выполняют разнообразные функции в нервных клетках. В частности, молекулы клеточной адгезии и другие синаптические белки изменяют связи нейрона, устанавливая функциональную специализацию клетки в системе межклеточных отношений. Сходство молекулярных механизмов клеточной специализации на границе между завершающими стадиями созревания нервных связей и началом их модификации в поведении настолько велико, что, пользуясь одними лишь критериями молекулярного анализа, часто невозможно определить, относится ли рассматриваемый клеточный процесс к развитию или к научению. Physiological Mechanisms of Memory Memory regulation systems: in memory regulations, different structures are involved depending on whether it is arbitrary memory or involuntary. The memory management and control system includes:

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1) Nonspecific components: reticular formation, hypothalamus, nonspecific thalamus, hippocampus, frontal cortex. 2) Modal-specific components (associated with the activity of analyzer systems). It is provided by the activity of analyzer systems, mainly at the level of primary and associative zones. In the provision of voluntary memorization, frontal lobes (especially the left hemisphere) play a leading role. Forming Engrams Engram is a trace left in the brain by one or another event. The formation of the engram takes place in 3 stages: 1. Based on the activity of the analyzers, a sensory trace (sensory memory) 2. Sensory information is sent to higher departments. In the cortical zones, the hippocampus and limbic system, analysis, sorting and processing of signals takes place. The hippocampus acts as a selective input filter. He classifies all signals and discards random signals, facilitating the organization of sensory traces. He also participates in extracting traces from long-term memory under the influence of motivation. The temporal region establishes a connection with the places of storage of traces of memory in other parts of the brain, i.e. Responsible for reorganization of nerve networks in the process of assimilation of new knowledge. 3. The ice processes are transformed into stable structures of long-term memory (this can happen in a dream and in wakefulness). Keeping information: Karl Lashley in his experiments came to the conclusion that memory is simultaneously in the brain everywhere and nowhere. Traces of memory are widely represented in the cortex and at the same time they are repeatedly duplicated, it is impossible to find exact localization of those or other memories. Neural Mechanisms of Memory With the development of microelectrode technology, it became possible to study the electrophysiological processes underlying memory at the level of the nerve cell.


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The most effective method was the intracellular diversion of the electrical activity of an individual neuron. With its help, one can analyze the role of synaptic processes in changing the activity of a neuron. In particular, on this basis, neural mechanisms of a simple form of learning - habituation - were established. The study of the neural bases of memory involves the search for structures whose neurons exhibit plastic changes in learning. Experimentally, such neurons were found in animals in the hippocampus, the reticular formation and some areas of the cortex. Stages of Consolidation Making a memory permanent involves multiple stages and different processes.

Studies by Hiden have shown that the formation of traces of memory is accompanied by changes in the properties of RNA and protein in neurons. Irritation in the cell causes long biochemical traces. But in later works it was shown that DNA plays the leading role in the formation of engrams, which can serve as a repository of not only genetic but also acquired information, and RNA provides transmission (therefore neurons do not divide so as not to destroy acquired information).

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(1) A subset of information in sensory buffers is encoded and placed into short-term memory (STM) (2) If information is rehearsed or used, it may be consolidated into long-term memory (LTM), lasting from minutes up to a lifetime (3) When we probe a participant’s memory, she must retrieve information from LTM and place it into STM to perform a task, such as reporting the items in a list (4) At any stage of the process, information may be forgotten.

The information is encoded in neural structures of the brain in the form of special memory vectors, which are created by a set of postsynaptic loci on the body of a neuron detector having different electrical conductivity. This vector is defined as the unit of the structural code of memory. The perception vector consists of a set of postsynaptic potentials of various amplitudes. The dimensions of all the vectors of perception and all memory vectors are the same. If the potential pattern completely coincides with the conductivity pattern, then this corresponds to the identification of the perceived signal.


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Mechanisms of Visual Perception Perception is a kind of action aimed at examining the perceived object and creating its copy, its similarity. An essential component of perception are motor processes. These include the movements of the hand that feels the object, the movement of the eye, tracing the visible outline of the object, the movement of the larynx that reproduces the audible sound, and so on. Any perception is carried out with the help of sensory receptors. The receptor is a device that interacts with a certain factor (lock-key). The absolute receptor sensitivity threshold is the minimum stimulus strength to which the receptor responds. This threshold is constantly changing, depending on the individual characteristics of the NS and its state. The differential threshold is the minimum increase in stimulus strength, accompanied by a significant change in the response of the sensory neuron. The relative (difference) threshold is the perceived minimum difference in the strength of two similar types of stimuli (?). The spatial threshold is the minimum distance between stimuli, on which they are perceived as separate. Similarly, the time threshold is determined. The information accumulated over the last decades on the neurons of sensory systems confirm the detector principle of the neuronal organization of the most diverse analyzers. For the visual cortex, neurons-detectors, selectively responding to the elements of the figure, contours-lines, bands, corners, were described. The classification of neurons-detectors of the visual cortex, selectively sensitive to different orientation of lines and their size, was also developed, linking them with simple, complex and super complicated receptive fields. It was also shown the existence of color detectors selectively tuned to different shades of colors. An important step in the development of the theory of sensory systems was the discovery of constant neurons-detectors, taking into account, in addition to visual signals, signals about the position of the eyes in orbits. In the cortex, the reaction of constant neurons-detectors is attached to a certain area of the outer space, forming a constant screen. In addition, another type of constant neuron encoding light was discovered. Their reaction to certain reflective properties of

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the object's color surface does not depend on the lighting conditions. In the cortex there is not only vertical (columnar) ordering of neuronal placement, but also horizontal (layered). The neurons in the column are combined on a common basis. And the layers are joined by neurons that distinguish different signs, but of the same level of complexity. Neurons-detectors that react to more complex signs are localized in the upper layers. Thus, the columnar and layered organization of the cortical neurons indicate that the processing of information about the features of the object, such as shape, movement, color, occurs in parallel neural channels. At the same time, the study of the detector properties of neurons shows that the principle of divergence of information processing paths along many parallel channels must be supplemented by the convergence principle in the form of hierarchically organized neural networks. The more complex the information, the more complex the structure of the hierarchically organized neural network is required for its processing. In the work, the hands and the eyes have much in common. The eye, like the hand, sequentially examines, "feels" the contours of the picture and the subject. Analysis of the functions of the movements of the hand in the process of touch and eye in the process of sight showed that they are divided into two large classes. The first includes search, adjustment and corrective movements. With their help, a search for a given object of perception is performed, setting the eye (or hand) to the "starting position", adjusting this position. The second class includes the movements involved in constructing the image, in measuring the spatial characteristics of the object, in identifying familiar objects, and so on. This is a class of proper gnostic movements, perceptual actions. Mechanisms of Auditory Perception The auditory sensory system ensures the perception of sounds and the construction of auditory images, i.e. hearing. An adequate stimulus for her is sound. This means that it is to the sounds that the auditory sensory system has an increased sensitivity and receptivity, and also creates such sensory images that correctly reflect the important characteristics of the sound stimuli and


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allow us to orient ourselves in the sound signals. To understand the physiology of hearing, we need to explain the occurrence of auditory sensory flow of excitation, its movement through the nervous system and the formation of an auditory sensory image. Stimulus An irritant for the auditory sensory system is sound. Sound is the longitudinal vibration of the particles of the medium that transmits sound. Sound vibrations are transmitted through air, water, skull bones, i.e. On gaseous, liquid and solid media. The main parameters of sound waves are the frequency of oscillations, their amplitude and timbre (frequency spectrum). Frequency is the tone of sound. The higher the tone of a sound, the higher the frequency of sound vibrations. The range of human perception of sound is about 20 to 20,000 Hz (hertz is one oscillation per second). Sounds below 20 Hz are called infrasound, their consciousness does not perceive, there may be subconscious reactions (anxiety, anxiety, fear and even inexplicable horror). Infrasound with a frequency of 4 Hz is considered the most dangerous, with a frequency of 8-14 Hz - correspond to the alpha-rhythm of the brain and, apparently, can cause a trance state. Infrasound of this frequency is capable of producing professional equipment in discotheques and in such a way to cause in the people present there a special altered state of consciousness. Sounds tone above 20,000 Hz are called ultrasound, the person does not perceive them (however, cats, dogs and other animals perceive). The greatest sensitivity of the ear is in the range from 1000 to 3000 Hz - this is just the range of sounds of human speech. Musical reproducing devices have a wider range from 12-14 Hz to 16,000. Carrying out Stimulation (sound) to Receptors The reception (transduction) of sound is the perception of sound at the level of the ear's ear receptors, i.e. Transformation (transformation) of sound vibrations into nervous excitement. The receptors of sound are the hair cells (more precisely: internal hair cells),

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they are hidden in the cochlea of the inner ear, sit on the basement membrane of the organ of Corti. Therefore, they still need to deliver sound vibrations. Molecular Mechanisms of Transduction (reception) of Sound by Points 1. The hairs of the receptor hair cell are bent to the side when they rest against the cover membrane, rising to it together with the basal membrane. 2. Because of this, the cell membrane of the hair is stretched, and ion channels for sodium (Na+) are opened in it. These are mechanosensitive ion channels (stretch channels), which are opened directly by stretching the cell membrane. I propose to call such channels in the receptor cells "stimulated-controlled" ion channels, because they are opened by a stimulus-stimulus. 3. Na+ ions through the channels opened for them rush into the cell. 4. They bring with them positive electrical charges (+) and cause a decrease in electronegativity inside the cell. This is the process of depolarization. The electronegativity of the receptor hair cells decreases, the polarization of the membrane decreases, and this means that the receptor cells go into an excited state. 5. Now comes an important point, which should pay special attention. In response to depolarization, other channels are opened-potential-controlled ion channels for Ca2+. Note that in the receptor cells, unlike conventional neurons, "new characters" appear-calcium channels that are sensitive to depolarization. With depolarization excitation, these channels open and admit calcium ions into the receptor cell. Actually, it was for this purpose, for the introduction of calcium ions into the cell, that depolarization, obtained by the discovery of stimuli-dependent ion channels, was needed. 6. So, through the potential-dependent ion channels Ca2+, discovered by depolarization, enters the cell. It is very important to remember that Ca2+ is not only an ion, but also a biologically active substance, a secondary messenger. And he has an important role in the work of the receptor cell. Calcium binds to a special protein and causes the bubbles with the mediator to move to the membrane and throw the mediator outward. Without calcium, nothing would have happened: the mediator would not stand out.


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7. And now the most important thing happens: from the receptor cell, under the action of the calcium entering into it, the neurotransmitter begins to be released. The neurotransmitter is the substance that transmits excitation to the bipolar neuron connected to the receptor hair cell. How will the neurotransmitter give excitement? He just makes a bipolar neuron generate a nerve impulse. All this logical chain of reception of a sound is those: - the stronger the sound, the more the basal membrane with the hair cells on it fluctuated, - the more she hesitated, the stronger the hairs on the receptor cells, - the more the hairs became more bent, the more depolarization turned out, - the more depolarization was, the more entered the calcium cell through the calcium channels open to it, - the more calcium ions entered, the more the neurotransmitter was released from the auditory receptor cell. Thus, the sound power is embodied in the amount of the neurotransmitter isolated by the hair receptor cells. Mechanisms of Proprioception Proprioception is a sensation of the relative position of parts of the body and their movement in animals, in other words - the sensation of their body. It is provided by various organs-proprioceptors (in particular muscles), information from which on large (therefore fast-conducting) nerve fibers in the peripheral nerves and posterior columns of the spinal cord goes to the nucleus of the central nervous system and then through the thalamus to the parietal region of the brain where the body pattern is formed. Thanks to proprioception, a person can feel position, movement and strength: The feeling of position is the ability to sense the angle at which each joint is located, and in the sum - the position and posture of the whole body. The feeling of position is almost not subject to adaptation. The sense of movement is information about the direction and speed of movement of the joints. The person perceives both active movement of a joint

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at a muscular reduction, and passive, caused by external reasons. The threshold of perception of motion depends on the amplitude and on the rate of change in the angle of flexion of the joints. A sense of strength is the ability to assess the muscular effort applied to move or hold the joint in a certain position. Proprioceptors are related to the perception of space, the location of individual parts of the body. The true proprioceptors include muscle spindles, tendon organs and articular receptors. With their help, without the participation of sight, it is possible to accurately determine the position of individual parts of the body in space. Proprioceptors participate in awareness of the direction, speed of movement of the limb, sensation of muscle effort. A close function, but with respect to the movement of the head, is performed by the receptors of the vestibular analyzer. Proprioceptors, along with mechanical and thermoreceptors of the skin, allow not only to correctly assess the position of individual parts of the body, but also to build a three-dimensional tangible world. The main source of information for this is the hand, when it is in motion, touching and probing the object. Mechanisms of Vestibular Sensitivity The vestibular apparatus is a complex receptor of the vestibular analyzer. The structural basis of the vestibular apparatus is a complex of ciliated cells of the inner ear, endolymph, lime formations included in it - otoliths and jelly-like cupules in ampoules of semicircular canals.


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Many types of sensory signals are integrated and weighted in an internal model that optimized balance and orientation

A. Внутренняя модель оценки физической реальности

E = (bs – bf) = fs

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From the receptors of equilibrium, signals of two types come in: static (related to the position of the body) and dynamic (associated with acceleration). Both these and other signals arise when the sensitive hairs are mechanically stimulated by the displacement of either otoliths (or cupules) or endolymph. Usually otolith has a greater density than the surrounding endolymph, and is supported by sensitive hairs. When the position of the body changes, the direction of the force acting from the side of the otolith to the sensitive hairs changes. Studies on fish have shown that an effective stimulating force acting on the sensitive epithelium is a component directed parallel to the surface of the epithelium (the so-called shearing force). This is probably the reason for the irritation of hair cells in other vertebrates. An annoying effect on the semicircular canals is the acceleration of the movement of the entire body or head acting in the plane of each channel. Mechanisms of Chemoreception To the specific and highly sensitive chemoreceptor systems are the organs of taste and smell. In humans and other terrestrial organisms, these two kinds of sensitivity are clearly differentiated, but in aquatic animals, especially at lower stages of phylogenetic development, it is often difficult to decide which receptors should be considered tasteful and which are olfactory. Taste is caused by chemicals dissolved in saliva or water. As research has shown, a person is able to distinguish 4 primary tastes: sweet, salty, bitter and sour. Each of the basic flavors corresponds to a certain class of physical stimuli. Sweet sensations are mainly caused by sugar, salty - substances such as sodium chloride. Bitter taste indicates the presence of toxic substances in plants or fruits. Taste sensations arise due to the influence of the stimulus on special organs located on the surface of the tongue - taste buds, each of which contains chemoreceptors. A person has from 9 000 to 10 000 taste buds. In this case, there are two approaches that explain the emergence of taste. According to the first of them, each taste cell and the neuron associated with it react solely to a specific chemical substance. For example, the presence of sugar, providing a


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specific link to the brain: the concept of address coding. According to the second approach, the taste bud and the neuron associated with it react to some of the specific qualities to some extent. So, by the way, color vision is organized: individual cones (for example, red ones) preferentially react to one wavelength, but they are also sensitive to other waves (for example, to green color). Our taste sensitivity is largely determined by which part of the language is stimulated. It is known that the tip of the tongue is most sensitive to the sweet, to the sour - its edges, to the saline - the anterior and lateral surfaces, and to the bitter - the soft palate. Mechanisms of Skin Sensitivity The touch and pressure (so-called sensitivity) are perceived by about 500 000 recipes. These are mechanoreceptors, which include free nerve endings that penetrate the epidermis and perceive pressure, and are not free (encapsulated-having a capsule). To the unfavorable sensory nerve endings, the large Platine corpuscles of Fatter-Paccini and the tactile bodies of Meissner are located in the skin proper. Feelings of touch and pressure make it possible not only to recognize objects, but also to determine their shape, size, nature of the material from which these objects are made. The temperature sensation (sense of cold and heat) is perceived by different receptors. Some of them are excited by the action of cold on the end of the nerve bodies (Krause flasks), others - by the action of heat on the bulbous Golgi-Mazzoni bodies. Cold receptors penetrating between epidermal cells are located more superficially than thermal receptors. Cold receptors are much larger (about 250,000) than thermal ones (about 30,000). The skin of the extremities (especially open spaces) is less sensitive than the skin of the trunk (closed places). It is known that receptors that perceive temperature effects adapt to changes in the temperature of the environment.

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Receptive Fields in the Monkey Somatosensory System

(a) Excitatory and inhibitory areas of the receptive field of a sinhle touch neuron in the somatosensory cortex. (b) Receptive field of a somatosensory neuron that responded most to a horizontal edge. The recording to the right indicate the strength of the neuron’s response to edges of different orientation. (c) Receptive field of a neuron responsive to movement across, the fingertip in one direction but not the other.

The feeling of pain is perceived by special free nerve endings. The number of pain receptors in the human skin is very high, about 100-200 per 1 cm2 of skin surface. The total number of such receptors reaches 2-4 million. The place of origin of pain is determined by the person quite accurately. Neurochemical Basis of Motivation and Emotions The emergence of any emotion is based on the activation of various groups of biologically active substances in their complex interactions. Modality, quality of emotions, their intensity are determined by the relationship between noradrenergic, dopaminergic, serotonergic, cholinergic systems, as well as a number of neuropeptides, including endogenous opiates. An important role in the development of pathology of mood and affect is played by biogenic amines (serotonin, dopamine, norepinephrine). In S. Keti's opinion, as the concentration of serotonin in the brain increases, the mood in a person rises, and his deficiency causes a state of depression. Substances that improve mood, increase the content of norepinephrine and dopamine in nerve endings. The results of a brain examination of patients who committed suicide in a state of depression showed that it is depleted both by norepinephrine and serotonin. And the deficiency of norepinephrine is


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manifested by depressed angst, and the lack of serotonin is a depression of anxiety. Disturbances in the functioning of the cholinergic system lead to psychosis with the predominant defeat of intellectual (information) processes. The cholinergic system provides information components of behavior. Cholinolytics - substances that reduce the level of activity of the cholinergic system, worsen the performance of food-producing behavior, violate the perfection and accuracy of motor reflexes of avoidance, but do not eliminate the reaction to pain and relieve feelings of hunger. The state of aggression depends on the ratio of activity of the cholinergic and noradrenergic systems. The increase in aggressiveness is explained by the increase in the concentration of noradrenaline and the weakening of the inhibitory effect of serotonin. In aggressive mice, a decreased serotonin level in the hypothalamus, amygdala, and hippocampus is seen. Introduction of serotonin inhibits the aggressiveness. Thus, modern data indicate a strict dependence of our moods and experiences on the biochemical composition of the internal environment of the brain. The brain has a special system - a biochemical analyzer of emotions. This analyzer has its own receptors and detectors, it analyzes the biochemical composition of the internal environment of the brain and interprets it in the categories of emotions and mood. Biochemical basis for the formation of motivations of different biological quality are several groups of biologically active substances. First of all, they are neurotransmitters (acetylcholine, norepinephrine, serotonin, dopamine, etc.), which are distinguished by nerve endings and serve as mediators in the process of synaptic transmission. The other group consists of hormones secreted by the glands of internal secretion, and neurohormones produced by neurosecretory cells of the nervous tissue. Hormones and neurohormones enter the blood, lymph, into the tissue and spinal fluid and have a long-term regulatory effect on the central nervous system and visceral organs. An important role in the formation of motivations is played by polypeptides, vasopressin, oxytocin, etc., which have polyfunctionality: each neuropeptide has an unusually wide range of actions,

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simultaneously participating in the regulation of a variety of brain functions. Polyfunctionality, multicast peptides allow them to exert a regulatory influence on the body as a whole, capturing both central and peripheral mechanisms, thereby ensuring the organization of holistic behavioral acts. Partially this property is due to their ability to interact at the subcellular-molecular level with "classical" neurotransmitters and information macromolecules (DNA, RNA and proteins). The interruption of the synthesis of proteins in the center of hunger in the hypothalamus at any stage is accompanied by selective destruction of the food-producing behavior caused both naturally by food deprivation and by electrical stimulation of the "hunger center" in the lateral hypothalamus. At the same time, defensive reactions caused by electrical stimulation of the ventromedial hypothalamus do not suffer. Traditionally, it is customary to identify and characterize four types of temperament, the behavioral characteristics of which depend on the properties of the nervous system: 1. Sanguine (strong, balanced, moving). Sanguine people are characterized by activity, sociability and emotional stability. Conditional reflexes are formed quickly and differ in stability. The intensity of the reactions corresponds to the strength of the stimuli. The structures of the cortex and subcortex are characterized by strength, mobility and balanced excitability. 2. Phlegmatic (strong, balanced, inert). Phlegmatic are more sluggish and less active than sanguine, emotionally stable. Conditional reflexes are formed at a normal rate and are particularly strong. The relationship between the cortex and the subcortex is balanced, which provides good control over the behavior. 3. Choleric (strong, unbalanced). Choleric people are emotionally unstable, characterized by poorly controlled activity and sociability. Conditioned-reflex connections are formed more slowly than in sanguine and phlegmatic. Increased intensity of subcortical activity, not always regulated by the cortex. 4. Melancholic (weak). Melancholics are characterized by low activity and emotional instability. Reflexes are weak and formed slowly. The general energy of behavior is reduced. Low level of cortical activity and subcortical centers.


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Synthesis and Raman Spectra of New Kaz Smart and Kaz Mind Drugs to Improve Brain Function 1. Introduction Recently, in Kazakhstan and world work is widely carried out to find new nootropic drugs [1-7]. Nootropic drugs can accelerate learning processes, improve memory and mental activity, increase brain resistance to hypoxia, trauma, intoxication, etc., facilitate the processes of interhemispheric transmission of information, strengthen cerebral cortex control over subcortical structures. The novelty of the work lies in the fact that we have a new approach to finding new ways to improve brain function. Practical significance is the recommendations for the synthesis and use of Kaz Smart and Kaz Mind Drugs to improve brain function. The aim of the work is to synthesize and IR spectra of the new Kaz Smart and Kaz Mind Drugs to improve brain function. 2. Theory Currently, the world is actively searching for new drugs for the treatment of mental disorders - psychostimulants, antidepressants, anxiolytics, nootropics, etc. The urgency of the problem is related to the fact that mental disorders remain one of the most widespread diseases of mankind. The mechanisms of action of nootropic drugs are different. It is assumed that nootropic effects can be caused by: - direct impact on neurons; - improvement of cerebral blood flow and microcirculation of blood in the brain; - antiaggregant, antihypoxic, decongestant action and the like. At present, the main mechanisms of action of nootropic drugs are the influence on metabolic and bioenergetic processes in the nerve cell and interaction with the neurotransmitter systems of the brain. Neurometabolic stimulants improve the penetration through the BBB and utilization of glucose (especially in the cerebral cortex, subcortical ganglia, hypothalamus and

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cerebellum), improve the exchange of nucleic acids, activate the synthesis of ATP, protein and RNA. The effect of a number of nootropic drugs is mediated through neurotransmitter systems of the brain, among which the most important are: - monoaminergic (the drug causes an increase in the content in the brain of dopamine and norepinephrine, some other nootropics - serotonin); - cholinergic (the drug increases the content of acetylcholine in synaptic endings and the density of cholinergic receptors, choline alphoscerate, pyridoxine derivatives and pyrrolidine improve the cholinergic transmission in the CNS); - glutamatergic (the components act through N-methyl-D-aspartate (NMDA) receptor subtype). Thus, Kaz Smart and Kaz Mind affects the metabolic processes and blood circulation in the brain, increases the activity of enzymes in the respiratory chain, stimulates the synthesis of RNA and protein. 3. Results and Discussion We synthesized the composition to improve brain function. It is effective in treating cerebrovascular dementia, dementias represented by Alzheimer’s and Parkinson’s diseases, mental symptom disorders represented by depression, nervous symptom disorders represented by Parkinson disease, degenerative or regressive diseases of the central nervous system, brain disorders due to cerebral ischemia or hemorrhage represented by cerebral infarction, brain disorders due to traumas such as contusion, etc. Also this composition can be used for pilots and submariners when performing special works in extreme conditions. Tests of these drugs were carried out on 3 groups of volunteers, who after four hours of hypoxia were given the task. Table 1 shows the test results. Table 1. Results of Kaz Smart and Kaz Mind tests Index

Placebo

Kaz Smart

Kaz Mind

Dose, mg / kg

10

10

10

The correct solution of the problem,%

39,25

91,67

94,87


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As can be seen from the table, the greatest positive effect was shown by Kaz Mind. Figures 1 and 2 show Raman spectra of Kaz Smart and Kaz Mind. As seen from the spectra, the absorption band of 1110-1129 cm-1 is the characteristic band of vibrations of the CO2-- groups; 2629-1913 cm-1 - oscillations of the O-H groups; 3159 cm-1 - stretching vibrations of the N-H group of amino acids and nucleoside triphosphates (ATP, GTP, etc.).

Figure 1. Raman spectra of Kaz Smart Drugs to improve brain function

Figure 2. Raman spectra of Kaz Mind Drugs to improve brain function

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4. Conclusions Thus, the application of Kaz Smart and Kaz Mind significantly increases the speed of formation of the skill of visual-motor tracking, mental and physical performance. The composition can also be used as a material for food and beverages. It can be considered a functional food product for a specific health use that is effective for improving the brain functions. The dose of administration or administration to the present composition is preferably from 0.1 to 10 mg /kg of body weight per administration in order to obtain the desired effects. The novelty of the work lies in the fact that we have proposed a new approach to finding new nootropics that improve brain function. We proposed a new approach to the search for new nootropics, which improve brain function. It is shown that the IR spectrum of the new Kaz Smart and Kaz Mind Drugs to improve brain function. It was found that the absorption band of 1165 cm-1 is the characteristic band of the IR spectrum of nucleoside triphosphates (ATP, GTP, etc.). The search for the hypothesis of the action of nootropics, which is able to integrate already known aspects of the mechanism of action of nootropic drugs, continues. The search for new drugs with greater pharmacological activity and providing selective effects on the integrative functions of the brain, improving the patient's condition, his mental activity, orientation in everyday life. REFERENCES [1] Hu, H.P., Wu, M.X. (2006a) “Nonlocal Effects of Chemical Substances on the Brain Produced Through Quantum Entanglement,” in Progress in Physics, 3: 20-26. [2]

Hu, H.P., Wu, M.X. (2006b) “Photon Induced Non-Local Effects of General Anaesthetics on the Brain,” in NeuroQuantology, Vol. 4(1): 17-31.

[3]

Likhtenshtein G.I. «Spin labeling methods in molecular biology», 1974.

[4]

Likhtenshtein G.I., Yamauchi J., Nakatsuji S., Smirnov A., Tamura


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R.,"Nitroxides: applications in chemistry, biomedicine, and materials science (2008). [5]

Aibassov Y., Yemelyanova V., Savizky R. “Magnetic effects in Brain Chemistry, CA, USA, 2015.

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IR Spectra and X-ray Examination of the Complex Adenosine with UO22+ and Th4+ ions Aibassov Erkin Zhakenovich1, Yemelyanova Valentina Stepanovna1, Shakieva Tatyana1, Nakisbekov Narymzhan2, Tussupbaev Nessipbay1, Abenov Bakhyt1, Blagikh Evgeniy1 1

Research Institute of New Chemical Technologies and Materials, Kazakh National University Al-Farabi, Almaty, Kazakhstan 2 Institute of Fundamental and Applied Medicine, Kazakh National Medical University, Almaty, Kazakhstan

Abstract Interaction of dioxouraniun (VI) UO22+ and thorium Th4+ ions with ATP was obtained a complex of adenosine with uranium UO22+ and thorium Th4+ ions and X-ray method to explore these complexes. Keywords Uranyl ion, X-ray, IR spectra, Adenosine-5’-triphosphate complexs 1. Introduction Metal complex formation of nucleotides is well documented, as well as its biological importance. Metal-nucleotide complex may act as cofactor, substrate or modifier in promoting enzymatic catalysis of displacement reactions of phosphorus and maintaining structural integrity and specificity of nucleic acids. Nucleotides bing metal through three potential binding sitcs: phosphate groups, sugar hydroxo groups and ring nitrogen of base. The purpose of our work to obtain a complex of adenosine with uranium UO22+ and thorium Th4+ ions and X-ray method to explore these complexes. 2. Experimental Dioxouranium (VI) (UO22+) and thorium (Th4+) cations was used as nitrate salts. ADP (adenosine 5’-diphosphate) was used as disodium salt. 3. Results and Discussion In work [1] has been studied interaction of dioxouranium (VI) (uranyl) ion


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with ATP was studied by ligand / proton and metal / hydroxide displacement technique, at very low ionic strength and at I = 0.15 mol L (-1), in aqueous Me4NCl and NaCl solutions, at t = 25 degrees C. The interaction of adenosine with uranyl ions is described by the equation: pUO22+ + q(ATP4-) + rH+  (UO2)p(ATP)qHr(2p – 4q + r) Analysis of the complex of adenosine with uranium UO22+ and thorium Th4+ ions was performed by X-ray microanalysis. Instrument: electron probe microanalyzer. Brand: Superprobe 733, Japan Electron Optics Laboratories, Japan. The analysis of the elemental composition of the resulting of the Microsphere Magnetic Catalyst with salts of Thorium and of Uranium was performed using energy-dispersive spectrometer Energy Oxford Instruments, England, established by electron probe microanalyzer Superprobe 733 at an accelerating voltage of 25 kV and a probe current of 25 nA. Figures 1 and 2 show the laboratory unit and X-ray spectrum of the complex Adenosine with UO22+ and Th4+.

Figure 1. Obtain a complex of adenosine with UO22+ and Th4+

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Figure 2. X-ray spectrum of the complex Adenosine with UO22+ and Th4+

Table 1 shows the elemental composition of the complex Adenosine with uranium (UO22+) and thorium (Th4+) ions. Table 1. Elemental composition of the complex Adenosine with UO22+ and Th4+ ions Element Unit, %

C

H

O

N

P

Na

Th

U

3.556

9.055

0.100

84.421

Figure 3 shows the IR spectra of pure Adenosine (a) and complex of the complex Adenosine with UO22+ and Th4+ (b).

(a)


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(b) Figure 3. IR spectrum of pure Adenosine (a) and of the complex Adenosine with UO22+ and Th4+ (b)

Thus, we obtained a complex of adenosine with uranium UO22+ and thorium Th4+ ions and X-ray method to explore these complexes. 4. Conclusions Interaction of dioxouraniun (VI) UO22+ and thorium Th4+ ions with ATP was obtained a complex of adenosine with uranium UO22+ and thorium Th4+ ions and X-ray method to explore these complexes. ACKNOWLEDGMENTS The authors would like to thank Lynn C. Francesconi (Hunter College CUNY), Ruben M. Savizky (Columbia University, New York), Peter C. Burns (Notre Dame University, Indiana) and Chistopher L. Cahill (George Washington University) for discussion of the results. REFERENCES [1] Concetta De Stefano, et. Al. Interaction of UO22+ with ATP in aqueous ionic media, Biophys. Chem., 117 (2005), p. 147. [2]

I. Feldman, J. Jones, R. Cross, Chelation of uranyl ions by adenine nucleotides, J. Am. Chem. Soc., 89 (1967), v. 49, p. 53.

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[3]

K.E. Rich, R.T. Agarwal, I. Feldman, Chelation of uranyl ions by adenine nucleotides: IV. Nuclear magnetic resonance investigations, hydrogen-1 and phosphorus-31, of the uranyl-adenosine 5’-diphosphate and uranyl-adenosine 5’-triphosphate systems, J. Am. Chem. Soc., 92 (1970), p. 6818-6825.

[4]

M. Ozmen, M. Yurekli, Subacute toxicity of uranium acetate in Swiss-Albino mice, Environ. Toxicol. Pharmacol., 6 (1998), p. 111.

[5]

J. I. Domingo, et. al., Acute toxicity of uranium in rats and mice, Bull. Environ. Contam. Toxicol., 39 (1987), p. 168.

[6]

J.E. Ballon, et. al., Deposition and early disposition of inhaled 233UO2(NO3)2 and 232 UO2(NO3)2 in the rats, Health Phys., 51 (1986), p. 755.

[7]

R.B. Harvey, et. al., Acute toxicity of uranyl nitrate to growing chicks: a pathophysiologie study, Bull. Environ. Contam. Toxicol., 37 (1986), p. 907.

[8]

C.T. Garten, A review of parameter values used to assess the transport of plutonium, uranium and thorium in terrestrial food chaims, Environ. Res., 17 (1978), p. 437.

[9]

R. Guillaumont, et. al., Chemical Thermodynamics Series. Update on the Chemical Thermodynamics of Uranium, Neptunium, Plutonium, Amercium and Technecium, vol. 5, OECD Nuclear Energy Agency, 2003, Elsevier Scienze and references therein.

[10] C. De Stefano, et. al., Dependence on ionic strength of hydrolysis constants for dioxouranium (VI) in NaCl(aq) and NaNO3(aq) at pH  6 and t = 25 oC, J. Chem. Eng. Data, 47 (2002), p. 533. [11] A. Giangezza, et. al., Hydrolysis and chemical speciation of dioxouranium (VI) ion in aqueous media simulating the major composition of seawater, Mar. Chem., 85 (2004), p. 103. [12] F. Crea, et. al., Hydrolysis of dioxouranium (VI) a colorimetric study in NaCl(aq) and NaClO4(aq) at 25 oC, Thermochim. Acta, 414 (2004), p. 185. [13] A. Giangezza, et. al., Interaction of dioxouranium (VI) ion with aspirate and glutamate in NaClaq at different ionic strengths, J. Chem. Eng.


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X-ray Examination of the Complex Albumin Human with UO22+ Aibassov Erkin Zhakenovich, Yemelyanova Valentina Stepanovna, Shakieva Tatyana, Tussupbaev Nessipbay, Abenov Bakhyt, Blagikh Evgeniy Research Institute of New Chemical Technologies and Materials, Kazakh National University Al-Farabi, Almaty, Kazakhstan

Abstract Interaction of dioxouraniun (VI) UO22+ ion with Albumin serum human was obtained a complex of Albumin human with uranium UO22+ ion and X-ray method to explore these complexes. Keywords complex

Albumin serum human, Dioxouraniun (VI) UO22+ ion, X-ray,

1. Introduction Human serum albumin is the most abundant protein in human blood plasma. It is produced in the liver. Albumin constitutes about half of the blood serum protein. It is soluble and monomeric. Albumin transports hormones, fatty acids, and other compounds, buffers pH, and maintains osmotic pressure, among other functions. Albumin is synthesized in the liver as preproalbumin, which has an N-terminal peptide that is removed before the nascent protein is released from the rough endoplasmic reticulum. The product, proalbumin, is in turn cleaved in the Golgi vesicles to produce the secreted albumin. The approximate sequence of human serum albumin is: MKWVTFISLL FLFSSAYSRG VFRRDAHKSE VAHRFKDLGE ENFKALVLIA FAQYLQQCPF EDHVKLVNEV TEFAKTCVAD ESAENCDKSL HTLFGDKLCT VATLRETYGE MADCCAKQEP ERNECFLQHK DDNPNLPRLV RPEVDVMCTA FHDNEETFLK KYLYEIARRH PYFYAPELLF FAKRYKAAFT ECCQAADKAA CLLPKLDELR DEGKASSAKQ RLKCASLQKF GERAFKAWAV

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ARLSQRFPKA EFAEVSKLVT DLTKVHTECC HGDLLECADD RADLAKYICE NQDSISSKLK ECCEKPLLEK SHCIAEVEND EMPADLPSLA ADFVESKDVC KNYAEAKDVF LGMFLYEYAR RHPDYSVVLL LRLAKTYETT LEKCCAAADP HECYAKVFDE FKPLVEEPQN LIKQNCELFE QLGEYKFQNA LLVRYTKKVP QVSTPTLVEV SRNLGKVGSK CCKHPEAKRM PCAEDYLSVV LNQLCVLHEK TPVSDRVTKC CTESLVNRRP CFSALEVDET YVPKEFNAET FTFHADICTL SEKERQIKKQ TALVELVKHK PKATKEQLKA VMDDFAAFVE KCCKADDKET CFAEEGKKLV AASQAALGL The italicized first 24 amino acids are signal and propeptide portions not observed in the transcribed, translated, and transported protein but present in the gene. There are 609 amino acids in this sequence with only 585 amino acids in the final product observed in the blood. In work [1] has been studied chemical and biological insights into uranium-induced apoptosis of rat hepatic cell line. Uranium release into the environment is a threat to human health, and the mechanisms of cytotoxicity caused by uranium are not well-understood. To improve our understanding in this respect, we herein evaluated the effects of uranium exposure on normal rat hepatic BRL cells. As revealed by scanning electron microscopy and transmission electron microscope analysis, uranyl nitrate was found to be transformed into uranyl phosphate particles in the medium and taken up by BRL cells in an endocytotic uptake manner, which presumably initiates apoptosis of the cell, although soluble uranyl ion may also be toxic. The apoptosis of BRL cells upon uranium exposure was also confirmed by both the acridine orange and ethidium bromide double staining assay and the Annexin V/propidium iodide double staining assay. Further studies revealed that uranium induced the loss of mitochondrial membrane potential in a dose-dependent manner. Moreover, the uranium-induced apoptosis was found to be associated with the activation of caspase-3, caspase-8 and caspase-9, indicating both a mitochondria-dependent signaling pathway and a death receptor pathway by a crosstalk. This study provides new chemical and biological insights into the mechanism of uranium toxicity toward hepatic cells,


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which will help seek approaches for biological remediation of uranium. 2. Experimental Dioxouranium (VI) (UO22+) cation was used as nitrate salts. Albumin human was used as disodium salt. 3. Results and Discussion In work [1] has been studied Structural Consequences of Binding of UO22+ to Apotransferrin.

It has been established that transferrin binds a variety of metals. These include toxic uranyl ions which form rather stable uranyl-transferrin derivatives. We determined the extent to which the iron binding sites might accommodate the peculiar topographic profile of the uranyl ion and the consequences of its binding on protein conformation. Indeed, metal intake via endocytosis of the transferrin/transferrin receptor depends on the adequate coordination of the metal in its site, which controls protein conformation and receptor binding. Using UV−vis and Fourier transform infrared difference spectroscopy coupled to a microdialysis system, we showed that at both metal binding sites two tyrosines are uranyl ligands, while histidine does not participate with its coordination sphere. Analysis by circular dichroism and differential scanning calorimetry (DSC). Showed major differences between structural changes associated with interactions of iron or uranyl with apotransferrin. Uranyl coordination reduces the level of protein stabilization compared to iron, but this may be simply related to partial lobe closure. The lack of interaction between uranyl-TF and its

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receptor was shown by flow cytometry using Alexa 488-labeled holotransferrin. We propose a structural model summarizing our conclusion that the uranyl-TF complex adopts an open conformation that is not appropriate for optimal binding to the transferrin receptor. In work [2] has been studied UO22+ Uptake by Proteins. The capture of uranyl, UO22+, by a recently engineered protein with high selectivity and femtomolar sensitivity has been examined by a combination of density functional theory, molecular dynamics, and free-energy simulations. It was found that UO22+ is coordinated to five carboxylate oxygen atoms from four amino acid residues of the super uranyl binding protein (SUP). A network of hydrogen bonds between the amino acid residues coordinated to UO22+ and residues in its second coordination sphere also affects the protein’s uranyl binding affinity. Free-energy simulations show how UO22+ capture is governed by the nature of the amino acid residues in the binding site, the integrity and strength of the second-sphere hydrogen bond network, and the number of water molecules in the first coordination sphere. Alteration of any of these three factors through mutations generally results in a reduction of the binding free energy of UO22+ to the aqueous protein as well as of the difference between the binding free energies of UO22+ and other ions (Ca2+, Cu2+, Mg2+, and Zn2+), a proxy for the protein’s selectivity over these ions. The results of our free-energy simulations confirmed the previously reported experimental results and allowed us to discover a mutant of SUP, specifically the GLU64ASP mutant, that not only binds UO22+ more strongly than SUP but that is also more selective for UO22+ over other ions. The predictions from the computations were confirmed experimentally. Analysis of the complex Albumin human with uranium UO22+ ion was performed by X-ray microanalysis. Instrument: electron probe microanalyzer. Brand: Superprobe 733, Japan Electron Optics Laboratories, Japan. The analysis of the elemental composition of the resulting of the Microsphere Magnetic Catalyst with salts of Thorium and of Uranium was performed using energy-dispersive spectrometer Energy Oxford Instruments, England, established by electron probe microanalyzer Superprobe 733 at an accelerating voltage of 25 kV and a probe current of 25 nA.


253

Figures 1 and 2 show the laboratory unit and X-ray spectrum of the complex Albumin human with UO22+.

Figure 1. Obtain a complex of Albumin human with UO22+

Figure 2. X-ray spectrum of the complex Albumin human with UO22+

254


Table 1 shows the elemental composition of the complex Albumin human with UO22+ ion. Table 1. Elemental composition of the complex Albumin human with UO22+ Compound

C

Unit, %

H

O

N

S

P

U

0.847

0.423

71.212

4. Conclusions Interaction of dioxouraniun (VI) UO22+ ion with Albumin human was obtained a complex of adenosine with uranium UO22+ ion and X-ray method to explore these complexes. ACKNOWLEDGMENTS The authors would like to thank Lynn C. Francesconi (Hunter College CUNY), Ruben M. Savizky (Columbia University, New York), Peter C. Burns (Notre Dame University, Indiana) and Chistopher L. Cahill (George Washington University) for discussion of the results. REFERENCES [1] Fang Liu, Chemical and biological insights into uranium-induced apoptosis of rat hepatic cell line, Biochem, 2007, p. 147. [2]

Claude Vidaud, et. al., Structural Consequences of Binding of UO22+ to Apotransferrin: Can This Protein Account for Entry of Uranium into Human Cells?, Biochem, 2007, p. 153.

[3]

Lei Qi, et. al., Characterization of UO22+ binding to osteopontin, a highly phosphorylated protein: insights into potential mechanisms of uranyl accumulation in bones, Metallomics, 2014,6, p. 166-176.

[4]

Teniz Turkmen, Glutamic acid containing supermacroporous poly(hydroxyethyl methacrylate) cryogel disks for UO22+ removal, Materials Science and Eng., 2012, p. 2052.

[5]

Aibassov Yerkin, Yemelyanova Valentina, Spin Chemistry and Magnetic of Uranium-Thorium Catalysts, Scientific & Academic Publishing, USA, 2015, 232 p.


Chapter III Philosophy of Hyper-Information

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The philosophy of information is a branch of philosophy that studies the concept of information. This philosophy took shape at the end of the twentieth century; The name was introduced by L. Floridi in the 1990s. Information Objectives: 1) Being information; 2) Philosophical status of information; 3) Information in the environment. Functional information. The word "fish" and "slaves" - the amount of information is equal, but the meaning is different. There is an Information field. Information does not depend on our consciousness. It is objective. Information is the third, along with matter and energy, the substance of the material world. But for information, fundamental laws of conservation and transition to equivalent quantities of matter or energy have not yet been formulated. The Shannon-Weaver communication model was called "the mother of all models." Social scientists use this term to refer to an integrated model of the concepts of information source, message, transmitter, signal, channel, noise, receiver, destination information, error probability, encoding, decoding, data rate, channel capacity. Information can be expressed both as a property of objects, and as a result of their interaction. The fact of objective existence of information regardless of our consciousness for some researchers served as an occasion for constructing a very non-ordinary point of view that information is the third (along with matter and energy) substance of the material world. But for information, fundamental laws of conservation and transition to an equivalent quantity of matter and / or energy have not yet been formulated. At the moment it is considered to be that information exists regardless of whether it is perceived or not, but manifests itself only when interacting. Information entropy (H) — measure the chaos of information, the uncertainty of the appearance of any symbol of the primary alphabet. In the absence of information loss is numerically equal to the amount of information per symbol of the transmitted message. Entropy is the quantity defined in the

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context of the probability model for the data source. The degree of entropy of the data source means the average number of bits per data element required to encrypt it without losing information, with optimal coding. Entropy limits the maximum possible lossless compression that can be realized by using a theoretical-typical set or, in practice, Huffman coding, Lempel-Ziva-Welch coding, or arithmetic coding. Entropy properties: • entropy can not be negative H(X) ≥ 0; • entropy is limited H(X) ≤ log2 |X| (if all elements of X are equally probable); • if X, Y are independent, then H(XY) = H(X) + H(Y); • if X, Y have the same probability distribution of elements, then H(X) = H(Y); • some data bits may not carry information; • the amount of entropy is not always expressed as an integer number of bits. Shannon's Formula The measure of Shannon's entropy expresses the uncertainty of the realization of a random variable. Thus, entropy is the difference between the information contained in the message and that part of the information that is accurately known in the message. Shannon suggested that the increase in information is equal to the lost uncertainty, and, having set new requirements for its measurement, obtained the formula: -K Σ p(i) log p(i), where K - constant, which is needed to select units of measure. Law of Information Preservation 1. In a closed system, the amount of information remains unchanged: 2. The information does not disappear. The law of the necessary diversity of information management. Shannon proposed a general scheme of the communication system, consisting of five elements (information source, transmitter, signal transmission channel, receiver and addressee), theorems on capacity, noise immunity, coding, etc. were formulated. Wiener developed a statistical theory of the amount of information.


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Identifying information with negative entropy, he characterized it along with matter and energy as a fundamental phenomenon of nature. Facebook is a hyper mass media that covers billions of people anywhere in the world. Neuroinformatics is a field of scientific research that lies at the intersection of neuroscience and informatics. The field of neuroinformatics includes the collection of results obtained during neurobiological research, the translation of these results into a database format for their subsequent analysis using computational models and specialized computer analytical tools, ensuring compatibility between databases, model formats and other collections of data to facilitate exchange information on various aspects of the functioning and structure of nervous systems. The First "Chemical Memory" was Created The new unit of information was called "chit" - the union of the English words "chemical" and "bit". Sometimes the search for new ways of storing information forces scientists to discover hitherto unknown properties of habitual things. For example, everyone knows that the "classical" unit of information storage is a bit. In quantum systems - the quantum bit (qubit). But scientists from the Physico-Chemical Institute of the Polish Academy of Sciences discovered a new unit of information: the chemical bit, which consists of three separate drops of chemical reagents located relative to each other in such a way that the reactions that take place inside are data carriers. Dr. Konrad Gizinsky's scientific team and Professor Jiri Gorecki are in charge of the discovery. The new unit of information was called "chit" - the union of the English words "chemical" and "bit". In customary physical memory, bits can take the value 1 and 0. They are recorded, stored and read using electric current, magnetic field, laser action and other phenomena, all of which can be combined with the general term "physical impact". Quantum computers use quantum superposition and quantum entanglement for data operations. To transfer and process data in chemical memory, chemical processes are

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used that take place during the cyclic reactions of Belousov-Zhabotinsky. The peculiarity of these reactions is that as soon as the first cycle of reaction is completed, the next one immediately begins. And the raw materials needed for the next stage are fully formed in the course of the previous one. Such reactions fade with time, but hundreds of cycles may be required to completely stop them. Polish researchers used Belousov-Zhabotinsky reaction variant for their developments, where each cycle was accompanied by a change in the color of the solution in order to better monitor the course of the reaction. In addition, a ruthenium-based inhibitor was added to the solution. When illuminated with blue light, due to ruthenium, the reaction was stopped. In their experiments, scientists have investigated many options for the mutual arrangement of droplets of a solution, changing their number. As a result, the best results were shown by a system of three drops of different sizes. It was possible to reveal that if a system of three droplets enters one of the states of rotational propagation of the Belousov-Zhabotinsky reactions, then this state remains stable for a long time. In this case, the correct combination of a sequence of light pulses with a certain duration makes it possible to obtain the required direction of rotation of the reaction fronts, which is a cell for storing one bit of information. In 1929, Leó Szilárd invented a feedback protocol in which a hypothetical intelligence—dubbed Maxwell’s demon—pumps heat from an isothermal environment and transforms it into work. After a long-lasting and intense controversy it was finally clarified that the demon’s role does not contradict the second law of thermodynamics, implying that we can, in principle, convert information to free energy. An experimental demonstration of this information-to-energy conversion, however, has been elusive. Here we demonstrate that a non-equilibrium feedback manipulation of a Brownian particle on the basis of information about its location achieves a Szilárd-type information-to-energy conversion. Using real-time feedback control, the particle is made to climb up a spiral-staircase-like potential exerted by an electric field and gains free energy larger than the amount of work done on it. This enables us to verify the generalized Jarzynski equality, and suggests a


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new fundamental principle of an ‘information-to-heat engine’ that converts information into energy by feedback control.

a, The particle was pinned at a single point of the top glass surface and exhibited rotational Brownian motion. To impose a tilted periodic potential on the particle, an elliptically rotating electric field (blue and pink curves) was induced (not to scale; see Methods and Supplementary Information for details). b, Typical potentials with opposite phases to be switched in the feedback control. The particle experienced a tilted periodic potential with a period of 180°. The height and slope were 3.05±0.03 kBT and 1.13±0.06 kBT/360° (mean±S.E., seven particles), respectively. c, Feedback control. At time t=0, the particle’s angular position is measured. If the particle is observed in the angular region indicated by ‘S’, we switch the potential at t=ɛ by inverting the phase of the potential (right). Otherwise, we do nothing (left). At t=τ, the next cycle starts. The location of region S is altered by the switching. The potential wells correspond to the steps of the spiral stairs in Fig. The switching of potentials corresponds to the placement of the block. Figure 1. Experimental set-up

Philosophy and Thermodynamics of Biological Systems Information and Entropy Thermodynamics considers the general laws of the transformation of energy in the form of heat and work between bodies. In open biological systems there is a constant exchange of energy with the environment. Internal metabolic

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processes are also accompanied by the transformation of some forms of energy into others. Suffice it to recall the mechanical processes, the transformation of the energy of a quantum of light into the energy of electronic excitation of pigment molecules, and then to the energy of the chemical bonds of the reduced compounds in photosynthesis. Another example is the transformation of the energy of the electrochemical transmembrane potential into the energy of ATP in biological membranes. Mechanisms of energy transformation in biostructures are associated with conformational transformations of special macromolecular complexes, such as photosynthetic reaction centers, H-ATPase of chloroplasts and mitochondria, bacteriorhodopsin. In addition to clarifying the detailed character of the processes occurring here, special characteristics are of general interest in the efficiency of energy conversion in such macromolecular machines. For the situation: when 1 / p events with the same probabilities p # 1 can occur for each of them, the amount of information I is determined by the formula: I = log2 p1/p, where р - a priori probability of some event (probability before the message is received), p1 - probability after receiving the message. If the messages are reliable and unambiguous, then p1 = 1 and I = - log2 p. As information unit I, the amount of information in a reliable event message is taken, the a priori probability of which is 1/2. This unit is called "binary digits". For any macrosystem at a temperature above absolute zero, the number of microstates W corresponding to a given macrostate is enormous. W is called the statistical weight or thermodynamic probability of a given macrostate. According to the basic postulate of statistical physics, all W microstates corresponding to one macrostate have the same a priori probability. Knowing the microstate of the system means knowing everything about the system! The quantity W is directly related to entropy. By the Planck-Boltzmann formula:


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S = k ln W, where Boltzmann's dimensional constant k = 1,38 x 10-16 erg/deg or 3,31 x 10-24 e.u. (eu - entropy unit, 1 eu = 1 cal/degree). We calculate how much information should be obtained about the system in the given macrostate in order to uniquely determine its microstate. How much information is lacking for a complete description of the system in a given macrostate? Let the microstate be determined by measurement or calculation (in fact, it can not be done). Before determining the probability that a macroscopic system was in exactly this microstate, it was 1/W, and after the determination it became equal to one. Received amount of information I = - log2 1/W = log2 W. The values of I and S are essentially identical. The situation here is the same as for the relationship between mass and energy: E = mc2, where the role of the dimensional factor is played by c2. The situation is analogous in the case of the relation between the frequency and energy of the quantum of light, where the dimensional factor is Planck's constant: ε = ħw. The entropy of a system in a given macrostate is the amount of information that is missing before its full description. In order to move from the amount of information in bits to the entropy in entropy units, it is necessary to go from the logarithm at base 2 to the natural logarithm and multiply by k: S(eu) = 2,3 x 10-24 I bit. The human body contains approximately 1013 cells. Suppose that among them there is not a single pair of the same and that no pair can be exchanged without disturbing the functioning of the organism. This means that the relative location of cells in the human body is unequivocal. The amount of information needed to build such a single structure out of 1013! possible, I = log2 (1013!) = 1013 log2 1013 = 4 x 1014 бит. Hence it follows that a decrease in entropy in the construction of the human body from cells will be ∆S ≈ 2 x 10-24 x 4 x 1014 ≈ 10-9 eu. When evaporation of one gram of water, the entropy rises by about 1 eu. Thus, the decrease in entropy in the transition from chaotically located cells

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to the human body is numerically equal to the increase in entropy upon evaporation of 10-9 grams of water. The accepted postulates about the absence of identical cells and the impossibility of their permutations only increased the amount of required information calculated by the formula, so that ΔS is in fact much smaller. The number of molecules of biopolymers (proteins, nucleic acids, poly-carbohydrates, etc.) in one cell is on average 108. Assume again that all the molecules are different, and their relative arrangement is unique. The amount of information needed to build a single cell from the finished biopolymers, I = 108 log2 108 ≈ 2,6 x 109 bit, for all cells in the human body 2,6 x 1022 bit, which corresponds to a decrease in the entropy by approximately 6 x 10-2 eu. The adult body contains about 7 kg of proteins and 150 g of DNA, which corresponds to ≈ 3 x 1025 amino acid and ≈ 3 x 1023 nucleotide residues. To create a single sequence from 203 x 1025 possible, for the protein is necessary ≈ 1026 bit. For DNA it is necessary ≈ 6 x 1023 bit. In terms of entropy, we obtain 300 and 1.4 eu for proteins and DNA. respectively. Thus, the ordering of the biological organization of the human body "costs" 301.5 eu and an overwhelming contribution is made by the ordered distribution of amino acid residues in proteins. Decrease in entropy in the occurrence of such a biological organization is easily compensated by trivial physical and chemical processes. Increase in entropy by 300 eu is provided by evaporation of 170 g of water. These estimates show that the emergence and complication of biological organization occurs almost "free". An example of the emergence of meaningful biological order. Let a large number of nucleotides - monomers, from which DNA is built - is dissolved in a vast water reservoir. There are four kinds of nucleotides: based on adenine (A), guanine (G), cytosine (C) and thymine (T). Condensation reactions can occur between nucleotides to form single-stranded di-, tri-, and so on. Polynucleotides, for example,


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А + Т → AT + H2O, AT + A → ATA + H2O and etc. The rate of decay of di-, tri-, polynucleotides is much greater than the rate of their formation, and the equilibrium in these reactions will be shifted toward monomers. The concentrations of polynucleotides will be small and the smaller the longer the chain. A small number of polymer filaments of different lengths, which will always be present in the solution in dynamic equilibrium with a huge excess of monomers, must have completely random nucleotide sequences (the rates of decomposition and synthesis reactions for all nucleotides are practically identical), and the a priori probabilities of all sequences will be identical. Due to the special chemical properties of nucleotides (the possibility of the formation of hydrogen bonds between them), in addition to the above-mentioned reactions of formation of single-strand chains, reactions of addition of a chain of other nucleotides and the formation of a new chain associated with the first can take place. This process is called matrix synthesis. The sequence of nucleotides in a new chain is completely determined by the sequence in the original chain: against A always stands T, and against G – C. ATTGCТАCGGА …. ТААCGАТГCUТ …. Matrix synthesis The molecule of a double-stranded polymer arising as a result of matrix synthesis is much more stable than a single-stranded molecule. After reaching a sufficient length, it forms a double helix, practically does not disintegrate and can be "redubbed" in time, by increasing the corresponding nucleotides on both strands: ТААCGАТGCCТ …. АТТGCТUCGGА …. → 2 (ТААCGАТGCCТ ….) ТААCGАТGCCТ …. (АТТGCТUCGGА ….) АТТGCТUCGGА …. Reduplication The first double-stranded molecule is formed as a result of a random and

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very unlikely process: one of the single-stranded polymer molecules has time to undergo matrix synthesis before it decays. The sequence of nucleotides in this single-stranded molecule could be any. However, after the double-stranded structure was formed, the situation changed dramatically. The sequence realized in such a long-lived double-stranded polymer has become meaningful. This meaning is that this sequence exists in a stable and redoxable molecule, and there are no other possible sequences. In the system, the concentration of polymers will grow rapidly with precisely this sequence, now special. Random deviations ("mistakes") from the "correct" sequence will also be reproduced and will give rise to independent systems that compete with the initial inventory of monomers. Thus, due to the memorization of a random choice, an order has arisen that makes sense, a system has emerged that can create meaningful information. This example of a stable self-replicating system. It is an attempt to demonstrate the most essential characteristics of the process of creating meaningful ordering by the example of biopolymers using some of their well-known properties. Before a polymer with a random sequence of nucleotides formed a stable double-stranded structure, or before a random sequence of three digits was entered into the lock of the safe, information that these sequences were "better" than others simply did not exist. Information was created, created. The unpredictable turned into an inevitable (Pierre Boule). Systems that create meaningful ordering have one common property: they contain components, designs whose lifespan exceeds the time of one cycle of the system. For a system of nucleic acids, this means that the double-stranded polymer does not decay until reduplication, and for another example - that the lock of the safe does not collapse before even one triple of digits is tested. The requirement of having long-lived, slowly relaxing designs is necessary for living matter. You can not build a living thing on the basis of the gas phase! Thus, the concept of construction becomes very important in the analysis of the functioning of living systems and their components. From the standpoint of statistical physics, the presence of a construction means the presence of boundaries between regions of the phase space, the intersection of which is


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forbidden for figurative points of the statistical system during a given time interval. Postulate by I.R. Prigogine is that the total change in the entropy dS of an open system can occur independently either due to the processes of exchange with the external environment (deS) or due to internal irreversible processes (diS): dS = deS + diS. In the cellular metabolism, it is always possible to distinguish such two groups of processes. For example, the intake of glucose from outside, the outward release of its oxidation products (deS) and the oxidation of glucose in the respiration process (diS). In photosynthesis, the influx of free light energy leads to a decrease in the entropy of the cell deS 0. Depending on the ratio of the rates of change, deS and diS, the total entropy dS of the open system can either increase or decrease with time. If the only reason for irreversibility and increasing the entropy of the system are its internal processes, then they lead to a decrease in its thermodynamic potential. In this case diS/dt = 1/T (dG/dT)T,p, where G is the total thermodynamic potential (or Gibbs energy G = U + PV TS). It can be shown that the rate of appearance of positive entropy within an open chemical system depends on the chemical affinity of A and the reaction rate u: diS/dt = 1/T Au > 0. The chemical affinity of A is determined by the difference in the chemical potentials of the reaction reagents, that is, its driving force. It shows that the rate of formation in the system of positive entropy in the course of an irreversible chemical process is directly proportional to its driving force A and velocity u. It is obvious that the quantity diS/dt is, generally speaking, variable, because in the course of a chemical reaction, the concentration variables of the reacting substances and, consequently, the quantities A and u, depending on them, change all the time.

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Processes of heat transfer and diffusion of matter through the membrane from one phase to another include driving forces - gradients of temperature and concentration, and flows correspond to the transfer of heat or matter between two phases. In all these cases, the increase in entropy has the form T diS/dt = X J > 0 (7) where Х is driving force, J is flow amount. If the system is near equilibrium, where the values of the driving forces and fluxes are very small, then there is a direct proportional relationship between them: J = LX, where L is constant linear coefficient. If several processes occur simultaneously in the open system in the open system, then there are thermodynamic relations between them reflecting their mutual influence. For two processes (J1 , X1) and (J2 , X2) these relations have the form J1 = L11X1 + L12X2 , J2 = L21X1 + L22X2, where the constant coefficients L11, L22 reflect the dependence of the flux on its strength, and the coefficients L12, L21 correspond to the mutual influence of the force of one process on the flow of another process. They are called the Onsager reciprocity coefficients. Near balance L12 = L21. Now we can establish a quantitative relationship between the simultaneous processes in the cell, without knowing their molecular mechanisms. Consider the process of active transport of matter through a biological membrane, which occurs due to the energy of the conjugating metabolic process and therefore can go against the gradient of the concentration of the transferred substance. Then J1 = L11X1 + L12X2, J2 = L21X1 + L22X2, L12 = L21, where the process (J1, X1) the conjugate transfer goes against the force gradient


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X1 (J1, X1 < 0) due to the energy of the coupling process (J2, X2 > 0). If there is no conjugation, then L12 = L21 = 0 and the processes go independently from each other under the action of only their driving forces J1 = L11X1, J2 = L22X2. At the initial moments of the system start-up, the high speed of the matching process J2 decreases to the minimum values, while the value X1 grows at the same time. As a result of these changes, a steady state is established when the resultant conjugate flow vanishes: J1 = 0. If the system is completely conjugate, then the stationary state J2 = 0 is established for the conjugating flow. In this case, there are no visible changes in the system and the entire energy of the conjugating flow is spent on maintaining the power of X1. One can imagine the turbine wheel in water (X1), the speed of its movement (J1) and the flow of water (J2). These considerations are valid not only for active transport, but also for other cases. Thus, in mitochondria, the rate of oxidation of the substrate, i.e., the speed of movement (J2), is related to the ratio of ADP/ATP, i.e., the driving force of X1. In the mitochondrial state, when the concentration of ADP is zero and there is no visible formation of ATP (J1 = 0), all energy is expended to maintain the maximum level. Adding uncouplers reduces the value of X1, but then J1 ≠ 0, which leads to an acceleration of the matching flow. The coefficient of energy transformation in the conjugating processes is | J1X1 |/J2X2 and in mitochondria can reach values of 80-90%. The application of the Onsager equations makes it possible to obtain the characteristics of macromolecular complexes - biological energy transformers, without resorting to a detailed analysis of the mechanisms of their functioning. We have already seen that in a stationary state in an open system dS/dt = deS/dt + diS/dt = 0, changes in diS/dt in time, predict the establishment of a stationary state in an open system. The answer to this question is given by Prigogine's theorem, according to which in the stationary state the positive function diS/dt assumes a minimum positive value. Consequently, as we approach the steady state, the rate of entropy formation inside an open system decreases monotonically, gradually approaching its minimum positive value. This is the criterion for the

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orientation of irreversible processes in open systems near equilibrium, where the Onsager relations are valid. From the monotonic nature of the variation of T diS / dt, it follows that near equilibrium the stationary state can not be a self-oscillatory regime. Indeed, in this case the concentration variables in the system (and consequently, the quantities J and X) vary periodically, which is incompatible with the unidirectional monotonous variation of TdiS / dt and its constancy at the stationary point. Experimental measurements of the rate of entropy formation within the system can be carried out in calorimeters, studying the thermal fluxes accompanying the formation of entropy in the case of irreversible changes in the system. In experiments on biological objects it was shown, for example, that the rate of heat production and the intensity of respiration during the development of embryos continuously decrease from the first stages of the development of the organism and reach constant values in the stationary phase of growth. It should, however, be borne in mind that the level of thermogenesis can change in the course of the development of the organism not only as a result of changes in the magnitudes of the driving forces and currents. The heat production of an organism depends on the state of the membrane structures and the degree of conjugation of oxidative phosphorylation processes. Thermodynamics of Active Transport We consider the active transport system of one ion (sodium), not associated with the transfer of other substances. For the sake of simplicity, we will assume that one metabolic process can be distinguished, which drives the active sodium transport. Let us denote the rate of active transport of the cation through Ja+, metabolic rate through Jr , then Ja+ = La+X+ + La+rA, Jr = La+rX+ + LarA, where Х+ - a negative difference in the electrochemical potentials of the cation (going against the gradient of its "own" driving force), A is the affinity of the metabolic reaction providing transport. In the case of a single metabolic reaction (hydrolysis of ATP), the rates of consumption and production of all


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metabolites are related stoichiometrically. Therefore, to estimate the rate of metabolism, we can take, for example, the rate of intake of O2 in respiration. Then the affinity of A can be expressed as a negative change in the total thermodynamic potential of the metabolic reaction (hydrolysis of ATP) per mole of O2 consumption. Putting the same solutions on both sides of the membrane (∆C = C0+ - C0+ = 0) and changing the transmembrane potential difference Δφ, one can find from the phenomenological coefficients , La+, La+r, which are determined from the slope of the corresponding straight lines ∆Ja+ = - La+∆(F∆φ) and ∆Ja+ = La+r∆(F∆φ). Under experimental conditions, in order to find the coefficients, it is important to preserve the parameters of the system and to be able to vary Na directionally with constant A. Experiments were carried out on the frog skin, where the values of XNa varied by changing Δφ. At the same time, the composition of the washing liquid was preserved and the concentration of sodium was maintained unchanged. In direct experiments, the linear dependence of the speed of active transport JaNa from ∆φ on the skin of the frog, where ∆φ changed symmetrically in the region 0 → ±80 mV. The amount Jr can be determined from the absorption of O2 with the use of oxygen electrodes. It turned out that for symmetric perturbations of the potential, the ratio between Jr and ∆φ was linear in the interval 0 → ±70 mV. The dependence JaNa and J2 from the external concentration of sodium under conditions of constancy of its internal concentration at a constant of zero difference of electric potentials (Δφ = 0). Under these conditions, a linear dependence of the JNa active transport velocity and Jr oxygen absorption on the difference in chemical potentials ΔμNa on the membrane was also observed. However, if XNa is changed by varying the internal concentration of sodium, linearity is no longer observed. This is due to changes in the microstructure and composition of the membrane itself. Similar studies have also been successfully carried out for the active transport of protons using the equations of nonequilibrium thermodynamics for two flows. In all cases, the variation of X + makes it possible to evaluate the phenomenological coefficients and affinity of A of the driving metabolic

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reaction. Recently, successful attempts have been made to apply such a formalism to describe the processes of phosphorylation in mitochondria and chloroplasts. It is generally accepted that in these objects there is a close conjugation between the three main processes underlying the bioenergetics of cell membranes: electron transport with substrate oxidation (J0, A0), phosphorylation of ADP with the formation of ATP (JP, AP), translocation of protons through the conjugating membrane JH, ΔμH). A key role is played by the transmembrane proton circulation, which is induced by the transfer of electrons and, in turn, triggers the synthesis of ATP. As it turned out, here also there is a linear relationship between forces and flows, which should allow us to find experimentally the coefficients of L. Entropy and Biological Information According to Boltzmann's formula, entropy is defined as the logarithm of the number of microstates possible in a given macroscopic system: S = kB ln W, where kB = 1,38 x 10-16 erg/deg, or 3,31 x 10-24 (1 eu = 1 cal/deg = 4.1 J/K), or 1.38 x 10-23 J/K is the Boltzmann constant, W is the number of microstates (for example, the number of ways that can be placed molecules of gas in the vessel). It is in this sense that entropy is a measure of the disorder and chaos of the system. In real systems, there are stable and unstable degrees of freedom. According to information theory, in this case the amount of information about the only real state of the system I = log2 W. For a unit of information amount (bit), the information contained in a reliable message is received when the number of initial possible states was equal to W = 2: I = log2 W = 1 bit. Comparing the formulas, one can find the relationship between entropy (in entropy units) and information (in bits) S (eu) = 2,3 x 10-24. Let's try to formally estimate the amount of information contained in the


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human body, where there are 1013 cells. We get the value I = log2 (1013!) ~ 1013 log2 1013 ~ 4 x 1014 bit. Such an amount of information would have to be initially obtained in order to realize the only correct arrangement of cells in the body. This is equivalent to a very slight decrease in the entropy of the system by ∆S = 2,3 x 10-24 x 4 x 1014 ~ 10-9 eu ~ 4 x 10-9 J/К. If we assume that the organism also carries out the unique character of the arrangement of amino acid residues in proteins and nucleic residues in DNA, the total amount of information contained in the human body will be I = 1,3 x 1026 bit, which is equivalent to a slight decrease in entropy by ΔS = 300 eu = 1200 J/K. In metabolic processes, this decrease in entropy is easily compensated by an increase in entropy in the oxidation of 900 glucose molecules. Thus, these equations show that biological systems do not possess any increased information capacity in comparison with other nonliving systems consisting of the same number of structural elements. This conclusion at first glance contradicts the role and importance of information processes in biology. The value of biological information is determined not by the quantity, but primarily by the possibility of its storage, storage, processing and further transfer for use in the life of the organism. The basic condition for the perception and memorization of information is the ability of the receptor system to move, due to the information received, to one of the stable states predetermined by virtue of its organization. The information capacity in DNA, for example, is determined not only by the number of certain nucleotides, but by the total number of microstates including the vibrations of all atoms in the DNA strand. The process of remembering information in DNA is fixation of a certain location of nucleotides, which is stable due to the chemical bonds in the chain. Further transfer of genetic information is carried out as a result of biochemical processes in which energy dissipation and the formation of appropriate chemical stable structures ensure the efficiency of biological information processing. Physiological receptor processes, which play an independent

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informational role in the vital activity of the organism, are also based on the interactions of macromolecules. In all cases, macroinformation arises initially in the form of conformational changes in the dissipation of part of the energy over certain degrees of freedom in interacting macromolecules. REFERENCES [1]

Szilárd, L. On the decrease of entropy in a thermodynamic system by the intervention of intelligent beings. Z. Phys. 53, 840–856 (1929).

[2]

Shoichi Toyabe, Takahiro Sagawa, Masahito Ueda, Eiro Muneyuki, Masaki Sano, Nature Physics, 6, 988–992 (2010).

[3]

Shannon C.E., Weaver W. The Mathematical Theory of Communication. Univ. of Illinois Press, 1949.

[4]

Nikolis G., Prigogin I. Self-organization in non-equilibrium systems. M., 1979.

[5]

Blumenfeld L. Information, thermodynamics and the construction of biological systems// Soros Educational Journal. 1997. T 7. P. 88-92.

[6]

Brillouin L. Science and Information Theory. Moscow: Fizmatgiz, 1960.

[7]

H. Kastler. The emergence of a biological organization. Moscow: The World, 1967.


Chapter IV Phylosophy of Hyper-Thinking

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Thinking is the cognitive activity of a person. It is an indirect and generalized way of reflecting reality. The result of thinking is thought (concept, meaning, idea). Thinking is opposed to "inferior" ways of mastering the world in the form of sensation or perception, which are peculiar to animals as well. Many philosophers called thinking the essential property of man. Descartes maintained: "I think, therefore I am." A feature of thinking is the property of obtaining knowledge about such objects, properties and relationships of the surrounding world that can not be directly perceived. This property of thinking is realized through such deductions as analogy and deduction. Thinking is related to the functioning of the brain, but the very ability of the brain to operate with abstractions arises during the assimilation by man of forms of practical life, norms of language, logic, and culture. Thinking is carried out in diverse forms of spiritual and practical activity, in which the cognitive experience of people is generalized and preserved. Thinking is carried out in figurative and figurative form, the main results of its activity are expressed here in products of artistic and religious creativity, which genuinely generalize the cognitive experience of mankind. Thinking is also carried out in its own adequate form of theoretical cognition, which, with the support of the preceding forms, acquires unlimited possibilities of the speculative and model vision of the world. In psychology, thinking is the totality of the mental processes that underlie cognition; it is to thinking that the active side of cognition is taken: attention, perception, the process of associations, the formation of concepts and judgments. In a closer logical sense, thinking involves only the formation of judgments and inferences through the analysis and synthesis of concepts. Thinking is an indirect and generalized reflection of reality, a kind of mental activity consisting in the cognition of the essence of things and phenomena, the lawful connections and relations between them. Thinking as one of the higher mental functions is a mental process of reflection and cognition of the essential connections and relations of objects and phenomena of the objective world.

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By the way of solving problems, thinking (as a mental process whose biological purpose is the optimal solution of the problem that arises before an individual) can be convergent (correlated with intellect, linear thinking, resulting in a single result) and divergent (correlates with creativity, consists in finding multiplicity of variants of the solution of a problem or a diversified vision of one object). The term convergent and divergent thinking was suggested by the American psychologist J.Gilford (1950) and developed by E.Torrens. Thinking operations Analysis - the separation of the object / phenomenon into component components. Can be mental and manual. Synthesis - the union of the analyzed by analysis with the identification of significant connections. Analysis and synthesis are the basic operations of thinking, on the basis of which other typological units are built. Comparison - the comparison of objects and phenomena, while revealing their similarities and differences. Classification - the grouping of objects by feature. Generalization is the union of objects on general essential features. Specification - the allocation of the private from the general. Abstraction is the singling out of one side, the aspect of an object or phenomenon, while ignoring the other. The regularities of the considered operations of thinking are the essence of the basic internal, specific patterns of thinking. On their basis, only all the external manifestations of mental activity can be explained.

REFERENCES [1]

Schneider, Susan (2013). "Non-Reductive Physicalism and the Mind Problem1". Noûs. 47 (1): 135–153.

[2]

S. C. Gibb; E. J. Lowe; R. D. Ingthorsson (2013). Mental Causation and Ontology. OUP Oxford. p. 58.


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[3]

DePaul, Michael; Baltimore, Joseph A. (2013). "Type Physicalism and Causal Exclusion". Journal of Philosophical Research. 38: 405–418.

[4]

McGinn, C. "Can the Mind-Body Problem Be Solved", Mind, New Series, Volume 98, Issue 391, pp. 349–366.

[5]

Schmaltz, Tad (2002). "Nicolas Malebranche". The Stanford Encyclopedia of Philosophy (2002). Center for the Study of Language and Information, Stanford University.

[6]

Dennett D., (1991). Consciousness Explained, Boston: Little, Brown & Company.

[7]

McGinn, Colin. "Can We Solve the Mind–Body Problem?", Mind, New Series, Vol. 98, No. 391,1989, p. 350.

[8]

"Hard problem of Consciousness", The Internet Encyclopedia of Philosophy, Josh Weisberg.

[9]

Smart, J.J.C, "Identity Theory", The Stanford Encyclopedia of Philosophy (Summer 2002 Edition).

[10] Jackson, F. (1982) "Epiphenomenal Qualia." Reprinted in Chalmers, David ed.: 2002. Philosophy of Mind: Classical and Contemporary Readings. Oxford University Press. [11] Macpherson, F. & Haddock, A., editors, Disjunctivism: Perception, Action, Knowledge, Oxford: Oxford University Press, 2008. [12] Searle, John (1980). "Minds, Brains and Programs". The Behavioral and Brain Sciences (3): 417–424.


Chapter V Philosophy of Hyper-Consciousness

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Consciousness is a state of a person's mental life, expressed in the subjective experience of the events of the external world and the life of the individual himself, as well as in the account of these events. Consciousness can be understood in a broader or more narrow sense. From the point of view of the theory of reflection, consciousness in a broad sense is "a mental reflection of reality, regardless of the level at which it is carried out biological or social, sensory or rational", in the narrow sense - "the highest, peculiar only to people and associated with the ability to explain thoughts , the function of the brain, consisting in a generalized and purposeful reflection of reality, in the preliminary mental construction of actions and foreseeing their results, in reasonable regulation and self- SIC person due to reflection." The problem of what consciousness is and what its scope is, what is the meaning of the existence of this term is the subject of research philosophy of consciousness, psychology, disciplines that study the problems of artificial intelligence. The problems of practical consideration include the following questions: how can one determine the presence of consciousness in seriously ill or comatose individuals; can there be a non-human consciousness and how can one determine its presence; at what moment the consciousness of people arises; can computers reach conscious states. The Concept of Consciousness Perceiving a thing, remembering an event, admiring the work of art or striving for the realization of some goal, the subject may not know about his psychic life, which is a condition for the possibility of these actions or states. This psychic life makes available a reflexive turn of the eye, the realization of inner perception. What is revealed through reflection, has a common property to be a consciousness of something, a consciousness in which something is realized. So, in perception, something is perceived, in remembrance something is remembered, and so is the fear of something, of love for something, etc. This property is denoted as intentionality. Philosophical Theories of Consciousness In philosophy, consciousness is seen as the ability to relate, to recognize an object (Hegel). In this case, by "consciousness" is meant not the psychic ability

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of the body (as in psychology), but the fundamental way in which a person is related to his subject and the world in general. It is said about this that consciousness is a form or a way of givenness of an object, a form or a way of giving the world in general. So understood consciousness is always, can not begin or stop, can not disappear, just as the world can not disappear, which consciousness is constitutionally correlated. Consciousness and peace are the two poles of the same, single correlated consciousness. That is why in a strictly philosophical sense it is incorrect to consider consciousness independently, in isolation from its correlative pole - the world (psychology), like the world - in isolation from its correlative pole - consciousness (naivety). But consciousness is not only the ability of the relationship, but the attitude itself. This is clear from the fact that we can not distract from consciousness, "go out" beyond its limits. In fact, we are totally covered by consciousness. If there is no consciousness, then for us there is nothing. In this sense, consciousness itself is some co-attribution, a duality, a separation within itself. It is said about this that consciousness is intentional (Husserl). Consciousness always manifests itself as a structure of consciousness about [something]. Moreover, philosophy tries to justify the conclusion that such a nature of consciousness constitutes the very separation between subject and object, internal and external, I and the world. As an attitude, consciousness is some experience, a certain experience in which we relate to the world. This experience is understood simultaneously and as the activity of correlation in general and as the experience of the subject of this activity itself and its relationship to the world. That is why, sometimes in philosophy, the subject "distinguishes" from consciousness and under the "consciousness" in a narrow sense is understood the relation of the subject and his object. It is said that the subject (co) knows the object. At the same time, the term "consciousness" in philosophy is not used when it comes to the movement "inside" thinking, and not actually about the correlation with the world. This is due to the fact that outside the experience of correlation with the world, consciousness loses its independent meaning and becomes only the ability to reflect on the conceivable content. Inside thinking, the subject of the movement is not consciousness, but thinking itself, understood simultaneously as some general, impersonal activity


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space and as the subject of this activity itself. However, with this consciousness is always present as a possible position, in which the subject can move at any time - as an experience of possible correlation with the world. The following forms of consciousness stand out: self-consciousness as consciousness by the consciousness of oneself, reason as a thinking consciousness, that is, comprehending the world in terms (categories of reason), reason as a self-conscious mind and spirit as the highest form of consciousness that includes all other forms. The difference between reason and reason is that reason relates its concepts to the world and therefore its criterion of truth is consistency. Reason as a self-conscious mind rises to a dialectical retention of contradictions, because it relates not only its concepts to the world, but also to itself with its concepts. Philosophy tries to answer two basic questions about consciousness: what is the nature of consciousness and how consciousness is connected with physical reality, primarily with the body. For the first time, the problem of consciousness was explicitly formulated by Descartes, afterwards the consciousness received wide coverage in the New European philosophy, as well as in various philosophical traditions, such as phenomenology and analytical philosophy. Among the main philosophical theories of consciousness, you can list the following: Dualism is the theory that there are two kinds of substances: consciousness and physical objects. The founder of the theory of Rene Descartes, who argued that man is a thinking substance capable of questioning the existence of everything other than his own consciousness, and that consciousness is thus irreducible to the physical world. The dualism of the soul and body is a point of view according to which the consciousness (spirit) and matter (the physical body) are two independent substances that are mutually complementary and equal in value. Plato believed that the body belongs to the material world and therefore mortal, while the soul is part of the world of ideas and immortal. He believed that the soul is only temporarily tied to the body until the moment of his death, after which the soul returns to its world of forms. The soul, unlike the body, does not exist in space and time, which gives it access to the absolute truth of the world of ideas.

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Logical behaviorism is a theory that being in a mental state means being in a behavioral state, that is, either carrying out some behavior or having a disposition toward that behavior. Logical behaviorism is associated with behaviorism in psychology, but they should be distinguished: in the latter case, behaviorism is understood as a method for studying human beings, but does not attempt to solve philosophical problems regarding the nature of consciousness and the relationship of consciousness and body. Idealism is a theory according to which the soul (consciousness) is primary. And the body is for the second time. The idealists maintain that the objects of the physical world do not exist outside their perception. This thesis was most consistently developed in subjective idealism by George Berkeley, who argued that "being is being perceived." Materialism is a trend in philosophy, which as a primary recognizes a material substance. Consciousness is described by materialists as a property of highly organized matter. The materialists criticize both dualists and idealists, as well as behaviorists, proving that behavior is not consciousness, but the internal physical cause of consciousness. Functionalism (the philosophy of consciousness) is a theory according to which being in a mental state means being in a functional state, that is, performing a certain function. From the point of view of functionalists, consciousness refers to the brain in the same way as, for example, the function of showing time relates to a specific physical device of the clock. Functionalism takes a critical position in relation to materialism, since it negates the necessary connection between consciousness and the brain. So, according to the functionalists, consciousness can potentially be a function of a variety of physical objects, such as a computer. Functionalism is the methodological basis of the theory of artificial intelligence and cognitive science. A two-aspect theory is the theory that the mental and the physical are two properties of some underlying reality, which in fact is neither mental nor physical. The two-aspect theory, therefore, rejects dualism, idealism, and materialism as representations that there is a psychic or physical substance. Phenomenology is an attempt at an unpredictable description of the content


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of the experiment without any affirmation of the reality of its subject matter. Phenomenology attempts to discover the ideal (essential) features of human thought and perception, free from any empirical and individual impregnations, and to justify all other sciences as based on thinking. The main property of human consciousness according to phenomenology is intentionality. Emergent theory is the theory that although consciousness is the property of some physical object (usually the brain), it is nonetheless irreducible to the physical states of the latter and is a special irreducible entity with unique properties, just as the properties of the water molecule are irreducible to the properties of hydrogen and oxygen atoms. Consciousness, however, is an ordinary real object, which must be studied by science on a par with all others. In philosophy, Consciousness is a state of the individual's mental life, expressed in the subjective experience of the events of the external world and the life of the individual himself, in a report on these events. In sociology, Consciousness is knowledge which, with the help of words, mathematical symbols and generalizing images, can be transmitted, become the property of other members of society. In psychology, Consciousness is a form of reflection of objective reality in the human psyche, the highest level of reflection of psychic and self-regulation. In neurophysiology, Consciousness is a brain activity that carries out the processing of information coming from both the external world and internal organs. In medicine, Consciousness is a certain state of the waking brain, a specific level of brain reactivity, accompanied by its electrical activity. Electromagnetic Theory of Consciousness The electromagnetic theory of consciousness is a theory that claims that the electromagnetic field produced by the brain is the actual bearer of conscious experience. This theory was originally proposed by Johnjo McFadden, Susan Pockett and E. Roy John. The starting point of the theory is the fact that whenever a neuron is excited to produce an action potential, it also produces a disturbance in the surrounding electromagnetic field.

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The information encoded in the patterns of excited neurons is thus reflected in the electromagnetic field of the brain. The placement of consciousness in the electromagnetic field of the brain, rather than in neurons, has the advantage of clearly explaining how information located in millions of neurons scattered throughout the brain can be combined into a single conscious experience (sometimes called a unification problem): information is combined in an electromagnetic field. Thus, the electromagnetic field of consciousness can be considered to be a "unifier of information". This theory differently explains several puzzling facts, for example, as it turned out, attention and understanding tend to be correlated with the synchronous excitation of a multitude of neurons, and not with the excitation of individual neurons. When neurons are excited together, their electromagnetic field produces stronger perturbations of the general electromagnetic field of the brain; Thus, synchronous neuronal excitation will tend to have a greater impact on the electromagnetic field of the brain (and thus on consciousness) than the excitation of individual neurons. The various electromagnetic fields of the theory diverge relative to the influence of the proposed electromagnetic field of consciousness on brain function. In the CEMI field theory of McFadden, the global electromagnetic field of the brain affects the movement of electrical charges through neuronal membranes and thus affects the likelihood that individual neurons will be excited, providing a feedback loop that controls free will. Studies of a small-sized network of 3 EM neurons have shown that EM neurons are able to compete with each other for power sources. As a result of the competition, the neural network is self-organizing - the chaotic modes are replaced by synchronous ones, showing patterns with complex time codes. The issue of self-generation of consciousness in a network with such an architecture remains open, as research continues. Quantum Theory of Consciousness The quantum nature of consciousness is a group of hypotheses based on the


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assumption that consciousness is inexplicable at the level of classical mechanics and can only be explained by invoking the postulates of quantum mechanics, superposition phenomena, quantum entanglement, and others [1-49]. In 1989, Roger Penrose's book The New Mind of the King was published, in which the author expounds his thoughts on "quantum consciousness" and the theory of the so-called strong artificial intelligence, justifying the inconsistency of the implementation of such a form of artificial intelligence. Together with Roger Penrose, Stuart Hameroff created the "Neurocomputer Orch OR Consciousness Model" in 1994, on the basis of which the "Theory of Quantum Neurocomputing", called "The Theory of Hameroff-Penrose", was developed. According to this model, brain activity is regarded as an essentially quantum process that obeys the laws of quantum physics. Matthew P.A. Fisher struck data scientists Cornell University, in 1986, investigated the effect of lithium isotopes in rats and received differences in the behavior of rats that received isotopes of lithium-6 and lithium-7. Fischer suggested that, with identical chemical properties and a slight difference in the atomic masses of lithium isotopes, the difference in the behavior of rats is due to the spins of the atoms and the decoherence time. Lithium-6 has a smaller spin and, accordingly, may remain "entangled" longer than lithium-7, which, according to Fischer's argument, could indicate that quantum phenomena can have a functional role in cognitive processes. During the five-year search for a storehouse of quantum information in the brain, Fischer defined phosphorus atoms for this role, which, in his opinion, can bind to calcium ions with a sufficiently stable qubit. In 2015, Matthew Fisher published an article in the journal "Annals of Physics" on a hypothesis postulating that the nuclear spins of phosphorus atoms can serve as something like qubits in the brain, which can allow the brain to function on the principle of a quantum computer. In the article, Fisher stated that he identified a unique molecule (Ca9(PO4)6), which retains "neuro-qubits" for quite a long time. David Bohm viewed quantum theory and relativity as contradictory, which implied a more fundamental level in the universe. He argued that both quantum theory and relativity pointed to this deeper theory, which he formulated as a

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quantum field theory. This more fundamental level was proposed to represent the unshared integrity and implicit order from which the explanatory order of the universe arises when we experience it. The proposed order of Bohm is applied to both matter and consciousness. He suggested that he could explain the relationship between them. He saw mind and matter in the form of projections into our explanatory order from the basic implicit order. Bohm claimed that when we look at matter, we do not see anything, which helps us to understand consciousness. Bohm discussed the experience of listening to music. He believed that the sense of movement and changes that make up our experience in music stem from the joint presence of the immediate past and present in the brain. Music notes from the past are more of a transformation than memories. Notes that have been seen in the near past will be explained in the present. Bohm considered this as a consciousness emerging from an implicit order. Penrose, which determines the collapse of the wave function, was the only possible physical basis for a non-computable process. Dissatisfied with his accident, Penrose proposed a new form of the collapse of the wave function, which occurred in isolation and called it an objective reduction. He suggested that each quantum superposition has its own piece of curvature of space-time and that when they become separated by more than one Planck length they become unstable and collapse. Penrose suggested that objective reduction is neither accidental nor algorithmic processing, but instead an immeasurable influence in the geometry of space-time, from which the mathematical understanding and subsequent expansion follows. Hameroff hypothesized that microtubules would be suitable hosts for quantum behavior. Microtubules consist of subunits of tubulin dimer. Each dimer has hydrophobic pockets, separated by 8 nm, and which may contain delocalized pi-electrons. Tubulins have other smaller nonpolar regions that contain pi-electronically enriched indole rings, separated only about 2 nm. Hameroff suggested that these electrons be close enough to get confused. Hameroff originally suggested that the electrons of the tubulin subunit form a Bose-Einstein condensate, but this was discredited. He then proposed Frolich condensate, a hypothetical coherent oscillation of dipole molecules. However,


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this was also experimentally discredited. In addition, he suggested that condensates in one neuron can spread to many others through gap junctions between neurons, forming a macroscopic quantum function in the enlarged area of the brain. When the wave function of this expanded condensate collapsed, it was suggested not to calculate access to the mathematical understanding and, ultimately, the conscious experience hypothetically embedded in the geometry of space-time. Khimomi Umezawa proposed a quantum memory theory for storing memory. Giuseppe Vitello and Walter Freeman proposed a dialogue model of the mind. This dialogue takes place between the classical and quantum parts of the brain. Their models of the quantum field theory of brain dynamics fundamentally differ from the Penrose-Hameroff theory. The theory of the holonomic brain of Karl Pribram (quantum holography) caused quantum mechanics to be explained by a higher-order mind. He claimed that his holonomic model solves the binding problem. Pribram collaborated with Bohm in his work on quantum approaches to reason, and he presented evidence of how much of the treatment in the brain was performed as a whole. He suggested that the ordered water on the surfaces of the dendritic membranes can work by structuring the Bose-Einstein condensation, supporting quantum dynamics. Subhasha Kaka suggested that the physical substratum to neural networks have a quantum basis, but argued that the quantum mind has machine limitations. He points to the role of quantum theory in the difference between machine intelligence and biological intelligence, but in itself can not explain all aspects of consciousness. Henry Stupp suggested that quantum waves decrease only when they interact with consciousness. He argues from the Orthodox quantum mechanics John von Neumann that the quantum state is destroyed when the observer chooses one of the alternative quantum possibilities as the basis for the future action. Stamp does not have an intrinsic wave function or density matrix, but nevertheless she can act on the brain with the help of projection operators. Such use is incompatible with standard quantum mechanics, because any number of ghost minds can be attached to any point of space that act on physical quantum

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systems with any projection operators. Therefore, the Stapp model denies "the prevailing principles of physics. Hu postulated that consciousness is inextricably linked with the back, since the latter is the source of quantum effects in both Bohm and Hestens, a fundamental quantum process associated with the structure of space-time. That is, the spin is a "mind-pixel." The unity of the mind is supposedly achieved through the confusion of mind-pixels. He presented the following postulates: (a) Consciousness is inseparably linked with the quantum spin; (B) Um-pixel brain consists of nuclear spins distributed in nerve membranes and proteins, then pixel-activating agents consist of biologically available paramagnetic particles such as O2 and NO, and nervous memories consist of all possible entangled quantum states of mind-pixels ; (C) the action potential modulations of the input of nuclear spin interactions information for pixel minds and spin chemistry is the output of a scheme of classical nervous activities; (D) Consciousness arises from the collapses of these entangled quantum states that are able to survive the decoherence, said collapses are contextual, irreversible and non-computable and the unity of consciousness is achieved through the quantum entanglement of mind-pixels. He points out that nuclear spins in both nerve membranes and neuronal proteins serve as a reason for the pixels and suggest that biologically available paramagnetic species such as O2 and NO are the mind pixels of activating agents. We also suggest that Neural Memories consist of all possible intricate quantum states of mind pixels. This concept of memory is an extension to associative memory in neuroscience. He suggested that nervous memories consist of all possible entangled quantum states of nuclear spins inside nerve membranes and proteins. REFERENCES [1] "Quantum Approaches to Consciousness". Stanford Encyclopedia of Philosophy. May 19, 2011 [First published Tue Nov 30, 2004]. [2] Dyson, Freeman (2004). Infinite in All Directions: Gifford Lectures Given at Aberdeen, Scotland April--November 1985 (1st Perennial ed.). New York: Perennial. p. 297.


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[3] Searle, John R. (1997). The Mystery of Consciousness (1. ed.). New York: New York Review of Books. pp. 53–88. [4] Stenger, Victor. The Myth of Quantum Consciousness (PDF). The Humanist. 53 No 3 (May–June 1992). pp. 13–15. [5] Stephen P. Stich; Ted A. Warfield (15 April 2008). The Blackwell Guide to Philosophy of Mind. Blackwell Philosophy Guides. John Wiley & Sons. p. 126. [6] David J. Chalmers (1995). "Facing Up to the Problem of Consciousness". Journal of Consciousness Studies. 2 (3): 200–219. [7]

Chalmers, David J. (1997). The Conscious Mind: In Search of a Fundamental Theory (Paperback ed.). New York: Oxford University Press.

[8] Bohm, David (2002). Wholeness and the Implicate Order. (Online-Ausg. ed.). Hoboken: Routledge. [9] Piaget, Jean (1997). Jean Piaget: selected works. (The Origin of Intelligence in the Child) (Repr. ed.). London: Routledge. [10] Wade, Jenny (1996). Changes of Mind: A Holonomic Theory of the Evolution of Consciousness. Albany: State Univ. of New York Press. [11] Paavo Pylkkänen. "Can quantum analogies help us to understand the process of thought?". Mind & Matter. 12 (1): 61–91. p. 75. [12] "Discovery of Quantum Vibrations in...". sciencedaily.com. 2014. [13] "Discovery of Quantum Vibrations in "Microtubules" Inside Brain Neurons Corroborates Controversial 20-Year-Old Theory of Consciousness". Elsevier. 2014. [14] Gödel, Kurt (1992). On Formally Undecidable Propositions of Principia Mathematica and Related Systems (Reprint. ed.). New York: Dover Publications. [15] Bringsjord, S. and Xiao, H. 2000. A Refutation of Penrose's Gödelian Case Against Artificial Intelligence. Journal of Experimental and Theoretical Artificial Intelligence [16] Penrose, Roger (1999). The Emperor's New Mind: Concerning Computers, Minds, and the Laws of Physics ([New edition] ed.). Oxford: Oxford Univ. Press. [17] Penrose, Roger (1995). Shadows of the Mind: A Search for the Missing Science

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of Consciousness (Repr. (with corrections). ed.). Oxford [u.a.]: Oxford Univ. Press. [18] Hameroff, Stuart (2008). "That's life! The geometry of π electron resonance clouds". In Abbott, D; Davies, P; Pati, A. Quantum aspects of life. World Scientific. pp. 403–434. [19] Roger Penrose & Stuart Hameroff (2011). "Consciousness in the Universe: Neuroscience, Quantum Space-Time Geometry and Orch OR Theory". Journal of Cosmology. 14. [20] Reimers, Jeffrey R.; McKemmish, Laura K.; McKenzie, Ross H.; Mark, Alan E.; Hush, Noel S. (17 March 2009). "Weak, strong, and coherent regimes of Fröhlich condensation and their applications to terahertz medicine and quantum consciousness". PNAS. 106 (11): 4219–4224. [21] Khoshbin-e-Khoshnazar M.R. (2007). "Achilles' Heels of the 'Orch OR' Model". NeuroQuantology. 5 (1): 182–185. [22] Maurits van den Noort, Sabina Lim, Peggy Bosch (2016). "Towards a theory of everything: The observer's unconscious brain". Nature. 538: 36–37. [23] Kikkawa, M., Ishikawa, T., Nakata, T., Wakabayashi, T., Hirokawa, N. (1994). "Direct visualization of the microtubule lattice seam both in vitro and in vivo". Journal of Cell Biology. 127 (6): 1965–1971. [24] Kikkawa, M., Metlagel, Z. (2006). "A molecular "zipper" for microtubules". Cell. 127 (7): 1302–1304. [25] F. J. Binmöller & C. M. Müller (1992). "Postnatal development of dye-coupling among astrocytes in rat visual cortex". Glia. 6 (2): 127–137. [26] De Zeeuw, C.I., Hertzberg, E.L., Mugnaini, E. (1995). "The dendritic lamellar body: A new neuronal organelle putatively associated with dendrodentritic gap junctions". Journal of Neuroscience. 15 (2): 1587–1604. [27] Hameroff S (2013-08-12). "Consciousness, the brain, and spacetime geometry". Ann. N. Y. Acad. Sci. 929: 74–104. [28] Sahu S, Ghosh S, Ghosh B, Aswani K, Hirata K, Fujita D, Bandyopadhyay A (2014-05-14). "Atomic water channel controlling remarkable properties of a single brain microtubule: correlating single protein to its supramolecular


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assembly.". Biosens Bioelectron. 47: 141–8. [29] Osborne, Hannah (2014). "Quantum Vibrations in Brain Opens 'Pandora's Box' of Theories of Consciousness - Yahoo News UK". [30] Ricciardi L.M.; Umezawa H. (1967). "Brain physics and many-body problems". Kibernetik. 4 (2): 44. [31] Ricciardi L.M.; Umezawa H. (2004) [1967]. Gordon G. G.; Pribram K. H.; Vitiello G., eds. "Brain physics and many-body problems". Brain and Being. Amsterdam: John Benjamins Publ Co: 255–266. [32] G. Vitiello, My Double Unveiled. John Benjamins, 2001. [33] Freeman W.; Vitiello G. (2006). "Nonlinear brain dynamics as macroscopic manifestation of underlying many-body dynamics". Physics of Life Reviews. 3: 93–118. [34] Atmanspacher H. (2006), Quantum Approaches to Consciousness. A critical survey article in Stanford Univ. Encyclopedia of Philosophy. [35] Pribram K. H. (1999). "Quantum holography: Is it relevant to brain function?". Information Sciences. 115 (1–4): 97–102. [36] Pribram K.H. (2004). "Consciousness Reassessed". Mind and Matter. 2: 7–35. [37] Pribram, K. (1999) Status Report: Quantum Holography and the Braln. Acta Polyiechnica Scandinavica: Emergence Complexity, Hierarchy, Organization, Vol. 2, pp. 33-60. [38] Pribram, K.H. Holography, holonomy and brain function. Elsevier's Encyclopedia of Neuroscience, 1999. [39] Jibu M.; Pribrm K. H.; Yasue K. (1996). "From conscious experience to memory storage and retrieval: The role of quantum brain dynamics and boson condensation of evanescent photons". International Journal of Modern Physics B. 10: 1735–1754. [40] Kak, S. (1995). Quantum neural computing, In Advances in Imaging and Electron Physics, vol. 94, P. Hawkes (editor). Academic Press, 259-313. [41] Kak, S. (1996). The three languages of the brain: quantum, reorganizational, and associative. In Learning as Self- Organization, K. Pribram and J. King (editors).

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Lawrence Erlbaum Associates, Mahwah, NJ, 185-219. [42] Gautam A.; Kak S. (2013). "Symbols, meaning, and origins of mind". Biosemiotics. 6: 301. [43] Kak S (2000). "Active agents, intelligence, and quantum computing". Information Sciences. 128: 1. [44] Kak S (2005). "Artificial and biological intelligence". ACM Ubiquity. 6 (42): 1–22. [45] Bourget, D. (2004). "Quantum Leaps in Philosophy of Mind: A Critique of Stapp's Theory". Journal of Consciousness Studies. 11 (12): 17–42. [46] Georgiev, D. (2012). "Mind efforts, quantum Zeno effect and environmental decoherence". NeuroQuantology. 10 (3): 374–388.


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Multichemistry and Thermodynamics of the Process of Hyper Thinking Aibassov Yerkin1, Yemelyanova Valentina1, Nakisbekov Narymzhan2, Savizky Ruben3, Bulenbayev Maxat1, Blagikh Evgeniy1 1

Research Institute of New Chemical Technologies and Materials, Kazakh National University Al-Farabi, Almaty, Kazakhstan 2 Kazakh National Medical University, Tole bi, 94, Almaty, Kazakhstan 3 Columbia University, 3000 Broadway, New York, NY, USA

Abstract We have shown that the process of thinking can be modeled on the basis of chemical thermodynamics. We offer general equations to calculate the thinking of the work of judgment the L and of entropy solutions G in the presence of a magnetic field. As a result, studies have shown that the magnetic effects strongly influence the thermodynamics of the process of thinking. Keywords Multichemistry, Magnetic effect, Thermodynamics, Process of Gyperthinking 1. Introduction One of the most complicated problems of our time is the study of the mechanism of the operation of alpha and gamma rhythms of the brain and the search for their connection with mental activity. The brain carries out a huge number of chemical reactions responsible for the synthesis of memory molecular structures that form memory and the whole system of control of a living organism. The main task of the brain is the conversion of chemical energy into electrical energy (nerve impulses), and neurotransmitters are called to solve this problem. They control the web of impulses and potentials that guide all the functions of a living organism. In this case, the mechanisms of action of neuroprotectors are chemical. The purpose of this work is to consider the possibility of using the methods

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of multichemistry to solve this problem. At present, there are several quantum theories of thinking and consciousness. We believe that to solve the most complex tasks of brain thinking that occurs simultaneously in several parts of the brain, it is necessary to use 3D methods of multichemistry. In recent years, many works devoted to the thermodynamics of the thinking process [1-6]. We have previously been shown that the thermodynamic functions of internal energy dU and free energy dF in the presence of a magnetic field [5]: dU = TdS + 1/4π HdB (1) dF = - SdT + 1/4π HdB (2) It was also shown that the Nernst equation in a magnetic field change, and is described by the equation [6]: E = E0 + RT/nF ln aOx/aRed + 1/4π H dB (3) The purpose of this work is an attempt to study the magnetic effects in thermodynamics thought processes and to find patterns of thinking mechanism in living organisms. 2. Theory Thinking - certainly a biological phenomenon, and should therefore be subject to the atomic and molecular description. Science has established that the complex DNA and RNA molecules are capable of performing the function of storage n transmission of information is even more faith in the fact that the complex information processes, including thinking, made atomic-molecular mechanisms. Analysis of the literature data on complex chemical reactions occurring in the brain, show the need for a new science - multi-chemistry. Multichemistry describes the models of several different physico-chemical mechanisms in one or more brain regions, and the mathematical expressions for these mechanisms in a given model must be mutually compatible. A special case of this definition is a system of differential equations with more than one independent variable of different physical and chemical dimensions. The fundamental thermodynamic properties of Shannon-type thinking is that


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the solution to the problem of information is not a process of spontaneous and necessary, ie running with decreasing free energy, but, on the contrary, requires the expenditure of work. This expresses the basic property information, that it is not deducible from the known data as a deduction - otherwise it would not be at all necessary, as always could be obtained from these data - but gives the new independent information that do not have believed to be reliable. The process of logical thinking is similar to spontaneous thermodynamic process: In both cases, the original particle system (information) to be converted to a finite system of new particles or inferences. As spontaneous process in the thermodynamics with decreasing capacity of the free energy, and always leads to a more stable state. Spontaneous logical process flows down the free energy and give the thermodynamically stable as a result of the withdrawal or deduction. The process of thinking is described thermodynamically expression: Work Information: IInform < 0, ∆ϕInform < 0, The work of judgment (solution): LSolution >> 0, ∆ϕSolution >> 0,

(4) (5)

where ∆ϕ - the fall of the free energy in the act of information or discussions. Between these extremes there is an intermediate area in which the magnitude of the fall of the free energy is large enough to process the judgment was spontaneous, but not high enough for it to be unique. This is - an ambiguous area of probabilistic thinking. In connection with the (equation (4)) increase in free energy of the information and hence its instability, it has to be stored in anti-entropy devices in memory, in the records of a particular type, including a variety of codes otherwise it will inevitably dissipate. 3. Results and Discussion Dynamic energy E = Zλ - э energy action in a certain space, energy vektorization energy; Ψ - energy of the order. Dynamic energy is manifested in two forms: vector EV = Eη, giving direction and displacement of an object in its area of action and Brownian EB = E(1 - η), extending the scope and status of the process. Hence the total energy UTotal = EV + EB + Ψ.

(6)

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The information in contrast to the thinking can not appear as a product of pure inferences from other data. It is impossible, without spending any work, just standing on the platform, by "pure" reasoning to know address of your friend. Information data are logically independent of each other, it is as if from nowhere output set of "primary", independent data (in physical chemistry - the system of non-interacting particles). Thinking (especially in its marginal, formal logical form) operates on the information data according to the laws of logic, and it resembles a chemical reaction "dissimilar" of the particles of the gas mixture to react with strictly defined laws. The result of thinking is the conclusion that can be recorded. They include various elements of the original information. Thinking there where begins the act of judgment as a result of a conscious selection of the source data come parcels in the form of some data (information), self-evident position (axioms) and certain assumptions (hypotheses), and subjecting them to an algorithm constructed in accordance with the laws of logic'. With this information system, axioms and hypotheses thinking process always leads to a definite conclusion. This is a very important property of thinking. It is similar to some spontaneous process, the outcome of which, regardless of the physical and chemical properties of the medium, where it occurs, is always the same! It's like a roller coaster movement of rail road. Point of arrival is not dependent on anything. It is defined only by the desire to move the system to a stable state. Thus, the thinking process is modeled on the basis of chemical thermodynamics in the form of spontaneous transition (Z - 1) varieties of "chances" that are concentrated in a single cell in a k-th some sort of a drop in the free energy and entropy, expressed by the equation of thinking: We offer general equations to calculate the thinking of the work of judgment L and entropy solution G in the presence of a magnetic field: L = IVin + ∆ϕ + 1/4π H dB,

(7)


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G = HSannon + ∆H + 1/4π H dB,

(8)

The final result of the act of thinking - a conclusion or inference - and there is a stable state of mind in the thermodynamic sense of the word. Amazing uniqueness of the final result of mental activity proves it strictly directed, "spontaneous", the vector character, apparently independent from the chaos of Brownian motion of atoms and molecules that make up the substance of the brain or any other mechanism where there is thinking. Inference can be repeated numerous times with the same result. For example, you can repeat as often as proof of the Pythagorean theorem. This means that the probability of a thermodynamic system, which carries out the process of thinking is always equal to one, which corresponds to the only possible way of thinking of those responsible for the microparticles, their full order and they are not susceptible to thermal chaos. 4. Conclusions The analysis shows that the thinking process is modeled on the basis of chemical thermodynamics in the form of spontaneous transition (Z - 1) varieties of "chances" that are concentrated in a single cell in a k-th some sort of a drop in the free energy and entropy, expressed by the equation of thought. We offer general equations to calculate the Gyper thinking of the work of judgment L and entropy solution G in the presence of a magnetic field: L = IVin + ∆ϕ + 1/4π H dB,

(7)

G = HSannon + ∆H + 1/4π H dB,

(8)

We have shown that the magnetic effects strongly influence the thermodynamics of the process of Gyper thinking. The consequence of the above is the ability to save the information entropy and speed of thinking in three dimensions, so the speed of thought to increase by several orders of magnitude. We proposed to divide the thinking into three levels: simple thinking, super thinking and hyper thinking. We proposed a new science of multichemistry for solving complex physicochemical processes occurring in different parts of the brain. We proposed a new concept - hyper thinking.

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Research in this direction will be continued. REFERENCES [1] Tony Buzan, Barry Buzan, (1993). The Mind Map Book: How to Use Radiant Thinking to Maximize Your Brain's Untapped Potential, London, BBC books. [2] de Bono, Edward (1985). Six Thinking Hats: An Essential Approach to Business Management. Little, Brown, & Company. [3] Anne G. Osborn Gary Hedlund Karen L. Salzman, (2017). Osborn’s Brain, Elsevier, 1300. [4] Brown MM (2002). Brain attack: a new approach to stroke. Clin Med (Lond) 2:60–65. [5] Aibassov Yerkin, Yemelyanova Valentina, etc., Study of changes in the thermodynamic functions in a magnetic field, J. Chem. Chem. Eng., 8, (2014), p. 119-122. [6] Aibassov Yerkin, Yemelyanova Valentina, etc., Derivation of the equation Nernst-Aibassov in a magnetic field, J. Chem. Chem. Eng., 9, (2015), p. 218-220.


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Spin-Boson and Spin-Fermion Topological Model of Consciousness We propose a new approach to the theory of Spin-Boson and Spin-Fermion Topological Model of Consciousness. We will offer a common mechanism of Spin-Boson and Spin-Fermion Topological Model of Consciousness. 1. Introduction Recently, much attention is removed study of theory of Consciousness [1-5]. All processes in the human brain occur in the form of electromagnetic processes. Therefore, it was interesting to see consciousness in terms of spin-boson and spin-fermion topological model. The aim is to study the spin-boson and spin-fermion topological model of consciousness. The novelty of the work lies in the fact that we have proposed a new mechanism of spin-boson and spin-fermion topological model of work of consciousness. 2. Theory Neuronal membrane saturated carrier spin nuclei such as 1H, 13C and 31P [1, 2]. Neuronal membrane are the matrix of the brain electrical activity and play a vital role in the normal functions of the brain and conscious of their basic molecular components are phospholipids, proteins and cholesterol. Each phospholipid contains 1% 31P, 1,8% 13C and over 60% 1H lipid chain. Neuronal membrane proteins such as ion channels and receptors neural transmitters also contain large clusters spinsoderzhaschih nuclei. Therefore, they are firmly convinced that the nature of the spin quantum used in the construction of the conscious mind. They suggested within neurobiology that perturbation anesthetics oxygen nerve pathways in both membrane proteins and may play a general anesthesia. Each O2 comprises two unpaired valence electrons strongly paramagnetic and at the same time as the chemically reactive bi-radical. It is able to produce large pulsed magnetic field along its path of diffusing. Paramagnetic O2 are the only breed can be found in large quantities in the brain to the same enzyme producing nitric oxide (NO). O2 is one of the

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main components for energy production in the central nervous system. NO is unstable free radical with an unpaired electron and one recently discovered a small neural transmitter, well known in the chemistry of spin field concentrated on the study of free radical-mediated chemical reactions in which very small magnetic energy conversion can change the non-equilibrium spin process. Thus, O2 and NO can serve as catalysts in a spin-consciousness associated with neuronal biochemical reactions such as the double paths reaction initiated by free radicals. 3. Results and Discussion They present the following Postulates: (a) Consciousness is intrinsically connected to quantum spin; (b) The mind-pixels of the brain are comprised of the nuclear spins distributed in the neural membranes and proteins, the pixel-activating agents are comprised of biologically available paramagnetic species such as O2 and NO, and the neural memories are comprised of all possible entangled quantum states of the mind-pixels; (c) Action potential modulations of nuclear spin interactions input information to the mind pixels and spin chemistry is the output circuit to classical neural activities; and (d) Consciousness emerges from the collapses of those entangled quantum states which are able to survive decoherence, said collapses are contextual, irreversible and non-computable and the unity of consciousness is achieved through quantum entanglement of the mind-pixels. In Postulate (a), the relationship between quantum spin and consciousness are defined based on the fact that spin is the origin of quantum effects in both Bohm and Hestenes quantum formulism and a fundamental quantum process associated with the structure of space-time. In Postulate (b), they specify that the nuclear spins in both neural membranes and neural proteins serve as the mind-pixels and propose that biologically available paramagnetic species such as O2 and NO are the mind-pixel activating agents. We also propose that neural memories are comprised of all possible entangled quantum states of mind-pixels. In Postulate (c), they propose the input and output circuits for the mind-pixels. As shown in a separate paper, the strength and anisotropies of


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nuclear spin interactions through J-couplings and dipolar couplings are modulated by action potentials. Thus, the neural spike trains can directly input information into the mind-pixels made of neural membrane nuclear spins. Further, spin chemistry can serve as the bridge to the classical neural activity since biochemical reactions mediated by free radicals are very sensitive to small changes of magnetic energies. In Postulate (d), they propose how conscious experience emerges. Thus, they adopt a quantum state collapsing scheme from which conscious experience emerges as a set of collapses of the decoherence-resistant entangled quantum states. They further theorize that the unity of consciousness is achieved through quantum entanglements of these mind-pixels. Spin-Boson and Spin-Fermion Model of Consciousness Bosons, unlike fermions obey Bose - Einstein, who admits to a single quantum state could be an unlimited number of identical particles. Systems of many bosons described symmetric with respect to permutations of the particle wave functions.

Figure 1. Symmetric wavefunction for a (bosonic) 2-particle state in an infinite square well potential

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Bosons differ from fermions, which obey Fermi–Dirac statistics. Two or more identical fermions cannot occupy the same quantum state (Pauli exclusion principle). Since bosons with the same energy can occupy the same place in space, bosons are often force carrier particles. Fermions are usually associated with matter.

The Spin-boson interaction is described by the equation: H = - Δ/2 σx + h/2 σz + ½ σzΣcixi + Hosc

(1)

Fermions, unlike bosons, obey Fermi - Dirac statistics: in the same quantum state can be no more than one particle (Pauli exclusion principle).

Figure 2. Antisymmetric wavefunction for a (fermionic) 2-particle state in an infinite square well potential

The spin-fermion interaction is described by the equation: H = JzΣSiSi+ε + 1/2J⊥Σ(Si+Si+ε- + Si-Si+ε+) - tΣPG[ci,εci+ε,σ exp(iε.k) + ci+εci,σ exp(-iε.k)]PG

(2)

Topological Model of Consciousness It is known that the topological phase transition Kosterlitz- - Thouless -


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phase transition in a two-dimensional XY-model. This transition from the bound pairs of vortex-antivortex at low temperatures in a state with vortices and unpaired antivortices at a certain critical temperature. XY-model - a two-dimensional vector spin model which has symmetry U (1). For this system is not expected to have a normal phase transition of the second order. This is because the system is waiting for the ordered phase is destroyed by transverse vibrations, ie the Goldstone modes (see. Goldstone boson) associated with the breach of the continuous symmetry, which logarithmically diverge with increasing system size. This is a special case of Theorem Mermin- Wagner for spin systems. Figure 3 shows a schematic image of a vortex (a) and antivortex (b) in the example of a planar magnetic material (arrows - vectors of the spin magnetic moments).

a

b

Figure 3. Schematic image of a vortex (a) and antivortex (b) in the example of a planar magnetic material (arrows - vectors of the spin magnetic moments)

Thus, topology does not depend on measuring distances, it is so powerful. The same theorems are applicable to any complex symptom, regardless of its length or belonging to a particular species of animal. 4. Conclusions In conclusion, we have presented an alternative model of consciousness in which the unpaired electron spins are playing a central role as the mind pixels and unity of mind is achieved interweaving these mental pixels.

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We hypothesized that these entangled electron spin state can be formed by the action potential modulated exchange and dipolar interactions, plus O2 and NO drive activations and survive rapid decoherence by quantum Zeno effects or decoherence-free spaces. Further, we have assumed that the collective electron spin dynamics associated with these collapses can have effects through the spin on the classic chemistry of neural activity, thereby affecting the neural networks of the brain. Our proposals involve the expansion of the associative neural coding of memories dynamic structures of neuronal membranes and proteins. Therefore, in our electron spin based on the model of the neural substrates of consciousness consists of the following functions: (a) electronic spin networks embedded in neuronal membranes and proteins, which serve as "crazy" screen with unpaired electron spins as pixels, (b) the nerve membrane and the proteins themselves, which serve as templates for the mind and nervous screen memories; and (c) free O2 and NO, which serve as agents pixel activating. Thus, the novelty of our work is that we were the first to propose that the electromagnetic field and free radicals have a great influence on the mind. Thus, we have proposed a possible mechanism of the free radical O2 and N2O in the consciousness. REFERENCES [1] Hu, H.P., Wu, M.X. (2006a) “Nonlocal Effects of Chemical Substances on the Brain Produced Through Quantum Entanglement,” in Progress in Physics, 3: 20-26. [2] Hu, H.P., Wu, M.X. (2006b) “Photon Induced Non-Local Effects of General Anaesthetics on the Brain,” in NeuroQuantology, Vol. 4(1): 17-31. [3] Likhtenshtein G.I. «Spin labeling methods in molecular biology», 1974. [4] Likhtenshtein G.I., Yamauchi J., Nakatsuji S., Smirnov A., Tamura R.," Nitroxides: applications in chemistry, biomedicine, and materials science [2008]. [5] Aibassov Y., Yemelyanova V., Savizky R. “Magnetic effects in Brain Chemistry, CA, USA, 2015.


Chapter VI Phylosophy of Behavioral Chemistry

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Behavior - a certain established image of the interaction of a living being with the environment. Behavior is determined by the ability of humans and other animals to change their actions under the influence of internal and external factors. Behavior is of great adaptive importance, allowing to avoid negative environmental factors; Although behavior is also characteristic of simpler organisms, for example, the protozoans show the ability to move in response to stimuli of the environment and are capable of elementary forms of learning. In multicellular organisms, behavior is controlled by the nervous system. In general, it can be noted that behavior occurs at a high level of organization, when the body acquires the ability to perceive, store and transform information, using it for the purpose of self-preservation and adaptation to conditions of existence. Components of Mental Activity In science, the idea of the three components of mental activity was established. These components, instinct, the ability to learn and the ability to reason. Congenital instincts in a broad sense are a hereditary component of the behavioral act. In the sciences of the behavior of animals, instinct is a species-specific set of congenital complex reactions of the organism, which usually arise in unchanged form in response to external or internal stimuli. Unconditioned reflex is a relatively constant stereotyped innate response of the organism to the effects of the external and internal environment, carried out through the central nervous system and not requiring special conditions for its occurrence (for example, pulling the hand when touching very hot objects). Accustoming is the simplest form of learning, consisting in the weakening of the response to a stimulus with multiple presentation. A conditioned reflex consists in the formation of a biologically neutral stimulus with a biologically significant stimulus repeatedly, so that both stimuli partially overlap in time, reactions to a neutral stimulus. Within the framework of the reflex theory of GNI, the conditioned reflex was considered as the basic unit of individual experience. Rational activity is the ability of a person or an animal to catch empirical

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laws that connect objects and phenomena of the external world and operate with these laws in a new situation for him. Human intellect is a general cognitive ability that determines the readiness to assimilate and use knowledge and experience, as well as to rational behavior in problem situations. Forms of Behavior Nutritional behavior is inherent in all animals and is very diverse. It is inextricably linked with various activities associated with the search, food storage and metabolism. Search behavior is triggered by excitation processes caused by a lack of food. Comfortable behavior unites behavioral acts aimed at caring for the body. Comfortable behavior is an integral part of the life of a healthy animal. Reproductive Behavior Of the two main types of reproduction - sexual and asexual, the first is characterized by an exceptional variety of behaviors aimed at finding a partner, pairing, finding a partner, marriage rituals and proper mating. Asexual reproduction does not require such adaptations. There are three main types of marital relations: polygamy, monogamy and polyandry. Parent behavior combines behavioral acts associated with breeding offspring. To social behavior include manifestations of mental activity, directly related to the interaction between individuals and their groups. There are two main types of social behavior - group, which is characterized by the existence of mutual attraction between individuals and territorial, under which there is no such attraction. Research activity refers to activity aimed at studying the environment, not related to the search for food or a sexual partner. Higher animals, hitting an unfamiliar environment, begin to actively move around, inspect, feel and sniff around surrounding objects. Research behavior is suppressed by hunger, reaction of fear and sexual arousal. To know a person psychologically is to get information about his psychological characteristics, to understand his inner state and on the basis of this knowledge to predict his actions, actions, behavior in various life situations.


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Understanding, and most importantly anticipating the behavior of others, is one of the main motives for studying psychology for many students. The founder of behaviorism John Watson was proclaimed that the human soul is fundamentally unknowable, and human behavior is a manifestation of a two-link scheme: (S-R) stimulus-reaction. B = S – R, (1) where B is behavior, S is stimul and R is reaction.

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New Reaction Dorfman-Aibassov Reaction of Arsine, Stibine and Bismuthine with Alcohols in the Presence of a Metal Catalyst Aibassov Yerkin Zhakenovich, Yemelyanova Valentina Stepanovna Research Institute of New Chemical Technologies and Materials, Kazakh National University Al-Farabi, Almaty, Kazakhstan

Abstract We first discovered the New reaction Dorfman-Aibassov reaction of arsine, stibine and bismuthine with alcohols in the presence of a metal catalyst. We propose mechanism a new reaction of arsine, bismuthine and stibine with alcohols in the presence of a metal catalyst. Keywords Arsine, Stibine, Bismuthine, Alcohols, Metal catalyst In recent years, we found a lot of new organic reactions involving platinum halides (II) and (IV), например, окисления алканов, аренов, олефины, спирты, оксид углерода [1-7]. Oxidation activity of platinum halides (II), (IV), as a rule, a simultaneous kinetic constants ligand exchange and thermodynamic stability constant and antisymbatic redox potentials and energies of the Pt-X [1-5]. Usually platinum halides (II) catalyzes the reduction of platinum (IV) by formation of various dimers substatami containing platinum (II) and (IV). We first found that by passing a gas mixture AsH3-Ar, at 50°С through the alcoholic solution complexes Na2PtCl6, known for their high inertness and stability formed trialkilarsinits (RO)3Аs and trialkilarsenats (RO)3AsO. AsH3 + 3Na2PtCl6 + 3ROH → 3Na2PtCl4 + (RO)3Аs + 6HCl (1) AsH3 + 3Na2PtCl6 + 3ROH → (RO)3AsO + 2Pt + RCl + 7HCl, (2) где: R = CH3-, C2H5-, С3Н7-, C4H9-, изо-С4Н9-,-C5H11, C8H17. New reactions are very fast. Reaction (1) end after recovery Pt (IV) to Pt (II), and the reaction (2) - after recovery Pt (IV) to Pt (0), precipitated in the form of fine black precipitate. During absorption AsH3 redox potential (φ) Pt (IV)/Pt (II)


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is shifted toward the cathode. Changes AsH3-Na2PtCl6-ROH analyzed the nature of conversion (W - Q), kinetic (W - τ) and potentiometric (φ - Q, φ - τ) curves. Conversion and kinetic curves in all cases has a maximum. The rate of reaction (1) is described by equation (3): W = k1 [Pt(IV)]0,5 [Pt(II)] 0,5 [AsH3] 0,5 [ROH] 0,5 (3) The rate of reaction (2) is described by equation (4): W = k1 [AsH3] 0,5 [ROH] 0,5 ([Pt(IV)] 0,5 [Pt(II)] 0,5 + k2 [Pt(II)], (4) where k1, k2 - rate constant, mole-1s-1. From equations (3) and (4) shows that reaction (1) - (2) proceed in the coordination sphere of dimer and mixed galogenidoalkoksiarsina complexes and platinum (IV) and (II). As the recovery of Pt (IV) to Pt (II), the color of the solution changed from bright orange to dark brown, indicating the formation of bifunctional platinum complexes. Halides and platinum (II) catalyzes the introduction of AsH3 and ROH in the coordination sphere of the platinum chloride (IV). The complex was established by EPMA, RFE- and IR spectroscopy. It follows that trialkilarsenaty formed as follows: Pt2X5(AsH3)(RO) → 2PtX2 + (RO)AsH2 + HX (5) Pt2X5(ROAsH2)(RO) → 2PtX2 + (RO)2AsH + HX (6) Pt2X5[(RO)AsH](RO) → 2PtX2 + (RO)3Аs + HX (7) PtX2 [(RO)3Аs] + HX → 2PtX2 + (RO)AsH2 + HX (8) Pt2X5[(RO)2HAsO](RO) → 2PtX2 + (RO)3AsO + HX (9) According to equations (5) - (9), the alcohol is activated by deprotonation and forming a covalent bond Pt - O. Reactions (6) - (9) are faster than (5), since arsenite, unlike arsine readily form complexes with Pt (IV) and (II). Platinum (II) contributes not only to the introduction of AsH3 and ROH in the coordination sphere of the platinum (IV), and dealkylation trialkilarsenitov. Arsine, Stibine and Bismuthine behave like unsaturated compounds (olefins, carbon monoxide), which are characterized by the introduction of the reaction of the metal - ligand. Since at least the substitution of atoms on the functional group arsine arsenite resistance increases, the oxidation of arsenite platinum

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(IV) are faster than the oxidation of arsine. The driving forces of reaction are significant redox potential of Pt (IV) / Pt (II) and high energy of As-O. Similarly, new reactions occur Stibine and Bismuthine with alcohols in the presence of a metal catalyst: SbH3 + 3Na2PtCl6 + 3ROH → 3Na2PtCl4 + (RO)3Sb + 6HCl (10) BiH3 + 3Na2PtCl6 + 3ROH → 3Na2PtCl4 + (RO)3Bi + 6HCl (11) Spectra obtained tributylstibin (C4H9O)3Sb and tributylbismuthin (C4H9O)3Bi were confirmed by gas chromatography SHIMADZU GC-17A and mass spectrometer QPSOSO scan mode m/z range 10-350 (Figs. 1 and 2).

Figure 1. Mass spectrum of (C4H9O)3Sb

Figure 2. Mass spectrum of (C4H9O)3Bi

The above described work done in a very uncharted, but has great practical importance in organic chemistry of arsenic, bismuth and antimony. These activation mechanisms arsine, stibine bismuthine and can be used to


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open this type of reaction with other organic compounds and elements. The authors are grateful to Professor Ruben M. Savizky (The Cooper University, New York, 10003, USA) for the assistance in the analysis and discussion of the results. Conclusions 1. We first discovered the New reaction Dorfman-Aibassov reaction of arsine, stibine and bismuthine with alcohols in the presence of a metal catalyst. 2. We propose mechanism a new reaction of arsine, bismuthine and stibine with alcohols in the presence of a metal catalyst. REFERENCES [1]

Aibassov E.Zh., Aibassova S.M. New reactions of Arsine. Introduction to Organic Chemistry of Arsenic, Actinides, Lanthanides, Os187 and Re, New York, 2011, 100 p.

[2]

Aibassov E.Zh., Dorfman Ya.A. New reaction involving the oxidative O-, Cphosphorylation of organic compounds by Phosphine in presence of Metal Complexes Pt(IV) and Pt(II), Oxidation of U(IV) to U(VI) used of catalyst “Muhamedzhan-1”, New York, 2011, 60 p.

[3]

Aibassov Yerkin, Kenzhaliev Bagdaulet, The new reactions in organometallic chemistry arsenic, antimony, Lambert Academic Publishing, Germany, 2014, 112 p.

[4]

Aibassov Yerkin, Yemelyanova Valentina, The Magnetic and Relativistic Effects in Catalisis and Uranium Catalysts, Lambert Academic Publishing, Germany, 2014, 162 p.

[5]


[6]

Aibassov Yerkin, Yemelyanova Valentina, Spin Catalytic Reactions in the presence of Nitric Oxide and the New Reactions of Arsenic, Antimony and Bismuth, Scientific & Academic Publishing, USA, 2015, 346 p.

[7]


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New Aibassov’s - Yuriev's Reaction Transformation of Furan in Its Analogs Phosphorane, Arsanol, Stibinol and Vismutol Aibassov Erkin Zhakenovich, Baiguzhin Adil Alimbekovich, Umirkulova Zhanar Sempekovna, Serikbaeva Gulbarshyn Kuanyshkanovna LTD "Chemical Solution", Almaty, Kazakhstan, Zhamakaeva Str.

Abstract We first discovered a new transformation reactions of furan in its analogs - phosphorane, arsanol, stibinol and vismutol, where X = AsH, SbH, BiH, PH, NH, S, Se. First proposed a new mechanism of the reaction. Keywords Natural zeolite, Clinoptilolite, Arsine, Stibine, Vismutine, Arsanol, Stibinol, Vismutol 1. Introduction Recently, the discovery of new zeolite catalysts such as SAPO-34, containing SiO2, Al2O3, P2O5 and the reaction of arsine, stibine and bismuthine with alcohols, amines, and other organic compounds that are used as biologically active substances, drugs. We have studied the reaction of AsH3, SbH3, BiH3 with five-membered heterocycles. 2. Experimental Samples of γ-Al2O3 were prepared by incipient wetness impregnation of γ-Al2O3 with water solutions of HCl having the required concentration, dried in air at 110°C for 5 h and calcined in flowing air at 500°C for 2 h /1-5/. THF was purified from peroxides and distilled before application. AsH3, SbH3 and BiH3 was obtained from the reaction of As2O3 with hydrogen in the presence of catalyst. The products was determined in a flow-circulation reactor at atmospheric pressure. At first a mixture of AsH3 with argon was fed into a thermostated


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bubbling device changed with THF and then into the reactor. Chromatographic analysis was carried out on a LKHM-8MD chromatograph with a catharometer. The stationary phase was Porapak Q, the column was 1 m long with an internal diameter of 3 mm, T=175°C and the rate of the carrier gas (argon) was 3.6 L/h. 3. Results and Discussion We first discovered a new reaction conversion of five-membered (furan) and six-membered (pyran) heterocycles in its analogs - pentamerous (phosphorane, arsanol, stibinol and vismutol) or six-membered (pyran, pyridine, etc.) heterocycles, where X = AsH, SbH, BiH, PH, NH, S, Se in the interaction of phosphine, arsine, and stibine bismuthine with five-and six-membered heterocycles of alumina containing acid sites, at 400-450°C:

(1) where X = O, S, Se, N, PH, AsH, SbH, BiH. The mechanism of this reaction is the opening series of furan at the C-O and then joining hydride AsH3, SbH3, BiH3 and then elimination of water molecules from hydroxy compounds and ring closure with another heteroatom: (CH)4=O + H3X → [HO-CH = CH-CH = CH-XH] → (CH)4XH, (X=AsH, SbH, BiH) (2) Six-membered oxygen-, nitrogen-containing heterocycles (pyridine, pyran) with AsH3, SbH3, BiH3 give six-membered heterocyclic arsinin, stibinin and vismin. With increasing atomic number X (As, Sb, Bi) a six-membered ring is distorted: the length of the C = C 140, C = As 185, C = Sb 205, C = Bi 217 nm. New reaction provides a one-step key organometallics As, Sb, Bi used for the synthesis of pharmaceuticals and biologically active substances. 4. Conclusions Thus, we first observed that the AsH3, SbH3, BiH3 by passing the mixture through a modified furan halides zeolite - clinoptilolite - gives arsol, stibol and vismutol. This shows that the reaction of Yuriev's is a special case of our reaction.

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REFERENCES [1]

Yuriev Y.K. Proceedings of the Moscow State University, 1956, vol. 175, 159.

[2]

Heterocyclic compounds under. Ed. R. Elderfilda, trans. from English., vol.1, Moscow, 1953, p.130.

[3]

Yuriev Y.K Journal of General Chemistry, 1938, 8, issue 2, 116.

[4]

Yuriev Y.K Journal of General Chemistry, 1939, 9, issue 7, 628.

[5]

Yuriev Y.K Journal of General Chemistry, 1941, 11, No. 4, 344.

[6]

Aibassov E.Zh., Aibassova S.M. New reaction of Arsine. Introduction to Organic Chemistry of Arsenic, Actinides, Lanthanides, Os187 and Re. “Gitel Publishing House, New York, P 100.

United States Patent Application Kind Code Aibassov; Yerkin ; et al.

20130104698 A1 May 2, 2013

Method of catalytic oxidation of U4+ to U6+ using a catalyst Muhamedzhan-1

Abstract The proposed methods are exemplarily utilized in uranium hydrometallurgy for selective extraction of uranium out of ore by in situ or heap leaching. According to the disclosure, the methods encompass catalytic oxidation of U.sup.4+ to U.sup.6+ using a proposed oxidizing catalyst "Muhamedzhan-1", filtration of this solution through ore, transferring hexavalent uranium, trivalent iron, and other metal ions into a production solution, extraction of uranium yielding a barren solution and re-circulation of this solution back for ore leaching. The methods essentially improve known technologies by employing "Muhamedzhan-1", being a solution of d- and f-mixed valence metal salts (ML.sub.n, wherein M=Fe, U, Cu, Mn, and L=NO.sub.3.sup.-, SO.sub.4.sup.2-Cl.sup.-, Br.sup.-, I.sup.-) and alkali metal halogenides (MX, wherein M=Na.sup.+, Na.sup.+, K.sup.+, and X=Cl.sup.-, Br.sup.-, I.sup.-)


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used as an oxidizing agent, with the weight ratio of ML.sub.n: 0.01-25.0%, MX: 0.01-12.5%, and solvent: balance. Aibassov; Yerkin; (Almaty, KZ); Aibassova; Saltanat; (Almaty, KZ) ; Inventors: Aibassov; Gizatulla; (Shinhold, GB); Aibassov; Zhaken; (Almaty, KZ) ; Aibassov; Mukhamejan; (Almaty, KZ); Abenov; Bakhyt; (Almaty, KZ) Name

City

Aibassov; Yerkin Aibassova; Saltanat Applicant: Aibassov; Gizatulla Aibassov; Zhaken Aibassov; Mukhamejan Abenov; Bakhyt

Almaty Almaty Shinhold Almaty Almaty Almaty

State Country KZ KZ GB KZ KZ KZ

Serial No.: 317960 Series Code:

13

Filed:

November 1, 2011

Current U.S. Class: Class at Publication:

International Class:

75/399; 502/169; 502/172; 502/174; 502/200; 502/201; 502/218; 502/224; 502/225; 502/229 75/399; 502/169; 502/172; 502/174; 502/201; 502/200; 502/218; 502/225; 502/229; 502/224 C22B 60/02 20060101 C22B060/02; B01J 31/02 20060101 B01J031/02; B01J 27/232 20060101 B01J027/232; B01J 27/25 20060101 B01J027/25; B01J 27/24 20060101 B01J027/24; B01J 27/053 20060101 B01J027/053; B01J 27/122 20060101 B01J027/122; B01J 27/128 20060101 B01J027/128; B01J 27/08 20060101 B01J027/08; B01J 31/32 20060101 B01J031/32; B01J 31/30 20060101 B01J031/30; B01J 31/28 20060101 B01J031/28; B01J 27/20 20060101 B01J027/20; B01J 27/10 20060101 B01J027/10; B01J 27/055 20060101 B01J027/055; B01J 23/04 20060101 B01J023/04; B01J 31/26 20060101 B01J031/26

Claims

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1. A catalyst called "Muhamedzhan-1" for catalytic oxidation of U.sup.4+ to U.sup.6+, wherein "Muhamedzhan-1" comprises a mixture of: a first component consisting of d- and f-mixed valence metal salts ML.sub.n, wherein M is one of the following: Fe, U, Cu, and Mn, and wherein L is one of the following: NO.sub.3.sup.-, SO.sub.4.sup.2-Cl.sup.-, Br.sup.-, and I.sup.-; a second component consisting of alkali metal halogenides MX, wherein M is one of the following: Li.sup.+, Na.sup.+, K.sup.+, and NH.sub.4.sup.+ and wherein X is one of the following: Cl.sup.-, Br.sup.-, OH.sup.-, HCO.sub.3.sup.-, CO.sub.3.sup.2-, and I.sup.- in the solid or dissolved state; wherein the weight ratio of the first and the second components in the solid state m(ML.sub.n)/m(MX) ranges from 1:2 to 6:1 correspondingly; and a third component in the form of: water (H2O) and/or primary alcohols (ROH) and/or secondary alcohols (RRCHOH) used as a solvent, having a solution weight concentration ranging from 0.0001% to 30.0% of solid salts mixture in solution. 2. A method of catalytic oxidation of U.sup.4+ to U.sup.6+, using a catalyst added solution for extraction of uranium by in situ leaching or heap leaching, said method comprising the steps of: A1) preparation of a concentrated solution of a catalyst called "Muhamedzhan-1" in the form of: solution of d- and f-mixed valence metal salts ML.sub.n, wherein M=Fe, U, Cu, Mn, and L=NO.sub.3.sup.-, SO.sub.4.sup.2-Cl.sup.-, Br.sup.-, I.sup.- and alkali metal halogenides MX, wherein M=Li.sup.+, Na.sup.+, K.sup.+, NH.sub.4.sup.+ and X=Cl.sup.-, Br.sup.-, OH.sup.-, HCO.sub.3.sup.-, CO.sub.3.sup.2-, I.sup.- with the following composition in weight %: TABLE-US-00008 ML.sub.n: 0.01-25.0% MX: 0.01-12.5% H.sub.2O or primary and/or secondary alcohols ROH, RRCHOH: balance; B1) preparation of a leaching solution containing sulfuric acid or ammonia hydroxide with the following composition in weight %: TABLE-US-00009 H.sub.2SO.sub.4 or NH.sub.4OH: 0.5-10.0% H.sub.2O or primary and/or secondary alcohols ROH, RRCHOH: balance, C1) adding the concentrated solution of "Muhamedzhan-1", obtained on the step (A1), to the leaching solution, obtained on the step (B1), in the following volumetric % ratio: TABLE-US-00010 "Muhamedzhan-1": 0.1-10.0%


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Leaching solution balance, thereby obtaining a leaching solution modified with "Muhamedzhan-1"; D1) filtration of the leaching solution modified with "Muhamedzhan-1" obtained on the step (C1) through ore, with oxidation of uranium (IV) and iron (II) ions to uranium (VI) and iron (III), and a subsequent dissolution of uranium (VI), iron (III), and other metal ions in the leaching solution filtrated through ore, thereby obtaining a filtrated leaching solution containing uranium (VI) ions; E1) extraction of uranium from the filtrated leaching solution obtained on the step (D1), and yielding a barren solution; and F1) regeneration of "Muhamedzhan-1" in the barren solution obtained on the step (E1) by bubbling air therethrough and addition of H.sub.2SO.sub.4 or NH.sub.4OH to meet their concentration requirement of the step (B1), thereby yielding the leaching solution modified with "Muhamedzhan-1" in the oxidized form, and re-circulation of the leaching solution modified with "Muhamedzhan-1" in the oxidized form back for ore leaching at the step (D1). 3. A method of catalytic oxidation of U.sup.4+ to U.sup.6+, using a catalyst added solution for extraction of uranium by in situ leaching or heap leaching, said method comprising the steps of: A2) preparation of a leaching solution containing sulfuric acid or ammonia hydroxide with the following components composition in weight %: H.sub.2SO.sub.4 or NH.sub.4OH: 0.5-10.0%; H2O or ROH or RRCHOH: balance; B2) preparation of the leaching solution modified with "Muhamedzhan-1" by adding: d- and f-mixed valence metal salts ML.sub.n, wherein M is one of the following: Fe, U, Cu, and Mn, and wherein L is one of the following: NO.sub.3.sup.-, SO.sub.4.sup.2-Cl.sup.-, Br.sup.-, and I.sup.-, and alkali metal halogenides (MX, wherein M is one of the following: Li.sup.+, Na.sup.+, K.sup.+, and NH.sub.4.sup.+, and wherein X is one of the following: Cl.sup.-, Br.sup.-, OH.sup.-, HCO.sub.3.sup.-, CO.sub.3.sup.2-, and I.sup.-) in their solid state; directly to the leaching solution obtained in step (A2) thereby obtaining a leaching solution modified with "Muhamedzhan-1" with the following fractions in weight %: ML.sub.n: 0.00001%-15.0%, MX: 0.00001%-10%, and the leaching solution obtained on the step (A2): balance; C2) filtration of the leaching solution modified with "Muhamedzhan-1" obtained on the step (B2) through ore, with oxidation of

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uranium (IV) and iron (II) ions to uranium (VI) and iron (III), and a subsequent dissolution of uranium (VI), iron (III) and other metal ions in the leaching solution filtrated through ore, thereby obtaining a filtrated leaching solution containing uranium (VI) ions; D2) extraction of uranium from the filtrated leaching solution obtained on the step (C2), and yielding a barren solution; and E2) regeneration of "Muhamedzhan-1" in the barren solution obtained on the step (D2) by bubbling air therethrough and addition of H.sub.2SO.sub.4 or NH.sub.4OH to meet the concentration requirement of the step (A2), thereby yielding the leaching solution modified with "Muhamedzhan-1" in the oxidized form, and re-circulation of the leaching solution modified with "Muhamedzhan-1" in the oxidized form back for ore leaching on the step (C2). Description FIELD OF THE INVENTION [0001] The invention belongs to hydrometallurgical ore processing methods and can be utilized, in particular, in uranium hydrometallurgy for selective extraction of uranium out of ore by heap leaching and/or in situ leaching. BACKGROUND OF THE INVENTION [0002] There is known a related art method of uranium heap and in situ leaching utilizing sulfuric acid. The known method involves filtration of diluted solution of sulfuric acid through strata of ore body laid down in heaps or in-situ directly through an ore bearing stratum. During this process nitric acid is added into the solution to passivate equipment. A disadvantage of the aforementioned method is its low intensity and consequently its long duration (L. I. Lunev, Mine systems of uranium deposits development by in-situ leaching, Moscow, 1982, pp. 8, 13, 17). The instant inventors consider the above method as most closely related to the present invention. [0003] U.S. Pat. No. 4,049,769 titled "Separation of uranium isotopes by accelerated isotope exchange reactions" is known. It describes uranium isotopes segregation method that includes isotope exchange reaction during


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which uranium (IV) and uranium (VI) ions contact in the presence of catalyst dissolved in acid environment and consisting of compounds of Cu, In, Tl, Zr, Sn, V, Nb, As, Vi, Cr, Mo, Mn, Re, Rt, Pd, Fe, Hg, and Sb. Disadvantages of this method are the complex catalyst composition, use of expensive, and rare reagents (Pd, Zr, In, Nb, Re, Rh), and inability to regenerate the used up catalyst by air oxygen. The proposed "Muhamedzhan-1" catalyst has the following distinctions and advantages: 1) catalytic oxidation of U(IV) to U(IV) proceeds with high rate and selectivity; 2) the used up catalyst easily regenerates with the air oxygen; 3) catalytic oxidation proceeds in mild conditions and low temperatures (from +4 to +60.degree. C.); 4) the use of relatively low cost sulphuric acid; 5) simplicity and robustness of the technological process. [0004] U.S. Pat. No. 4,312,840 titled "Process for the in-situ leaching of uranium" is known. This patent describes a process for the in-situ leaching of uranium employing an alkaline lixiviant and an alkali metal or alkaline earth metal hypochlorite as an oxidizing agent. In the above process leaching solution pH is in range of 8-10 and hypochloride is present in range of 0.1-1.0 weight percents. Disadvantages of this method are: the use of costly, toxic and environmentally dangerous chlorine, and inability of the oxidizing agent to regenerate by air oxygen. The proposed "Muhamedzhan-1" catalyst has the following distinctions and advantages: 1) new process proceeds at low pH values in range 0.5-4.0; 2) new catalyst easily regenerates with the air oxygen; 3) new process is environmentally healthier and does not use toxic and corrosive chlorine. [0005] U.S. Pat. No. 4,402,921 titled "Ammonium carbonate and/or bicarbonate plus alkaline chlorate oxidant for recovery of uranium values" is known. This patent describes a method of low-valent uranium extraction using aqueous leaching solution that consists of alkaline chlorate, ammonium carbonate and/or ammonium bicarbonate, and compounds of the following ions: Cu.sup.2+, Co.sup.2+, Fe.sup.3+, Ni.sup.2+, Cr.sup.3+. The process is conducted at pH>9.0. Disadvantages of this method are: the use of costly, corrosive and toxic chlorates, and inability of the oxidizing agent to regenerate. In its turn, the proposed "Muhamedzhan-1" catalyst based process is conducted

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at low pH values (0.5-4.0), "Muhamedzhan-1" catalyst is environmentally friendly and can be regenerated by air oxygen. [0006] U.S. Pat. No. 4,405,567 titled "Uranium value leaching with ammonium carbonate and/or bicarbonate plus nitrate oxidant and optionally oxidation-catalytic metal compounds" is known. This patent describes a method of low-valent uranium extraction using aqueous leaching solution that contains NH.sub.4.sup.+ and NO.sub.3.sup.- ions, and metal compounds containing Cu.sup.2+, Co.sup.2+, Fe.sup.3+, Ni.sup.2+, Cr.sup.3+. The process is conducted at pH>9.0. A main disadvantage of this method is inability of the oxidizing agent to regenerate. The proposed "Muhamedzhan-1" catalyst can be easily regenerated by air oxygen. [0007] In the recent time a lot of research has been conducted in the field of in situ uranium leaching utilizing different oxidizing agents. At the moment, the development of methods of catalytic oxidation of U.sup.4+ to U.sup.6+ is an issue of immediate importance. BRIEF SUMMARY OF THE INVENTION [0008] The proposed methods are exemplarily utilized in uranium hydrometallurgy for selective extraction of uranium out of ore by in situ or heap leaching. The methods encompass catalytic oxidation of U.sup.4+ to U.sup.6+ using an inventive oxidizing catalyst "Muhamedzhan-1", filtration of this solution through ore, transferring hexavalent uranium, trivalent iron, and other metal ions into a production solution, extraction of uranium yielding a barren solution and re-circulation of this solution back for ore leaching. The inventive methods essentially improve known technologies by employing a catalyst herein further called "Muhamedzhan-1", being a solution of d- and f-mixed valence metal salts (ML.sub.n, where M=Fe, U, Cu, Mn, and L=NO.sub.3.sup.-, SO.sub.4.sup.2-Cl.sup.-, Br.sup.-, I.sup.-) and alkali metal halogenides (MX, where M=Li.sup.+, Na.sup.+, K.sup.+, and X=Cl.sup.-, Br.sup.-, I.sup.-) used as an oxidizing agent, with the weight ratio of: ML.sub.n: 0.01-25.0%, MX: 0.01-12.5%, and solvent: balance. DESCRIPTION OF THE INVENTION [0009] The proposed invention contemplates the catalyst "Muhamedzhan-1"


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usable for catalytic oxidation of U.sup.4+ to U.sup.6+ comprising a mixture of: d- and f-mixed valence metal salts (ML.sub.n, wherein M is one of the following: Fe, U, Cu, and Mn, and wherein L is one of the following: NO.sub.3.sup.-, SO.sub.4.sup.2-Cl.sup.-, Br.sup.-, and I.sup.-) and alkali metal halogenides (MX, wherein M is one of the following: Li.sup.+, Na.sup.+, K.sup.+, and NH.sub.4.sup.+, and wherein X is one of the following: Cl.sup.-, Br.sup.-, OH.sup.-, HCO.sub.3.sup.-, CO.sub.3.sup.2-, and I.sup.-) in the solid or dissolved state with the weight ratio of two components in the solid state m(ML.sub.n)/m(MX) ranging from 1:2 to 6:1 correspondingly, and water (H2O) and/or primary alcohols (ROH) and/or secondary alcohols (RRCHOH) used as a solvent, with the solution weight concentration ranging from 0.00001% to 30.0% of solid salts mixture in solution. [0010] The proposed invention contemplates a first method of catalytic oxidation of U.sup.4+ to U.sup.6+, using a catalyst solution for uranium extraction by in situ leaching or heap leaching, wherein the first method comprises the steps of: A1) preparation of a concentrated solution of "Muhamedzhan-1" in the form of solution of d- and f-mixed valence metal salts (ML.sub.n, wherein M=Fe, U, Cu, Mn, and L=NO.sub.3.sup.-, SO.sub.4.sup.2-Cl.sup.-, Br.sup.-, I.sup.-) and alkali metal halogenides (MX, wherein M=Li.sup.+, Na.sup.+, K.sup.+, NH.sub.4.sup.+ and X=Cl.sup.-, Br.sup.-, OH.sup.-, HCO.sub.3.sup.-, CO.sub.3.sup.2-, I.sup.-) with the following composition in weight %: TABLE-US-00001 ML.sub.n 0.01-25.0% MX 0.01-12.5% H.sub.2O (or primary and/or secondary alcohols ROH, RRCHOH) balance; B1) preparation of a leaching solution containing sulfuric acid or ammonia hydroxide with the following composition in weight %: TABLE-US-00002 H.sub.2SO.sub.4 or NH.sub.4OH: 0.5-10.0% H.sub.2O (or primary and/or secondary alcohols ROH, RRCHOH): balance, C1) adding the concentrated solution of "Muhamedzhan-1", obtained on the step (A1), to the leaching solution, obtained on the step (B1), in the following volumetric % ratio: TABLE-US-00003 "Muhamedzhan-1": 0.1-10.0% Leaching solution: balance,

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thereby obtaining a leaching solution modified with "Muhamedzhan-1"; D1) filtration of the leaching solution modified with "Muhamedzhan-1" obtained on the step (C1) through ore, with oxidation of uranium (IV) and iron (II) ions to uranium (VI) and iron (III), and a subsequent dissolution of uranium (VI), iron (III), and other metal ions in the leaching solution filtrated through ore, thereby obtaining a filtrated leaching solution containing uranium (VI) ions; E1) extraction of uranium from the filtrated leaching solution obtained on the step (D1), and yielding a barren solution; and F1) regeneration of "Muhamedzhan-1" in the barren solution obtained on the step (E1) by bubbling air therethrough and addition of H.sub.2SO.sub.4 or NH.sub.4OH to meet their concentration requirement of the step (B1), thereby yielding the leaching solution modified with "Muhamedzhan-1" in the oxidized form, and re-circulation of the leaching solution modified with "Muhamedzhan-1" in the oxidized form back for ore leaching on the step (D1). [0011] The proposed invention contemplates a second method of catalytic oxidation of U.sup.4+ to U.sup.6+, using "Muhamedzhan-1" for extraction of uranium by in situ leaching or heap leaching, wherein the second method comprises the steps of: [0012] A2) preparation of a leaching solution containing sulfuric acid or ammonia hydroxide with the following components composition in weight %: H.sub.2SO.sub.4 or NH.sub.4OH: 0.5-10.0%; H2O or ROH or RRCHOH: balance; B2) preparation of the leaching solution modified with "Muhamedzhan-1" by adding: [0013] d- and f-mixed valence metal salts (ML.sub.n, wherein M is one of the following: Fe, U, Cu, and Mn, and wherein L is one of the following: NO.sub.3.sup.-, SO.sub.4.sup.2-Cl.sup.-, Br.sup.-, and I.sup.-) and [0014] alkali metal halogenides (MX, wherein M is one of the following: Li.sup.+, Na.sup.+, K.sup.+, and NH.sub.4.sup.+, and wherein X is one of the following: Cl.sup.-, Br.sup.-, OH.sup.-, HCO.sub.3.sup.-, CO.sub.3.sup.2-, and I.sup.-) in their solid state, directly to the leaching solution obtained in step (A2) with the following component fractions in weight %: ML.sub.n: 0.00001%-15.0%, MX: 0.00001%-10%, the leaching solution obtained in step (A2): balance; thereby obtaining a leaching solution modified with


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"Muhamedzhan-1"; C2) filtration of the leaching solution modified with "Muhamedzhan-1" obtained on the step (B2) through ore, with oxidation of uranium (IV) and iron (II) ions to uranium (VI) and iron (III), and a subsequent dissolution of uranium (VI), iron (III) and other metal ions in the leaching solution filtrated through ore, thereby obtaining a filtrated leaching solution containing uranium (VI) ions; D2) extraction of uranium from the filtrated leaching solution obtained on the step (C2), and yielding a barren solution; and E2) regeneration of "Muhamedzhan-1" in the barren solution obtained on the step (E2) by bubbling air therethrough and addition of H.sub.2SO.sub.4 or NH.sub.4OH to meet the concentration requirement of the step (A2), thereby yielding the leaching solution modified with "Muhamedzhan-1" in the oxidized form, and re-circulation of the leaching solution modified with "Muhamedzhan-1" in the oxidized form back for ore leaching on the step (C2). [0015] The essence of the effect produced by "Muhamedzhan-1" consists in oxidation of insoluble U.sup.4+ contained in ore into soluble U.sup.6+ and subsequent dissolution of U.sup.6+ in acid environment in case of H.sub.2SO.sub.4 based leaching solution, or in alkali environment in case of NH.sub.4OH based leaching solution. Uranium (IV) salts interacting with the catalyst solution get oxidized according to the following overall reaction (1): U.sup.4++KT.sub.Ox=U.sup.6++KT.sub.Red (1) Used catalyst KT.sub.Red regeneration process by air oxygen is described by the following reaction (2): KT.sub.Red+O.sub.2=KT.sub.Ox (2) wherein KT.sub.Ox and KT.sub.Red are correspondingly oxidized and reduced forms of the catalyst's active complex. [0016] Uranium oxidation goes according to a complex multi-stage mechanism. Temperature of catalytic oxidation process is 25-30.degree. C., as most of the technological processes are conducted in this temperature range. In order to regenerate the used up catalyst, pressurized air is fed into a regenerator under a pressure of 2-4 atm. [0017] The inventive catalyst was successfully tested at three uranium deposits with real uranium containing solutions.

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PREFERRED EMBODIMENTS OF THE INVENTION [0018] While the invention may be susceptible to embodiment in different forms, there are be described in detail herein below, a specific exemplary embodiment of the present invention, with the understanding that the present disclosure is to be considered an exemplification of the principles of the invention, and is not intended to limit the invention to that as described herein. Example 1 [0019] In the period from 3.sup.rd to 9.sup.th of Dec., 2010 we have conducted laboratory tests of "Muhamedzhan-1" for oxidation of U.sup.4+ to U.sup.6+ on three samples at a physical-chemical laboratory of the "Uvanas" uranium deposit. Tests were conducted on production and leaching solutions from well #62 of Block 199 and well #125 of Block 201. Results of these tests are shown in Table 1 below. TABLE-US-00004 TABLE 1 Oxidation of U.sup.4+ to U.sup.6+ by " Muhamedzhan-1" in leaching solution samples from 7.sup.th of December 2010 Redox potential, # Catalyst, ml pH mV Block 201 - Well #125 1. 0 2.16 441 2. 1 1.53 452 3. 2 1.44 458 4. 3 1.34 464 5. 4 1.29 472 6. 5 1.28 476 7. 10 1.07 492 Block 199 - Well #62 1. 0 2.04 459 2. 1 1.80 471 3. 2 1.66 479 4. 3 1.54 485 5. 4 1.47 490 6. 5 1.38 495 7. 10 1.15 511 Leaching Solution 1. 0 1.90 441 2. 1 1.71 462 3. 2 1.60 476 4. 3 1.49 486 5. 4 1.43 496 6. 5 1.34 506 7. 10 1.14 1038 Redox potential, # Catalyst + KMnO.sub.4, ml pH mV Production Solution 1. 0 1.88 435 2. 1 1.98 996 3. 2 2.00 1008 4. 3 2.02 1015 5. 4 2.03 1018 6. 5 2.04 1025 7. 10 2.05 1042 Leaching Solution 1. 0 1.90 441 2. 1 1.95 990 3. 2 1.96 1028 4. 3 1.97 1039 5. 4 1.98 1046 6. 5 1.99 1050 7. 10 2.01 1059. [0020] As it is visible from test results shown in Table 1, in water solutions "Muhamedzhan-1" increases redox potential from 0.440 to 0.511V and decreases pH from 2.16 to 1.07, which allows decreasing the consumption of sulfuric acid. Example 2 [0021] In the period from 6.sup.th to 9.sup.th of Dec., 2010 laboratory tests of "Muhamedzhan-1" for oxidation of U.sup.4+ to U.sup.6+ were conducted on a leaching solution from sand pond at the physical-chemical laboratory of the


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"Ak Dala" uranium deposit. [0022] Results of the catalytic oxidation of U.sup.4+ to U.sup.6+ in the leaching solution using "Muhamedzhan-1" are presented in Table 2. TABLE-US-00005 TABLE 2 Oxidation of U.sup.4+ to U.sup.6+ using "Muhamedzhan-1" Redox Redox Catalyst, potential, Catalyst, potential, # ml pH mV # ml pH mV 1 0 2.06 393 1 0 2.06 387 2 1 1.96 402 2 1 1.93 416 3 2 1.95 419 3 2 1.91 420 4 3 1.93 424 4 3 1.90 429 5 4 1.90 434 5 4 1.80 439 6 5 1.89 440 6 5 1.76 447 7 6 1.78 450 7 6 1.68 452 8 7 1.60 488 8 7 1.47 480. [0023] As it is visible from test results shown in Table 2 utilization of "Muhamedzhan-1" increases redox potential from 387 to 480 mV and decreases pH from 2.06 to 1.47, which allows increasing the uranium yield of the leaching solution and decreasing the consumption of sulfuric acid. Example 3 [0024] We have conducted industrial pilot tests of "Muhamedzhan-1" on increasing the redox potential for sandstone and clay cores with an additional increase in uranium content in catalyst treated sulfuric acid solution at the "Appak" uranium deposit. [0025] Tables 3 and 4 compare results of sandstone and clay cores treatment with sulfuric acid and a solution of "Muhamedzhan-1". As it is shown in Table 3, treatment of sandstone core (4-4-4 B) with 25 g/l sulfuric acid yielded 147.8 g/l of uranium content in the resulting solution, whereas after treatment of core with 10 ml of "Muhamedzhan-1", resulting solution yielded 184.1 g/l of uranium content. Treatment of clay core with 25 g/l sulfuric acid yielded 62.8 g/l of uranium content in the solution, whereas treatment with the catalyst yielded 84.9 g/l of uranium content (see Table 4). [0026] Advantages of the inventive method follow: [0027] 1. Full (100%) substitution of hydrogen peroxide as oxidizing agent with the air. [0028] 2. Decrease of sulfuric acid consumption by 20%. [0029] 3. Decrease of leaching solution pH by 0.5-0.6 units. [0030] 4. Increase of redox potential by 100-150 mV due to air use. TABLE-US-00006 TABLE 3 Results of catalytic oxidation of U(IV) to

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U(VI) at "Appak" uranium deposit (sandstone core) Sampling Core: Sandstone -- 4-4-4 B time, Solution H.sub.2SO.sub.4, Catalyst, Catalyst, H.sub.2SO.sub.4, Catalyst, Catalyst, hours Parameters 25 g/l 5 ml 10 ml 12 g/l 1 ml 2 ml 1 U, mg/l 118.6 124.6 129.3 118.6 125.6 139.3 pH 0.93 0.96 0.91 0.93 0.95 0.92 Redox, mV 0.500 0.414 0.400 0.500 0.534 0.610 4 U, mg/l 126.5 147.3 149.4 139 149.4 154.6 pH 1.95 0.92 0.88 1.16 1.17 1.17 Redox, mV 0.446 0.504 0.695 0.450 0.546 0.635 16 U, mg/l 147.8 164.0 184.1 156.7 169.4 178.3 pH 0.93 0.89 0.86 1.14 1.17 1.15 Redox, mV 0.437 0.596 0.649 0.493 0.546 0.642. TABLE-US-00007 TABLE 4 Results of catalytic oxidation of U(IV) to U(VI) at "Appak" uranium deposit (claystone core) Sampling Core: Claystone -- 1-2-3 H time, Solution H.sub.2SO.sub.4, Catalyst, Catalyst, H.sub.2SO.sub.4, Catalyst, Catalyst, hours Parameters 25 g/l 5 ml 10 ml 12 g/l 1 ml 2 ml 1 U, mg/l 48.3 53.1 50.5 48.1 63.1 65.5 pH 0.91 0.92 0.90 0.91 0.92 0.90 Redox, mV 0.479 0.512 0.600 0.470 0.513 0.592 4 U, mg/l 55.7 65.2 62.8 55.2 74.7 77.2 pH 0.81 0.84 0.86 1.14 1.17 1.18 Redox, mV 0.455 0.502 0.691 0.454 0.446 0.445 16 U, mg/l 62.8 69.4 84.9 63.3 78.1 83.3 pH 0.94 0.88 0.87 1.1 1.15 1.18 Redox, mV 0.438 0.593 0.689 0.442 0.524 0.626. [0031] Thus, the results of tests of "Muhamedzhan-1" presented above indicate that the use of the proposed catalyst of "Muhamedzhan-1" allows oxidizing U.sup.4+ to U.sup.6+ in weak acid solutions. [0032] The low cost and availability of standard equipment for production of "Muhamedzhan-1" make this technology attractable for catalytic oxidation of U.sup.4+ to U.sup.6+. USED LITERATURE [0033] L. I. Lunev, Mine systems of uranium deposits development by in-situ leaching, Moscow, 1982, pp. 8, 13, 17.


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A New Approach Modification Atherton-Todd, Betti, Mannich and Doebner Reactions with of Arsine, Stibine and Bismuthine in Organometallic Chemistry Aibassov Erkin Zhakenovich, Baiguzhin Adil Alibekovich, Tusupbaev Nesipbay, Imanbaev Klysh, Serikbaeva Gulbarshyn Kuanyshkanovna LTD "Chemical Solution", Almaty, Kazakhstan, Zhamakaeva Str.

Abstract We first discovered A new approach modification reactions Atherton-Todd, Betti, Mannich and Doebner with of arsine, stibine and bismuthine in organometallic chemistry. For the first time, a mechanism possible new reactions. Keywords Atherton-Todd, Betti, Mannich and Doebner reaction, Organic compounds of arsine, Stibine and bismuthine 1. Introduction Arsine, stibine, and bismuthine used in organometallic chemistry for the formation of connections C-As, C-Sb-, C-Bi and synthesis of metal catalysts and important medicinal products. With diverse reactivities, they react with different classes of organic compounds with transition to a four-coordinate state, and substitution patterns on the - connection and radical initiation. In recent years, particularly actively investigated nucleophilic reaction hydrides phosphorus, arsenic, antimony and bismuth organilgalogenidami [1, 2], and also with electrophilic arylalkenyl [3, 4] are used as catalysts, and biologically active substances. Organometallic Chemistry, As, Sb, Bi little work because of their high toxicity. Kazakhstan has accumulated a huge amount of toxic waste polymetallic As, Sb, Bi. Actual therefore to find new ways of processing these wastes to

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valuable products such as pharmaceuticals and catalysts. The aim is to search for new reactions of organic compounds on the basis of As, Sb, Bi. Scientific novelty of the work lies in the fact that for the first time made a scientific forecast of new reactions based on classical reactions. The objects selected classic reaction Atherton-Todd, Betti, Mannich and Doebner and as basic reagents organic compounds As, Sb, Bi. The practical value is that the results suggest new reactions are synthesized novel organic compounds As, Sb, Bi, may be used as catalysts, pharmaceuticals. We have studied the possibility of opening a new reactions by reacting AsH3, SbH3, BiH3 and their alkyl derivatives with various organic compounds. 2. Theory An experimental study of the conditions of new reactions must precede their theoretical study that would predict the discovery of these reactions. This prediction is a serious problem. The most important in predicting new reactions is the question of the nature of the relationship and changing the chemical properties of complex molecules, as in the presence of a particular functional relationship between those and other elements can roughly assess the possibility of a new course of the reaction. In this regard, the present report offers an unconventional approach for qualitative and quantitative assessment of the differences of reactivity of these elements (AsH3, SbH3, BiH3) and forecast the probability of occurrence of new reactions. Known reaction of Atherton-Todd, which is the reaction of substituted amines with dialkoksifosfonatom and carbon tetrachloride, is one of the most effective ways to get (RO) 2P (O)-NRR ', currently used for the production of pharmaceutical and biologically active compounds [1-4]. RR’NH + (RO)2P(O)H + CCl4 → (RO)2P(O)-NRR’ + CHCl3 (1) Atherton-Todd reaction is one of the most convenient methods for the synthesis of amides and unbalanced acid esters of pentavalent phosphorus. We have studied the possibility of extending the scope of this reaction by the inclusion of arsine and stibine bismuthine and substituted derivatives thereof.


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Know the reaction Betty (Betti) - Aminobenzilirovanie condensation of phenols with primary aromatic amines (EH3) and benzaldehyde [5-8]: R-С6H4-OH + C6H6CHO + ArNH2 → R-C6H3(OH)-CH(C6H5)-NHAr (2) Known Mannich reaction. Aminomethylation compounds with labile hydrogen atom action of formaldehyde and ammonia or amines [9-15]: =C – H + CH2=O + HNRR’ → [=C- + +CH2- NRR’] → =C – CH2- NRR’ (3) Similarly formaldehyde react other aliphatic and aromatic aldehydes, and aliphatic, aromatic and heterocyclic aldehydes, β-ketoesters, malonic acid derivatives, nitro compounds, and aromatic heterocyclic compounds with labile hydrogen atom ring (pyrrole, quinaldine, α-picoline, etc.) and the acetylene derivative: (CH3)2CO + CH2=O + (C2H5)2NH → CH3COCH2CH2N(CH3)2 (4) RC=CH + CH2=O + (C2H5)2NH → RC=C-CH2N(CH3)2 (5) As the amine component, ammonia, aliphatic and cyclic amines, hydrazine, hydroxylamine. In the case of alcohols, amines or thiols, respectively, are O-, N-or S-Amination: C2H5OH + CH2=O + (C2H5)2NH → C2H5O – CH2 – N(C2H5)2 (6) C6H5SO2NHCH3 + CH2=O + (C2H5)2NH → C6H5SO2N(CH3) – CH2 – N(C2H5)2 (7) (CH3)2CH2SH + CH2=O + (C2H5)2NH → (CH3)2CHS– CH2 – N(C2H5)2 (8) The Mannich reaction is widely used in organic synthesis, particularly in the synthesis of natural products and pharmaceutical preparations. Know the reaction Doebner. Preparation quinolinecarboxylic acid condensation of aromatic amines with aldehydes and pyruvic acid [16-18]: R-C6H4-NH2 + R’-CHO + CH3-C(=O)-COOH → [R-C6H4-NH-CH(R’)-CH2-CO-COOH] → R-C9H4N(R’)COOH + R-C6H4-NC4H(=O)2R’ (9) In response Debnera also come getroaromaticheskie and condensed polycyclic amines. As the aldehyde component may be both aromatic and aliphatic aldehydes. In case the main reaction product ArCHO are quinolines,

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when AlkCHO - pirrolinindiony. Conducting the reaction using pyruvic acid analogues (S6H5CH2COCOOH, S6H5COCH2COCOOH, p-O2NC6H5CH2COCOOH) also promotes the formation of pyrrolidines. Since β-naphthylamine, in all cases formed only benzoquinoline. Although low yields quinolines Debnera reaction is widely used due to the ease and availability of methods starting compounds. 3. Results and Discussion We have studied the possibility of extending the scope of this reaction by the inclusion of arsine and stibine bismuthine and substituted derivatives thereof. Comparison reactions Atherton-Todd, Betti, Mannich Doebner and showed that they are all substitution reactions of amines with a variety of organic compounds which have a labile hydrogen atom. We have proposed a general view of the proposed new reactions Atherton-Todd, Betti, Mannich and Doebner the replacement of amines on the arsine, stibine and bismuthine. For reaction Atherton-Todd: RR’EH + (RO)2P(O)H + CCl4 → (RO)2P(O)-ERR’ + CHCl3 (10) Where E = N, P, As, Sb, Bi. For reaction Betti: R-С6H4-OH + C6H6CHO + ArEH2 → R-C6H3(OH)-CH(C6H5)-EHAr (11) Where E = N, P, As, Sb, Bi. For reaction Mannich we offer new reactions. Arsinoe-,-Stibine, vismutinometilirovanie compounds with labile hydrogen atom action of formaldehyde and arsine, stibine and Vismutin: =C – H + CH2=O + HERR’ → [=C- + +CH2- ERR’] → =C – CH2- ERR’ (12) Where E = N, P, As, Sb, Bi. For reaction Doebner: R-C6H4-EH2 + R’-CHO + CH3-C(=O)-COOH → [R-C6H4-EH-CH(R’)-CH2-CO-COOH] → R-C9H4E(R’)COOH + R-C6H4-EC4H(=O)2R’ Where E = N, P, As, Sb, Bi.

(13)


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Thus, the theoretical concept of the website allows you to scientifically proven to predict new reactions in organometallic chemistry. Set out the principle of prediction of new reactions involving arsine, stibine and bismuthine opens new reactions with other elements in the periodic system. 4. Conclusions These data in this work indicate that arsine, stibine, and bismuthine their alkyl-substituted derivatives as simple available arsenic, antimony and bismuth are convenient materials for forming a bond C - E (E = As, Sb, Bi) in the preparation of a variety of organometallic and functional arsine Stibine, Vismutin, which are increasingly being used as catalysts and pharmaceuticals. As a result of theoretical studies, we made the following conclusions. As a result of the proposed new reactions, a new element - carbon bond E - C, where E = As, Sb, Bi. For example, when heated EH3 (E = As, Sb, Bi) with ROH in presence Na2PtCl6 formed E (OR) 3. Possible new reaction can be widely used in cases where there is a need for compounds with a bond -CH = E, e.g., for many of As, Sb, Bi- organic insecticides, medicines and other biologically active compounds containing As, Sb, Bi. Thus, we first notice that the AsH3, SbH3, BiH3 and their derivatives by passing the mixture through a modified furan halides zeolite - clinoptilolite gives arsol, and stibol. It is hoped that the material presented will further expand the research in the chemistry of arsenic, antimony, bismuth, and, above all, on the development of new reactions based on their synthesis of various organometallic compounds. ACKNOWLEDGMENTS The authors would like to thank Ruben M. Savizky (Columbia University, New York) and Chistopher L. Cahill (George Washington University) for discussion of the results. REFERENCES [1]

Kosolapov G.M., Maier L. Organic Phosphorous Compounds. Vol. 1. Wiley-Interscience, New York, 1972.

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[2]

Homogeneous Catalysis with Metal Phosphine Complexes. (Ed. Pignolett E.). Pergamon Press, Oxford, 1983.

[3]

Trofimov B.A., Brandsma L., Gusarova N.K. Main Group Chem. News, 1996, v. 4, p. 18.

[4]

Harnisch H. Angew. Chem., 1976, v. 88, p. 517.

[5]

Atherton F.R., Openshaw H.T., Todd A.R. J. Chem. Soc., 1945, p. 382, 660.

[6]

Atherton F.R., Howard H.F., Todd A.R. J. Chem. Soc., 1948, p. 1106.

[7]

Nifantiev E.E. Zhurnal obshei chemii, 1971, v. 41, No. 9, p. 2011; 1974, v. 44, No. 1, p. 108.

[8]

Purdela D., Vulchanu R. Chemistry of organic compounds of phosphorus, Per. with rum., Ed. Kabachnik MI, M., "Chemistry", p. 381, 453.

[9]

Betti M., Gazz. Chim. Ital., 1900, v. 30, pt. II, p. 301; 1906, v. 36, pt. II, p. 392.

[10] Phillips J.P. e. a. J. Org. Chem., 1954, v. 19, p. 907; 1956, v. 21, p. 692. [11] Moerle H., Miller Ch., Wendisch D., Chem. Ber., 1974, Bd. 107, N 8, S. 2675-2682. [12] Elderfield, vol. 4, p. 103. [13] Mannich C., Krosche W. Arch. Pharm., 1912, Bd. 250, S. 647. [14] Phillips J.P., Chem Rev., 1956, v. 56, p. 286. [15] Krohnke F. Angew. Chem., 1963, Bd. 75, S. 187. [16] Moehrle H, Spiilmann P., Tetrahedron, 1969, v. 25, p. 5595. [17] Yakhontov L.N. and others J. Org. Chem., 1974, v. 10, No. 4, p. 868-873. [18] Hellmann H., Opitz G. α-Aminoalkylierung. Weinheim/Bergstr., “Chemie”, 1960, 336 S. [19] Organic Reactions, Ed. R. Adams, New York, 1942, v. 1, p. 399. [20] Doebner O., Ann., 1887, Bd. 242, S. 265; Ber., 1894, Bd. 27, S. 352, 2020. [21] Gallo N., Gazz. chim., ital., 1954, v. 84, p. 573. [22] Heterocyclic compounds. Ed. R. Elderfield, v. 4, p. 20; v. 6, p. 162, 168.


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A New Modification Michaelis-Arbuzov, Allen Milobendzky-Shulgin, Michaelis-Becker and Raymond Reactions with Organic Compounds Arsenic, Antimony and Bismuth Aibassov Erkin Zhakenovich, Kenzhaliev Bagdaulet Kenzhalievich, Berkinbaeva Ainura, Chukmanova Marzhan, Iskhakova Renata Kazakh-British Technical University, 59, Tole-bi street, Almaty, Kazakhstan

Abstract We discovered the possibility of modifying the new Michaelis-Arbuzov, Allen, Milobendzky-Shulgin, Michaelis-Becker, Raymond reactions with organic compounds of arsenic, antimony and bismuth. We have proposed a new mechanism for possible reactions. Keywords Michaelis-Arbuzov, Allen, Milobendzky-Shulgin, MichaelisBecker, Raymond reactions, Organic compounds of arsenic, Antimony, Bismuth 1. Introduction In recent years as effective catalysts and reagents in organic synthesis is increasingly used organometallic compounds of arsenic, antimony and bismuth provides enhanced selectivity, high speed and mild process conditions. Expanding the range of organometallic compounds of As, Sb and Bi, used for this purpose, of course, is an important task. In this regard, one of the fundamental problems of chemistry is the synthesis of stable organic compounds, arsenic, antimony, bismuth, and the study of their capabilities in this aspect. As-, Sb-, Bi- organic compounds are not only practical interest. The large size of the bismuth atom and features of its electronic structure produces a greater possibility of its coordination sphere. The purpose was to search for new methods of synthesis of As-, Sb-, Bi- organic compounds based on the Michaelis-Arbuzov, Allen, Milobendzky-Shulgin, Michaelis-Becker,

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Raymond reactions. 2. Theory Known reaction Michaelis-Arbuzov rearrangement trialkyl phosphonates in the reaction with alkyl halides: (R’O)3P + RX → [(R’O)P+R]X- → (R’O)2P(=O)R (90%) (1) Where X = Cl, Br, J. Reacting a halogenated variety: primary alkyl halides, CCl4, α- halo ethers, esters, halides. The easiest way to react AlkX and Ar3CX. Reactivity of RX decreases in the J Br Cl, as well as with increasing chain length of R. By a similar rearrangement is also capable of other compounds containing the group = POR', e.g., R'P (OR') 2 and R'2POR ', and also with a group of thioderivatives = PSR', except for P (SR') 3. reacting P (OR') 3 with αhaloketones flows abnormally (See Perkova reaction). The rearrangement is general in nature and can be defined as the transformation of phosphorous acid esters in the pentavalent phosphorus derivatives that occur under the influence of electrophilic reagents and accompanied by the formation of a new connection P - E (E = C, N, O, S, Si, etc.), for example: P(OC2H5)3 + BrSi(C2H5)3 → (C2H5)3Si – P(O)(OC2H5)2 (2) Reactions are widely used for the preparation of insecticides, medicinal substances, and other physiologically active organophosphorus compounds. Allen is known for reaction to form phosphorylated oxime reacting phosphorous acid esters with α-galogennitro-or α-galogennitroso-compounds: RXPR’2 + R’’R’’’C(Hal)-NO2 → R’2P(=X)O-N=CR’R’’ + RXP(=O)R’2 (3) Where R - ; X = O,S, Se, Te; R’ – Alk, Ar, OAlk, NAlk2, NHAlk, F, Cl, Br, J; R’’ – H, Alk, F, Cl, Br, J; R’’’ – Alk, COOAlk, F, Cl, Br, J; Hal – Cl, Br, J. The reaction is carried out in an organic solvent or without at temperatures of - 40 to 50°C. Nitroso compounds usually have a higher reactivity than nitro. Reaction rate increases with increasing the mobility of atoms and Hal atom with increasing nucleophilicity P; yield 10-80%. Byproducts - fosforilsoedineniya ROP (O) R'2 (in reactions with nitro derivatives ), compounds resulting from Arbuzov rearrangement [RHal by


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reacting the starting compounds with P (III)], as well as high molecular compound ( with involvement of the reaction of cyclic esters). It is believed that the initial reaction act - P attack atom per atom Hal to give intermediates I or II, which when cleaved RHal converted to the final product. [=P-O-N=C=]+Hal- (I) =P(Hal)-O-N=C= (II) Similarly, the reaction proceeds trialkyl, and dialkilgalogen alkildigalogenfosfitov with α-galogennitrozoalkanami: C2H5OPRR’’ + R’’R’’’CClNO → C2H5O-P(=O)(R)-ON=CR’’R’’’ (4) Where R, R’ = OC2H5; Cl; R’’ = CF3, CF2NO2,; R’’’ = CF3, F, Cl. The advantage of the nitroso compounds is the lack of a side reaction of oxidation. The resulting phosphorylated oximes are nitrogenous analogues enolfosfatov - Perkova reaction products. Allen's reaction was used in the laboratory. It is opened by J. Allen in 1957. Known reaction Milobendzki - Szulgin conversion in trialkyl O, O-diarilmetilfosfonaty when heated to 215 and a pressure operating with methanol: P(OAr)3 + CH3OH → [CH3O – P(OAr)2 → CH3-PO(OAr)2 + ArOH (5) Where Ar = C6H5, C6H4CH3. Similarly react trialkylphosphites: P(OC2H5)3 + CH3OH → CH3-PO(OC2H5)2 (60%)

(6)

When using ethanol yield decreases phosphonates: P(OC2H5)3 + C2H5OH → C2H5-PO(OC2H5)2 (15%)

(7)

In the case of higher alcohols, the main reaction is a transesterification: P(OC6H5)3 + n-C4H9OH → P(OC4H9)3 + C6H5OH (8) Know the reaction Michaelis - Becker for the synthesis of organophosphorus compounds by alkylation or arylation of compounds hydrophosphoryl neutral salts (phosphites, phosphonites and phosphinites of alkali metals) by reacting an alkyl or aryl halides or other alkylating or arylating agents: YZP-OM + RHal → YZP(=O)R + MHal (9) Where M = Li, Na, K; R = Alk, Ar; Y, Z = Alk, Ar, AlkO, ArO, Alk2N, AlkS.

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Reactivity AlkHal decreases from secondary to secondary to tertiary, and further, and with increasing molecular weight alkyl radical. Michaelis-Becker reaction used to prepare many organophosphorus pesticides, medicines, and other extractants. Reaction opened A. Michaelis and T. Becker in 1897. Know the reaction of alkyl halides Rydon getting action on alcohol алкилтрифеноксифосфонийгалогенидов: ROH + [(C6H5O)3P+R’]X- → RX (60-90%) (10) Where R = Alk; R’ = Alk; X = Cl, Br, J. Reacting a well alicyclic, allene and acetylenic alcohols, glycols, steroid alcohols. The reaction can be carried out without prior conversion into phosphonium triphenyl phosphite compound: ROH + (C6H5O)3P + R’X → RX + R’PO(OC6H5)2 + C6H5OH (11) ROH + (C6H5O)3P + X2 → RX + XPO(OC6H5)2 + C6H5OH (12) ROH + (C6H5O)3P + HX → RX + HPO(OC6H5)2 + C6H5OH (13) Unsaturated alcohols very smoothly converted to the bromide by the action of (C6H5O)3P + Br Br-in pyridine. Method Forsman - Lipkin - converting alcohols to iodides difenilhlorfosfitom reaction with a pyridine or-fenilenhlorfosfitom followed by treatment with iodine: ROH + (C6H5O)2PCl → (C6H5O)2POR + J2 → RX (60-80%) (14) 3. Results and Discussion We have studied the possibility of extending the scope of this reaction by incorporating atoms of arsenic, antimony, bismuth, and substituted derivatives. Comparison Michaelis-Arbuzov, Allen Milobendzky-Shulgin, Michaelis-Becker and Raymond reactions with organic compounds arsenic, antimony and bismuth showed that they all substitution reactions of amines with a variety of organic compounds which have a labile hydrogen atom. We have proposed a general view of the proposed new reaction Michaelis-Arbuzov, Allen Milobendzky-Shulgin, Michaelis-Becker and Raymond reactions of amines on the replacement of an atom of arsenic,


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antimony and bismuth. We propose a general Michaelis-Arbuzov rearrangement of trialkyl-(-arsine, stibine-, bismuth) itov in phosphine (arsine-,-stibine, bismuth) aty by reaction with alkyl halides: (R’O)3E + RX → [(R’O)E+R]X- → (R’O)2E(=O)R (90%) (15) Where E = P, As, Sb, Bi; X = Cl, Br, J. We propose to expand the Allen reaktsiiyu obtain phosphorus (arsenic, antimony, bismuth) pegylated oxime acid esters by reaction of trivalent phosphorus, arsenic, antimony and bismuth galogennitro-α-or α-galogennitroso compounds: RXER’2 + R’’R’’’C(Hal)-NO2 → R’2E(=X)O-N=CR’R’’ + RXE(=O)R’2 (16) Where E = P, As, Sb, Bi; X = O,S, Se, Te; R’ = Alk, Ar, OAlk, NAlk2, NHAlk, F, Cl, Br, J; R’’ = H, Alk, F, Cl, Br, J; R’’’ = Alk, COOAlk, F, Cl, Br, J; Hal – Cl, Br, J. We propose expanding region Milobendzki - Szulgin reaction conversion trialkyl (arsine, stibolyl, bismuth) to itov O, O-diarilmetilfosf (arsine, stibolyl, bismuth) onat when heated to 215 oC and the operating pressure with methanol: E(OAr)3 + CH3OH → [CH3O – E(OAr)2 → CH3-EO(OAr)2 + ArOH (17) Where E = P, As, Sb, Bi; Ar = C6H5, C6H4CH3. We propose to expand and modify the Michaelis-Becker reaction - synthesis of phosphorus (arsenic, antimony, bismuth) organic compounds, alkylation or arylation gidrofosfor neutral salts (arsine, stibine, bismuthine) yl compounds (phosphites, phosphonites and phosphinites of alkali metals), by reacting alkyl-or aryl halides or other alkylating or arylating agents: YZE-OM + RHal → YZE(=O)R + MHal (18) Where E = P, As, Sb, Bi; M = Li, Na, K; R = Alk, Ar; Y, Z = Alk, Ar, AlkO, ArO, Alk2N, AlkS. We propose to expand and modify the reaction of alkyl halides Rydon for action on alcohol alkiltrifenoksifosfony (arsonium, stibonium, vismutony) halides: ROH + [(C6H5O)3E+R’]X- → RX + R'EO(OC6H5)2 + C6H5OH (19) Where E = As, Sb, Bi; R = Alk; R’ = Alk; X = Cl, Br, J.

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Thus, the theoretical concept allows research to predict new reactions in organometallic chemistry. 4. Conclusions We discovered the possibility of modifying the new Michaelis-Arbuzov, Allen, Milobendzky-Shulgin, Michaelis-Becker, Raymond reactions with organic compounds of arsenic, antimony and bismuth. We have proposed a new mechanism for possible reactions. New proposed Michaelis-Arbuzov, Allen, Milobendzky-Shulgin, Michaelis-Becker, Raymond reactions are will used для синтеза новых катализаторов, bioactive substances, drugs. We hope that this material will further expand the research in the chemistry of arsenic, antimony, bismuth, and the development of new reactions based on their synthesis of various organometallic compounds. REFERENCES [1]

Michaelis A., Kaehne R. Ber., 1898, Bd. 31, S. 1048.

[2]

Arbuzov A.E. Journal Russuan Chem. Soc., 1906, v. 38, p. 687.

[3]

Burt D.W., Simpson P. J. Chem. Soc., 1969, Ser. C., p. 2273.

[4]

Rafikov S.R., Chelnokova G.N., Dzhilkibaeva G.M. Proceedings of the Institute of Chemistry. Kazakh SSR Academy of Sciences, v. 23, p. 80.

[5]

Arbuzov B.A. Z. Chem., 1974, Bd. 14, S. 41-49.

[6]

Kirby A., Warren C. The organic chemistry of phosphorus. Trans. from English. Ed. A.N. Pudovikov. Wiley, New York, 1971, p. 44.

[7]

Purdela D., Valchanov R. Chemistry of organic compounds of phosphorus. Trans. from Rum. Ed. M.I. Kabachnik. Moscow, Chemistry, 1972, p. 382.

[8]

Organic Reactions, v. 1-14. Trans. from English. Ed. K.A. Kocheshkov and I.F. Lutsenko. Moscow, Izdatinlit, 1948, vol 6, p. 276.

[9]

Reactions and methods of organic reactions. T 1-22. Ed. Rodionov V.M., Kazansky B.A., Knuniants I.L., Moscow, Chemistry, 1955, Vol 3, p. 7.

[10] Allen J.F. J. Am. Chem. Soc., 1957, v.79, N 12, p. 3071-3073. [11] Martynov I.V., Kruglyak Y.L., Perevezentseva N.F. Zh. Obsh. Chem. USSR,


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1967, v. 37, p. 1125, p. 1130, p. 1132. [12] Malekin S.I., Yakutin V.I., Sokolsky M.A. Zh. Obsh. Chem. USSR, 1972, v. 42, p. 807. [13] Purdela D., Valchanov R. Chemistry of organic compounds of phosphorus. Trans. From Rum. Ed. M.I. Kabachnik, Moscow, Chemistry, 1972, p. 390. [14] Milobendzki T., Szulgin K. Chem. Polski, 1917, v. 15, p. 66; C. A., 1919, v. 13, p. 2867. [15] Cason J., Baxter W. N. J. Org. Chem., 1958, v. 23, p. 1302. [16] Purdela D., Valchanov R. Chemistry of organic compounds of phosphorus. Trans. From Rum. Ed. M.I. Kabachnik, Moscow, Chemistry, 1972, p. 387. [17] Michaelis A., Becker T. Ber., 1897, Bd. 30, S. 1, 1003. [18] Shreybert A.I., Wise L., Wise FW, 1969, v. 39, p. 1416. [19] Vilceanu R., Neamtiu J. Rev. Chim. (Bucharest), 1973, v. 24, N 3, p. 153. [20] Landauer S.R., Rydon H.N. J. Chem. Soc., 1953, p. 2224. [21] Forsman J.P., Lipkin D. J. Am. Chem. Soc., 1953, v. 75, p. 3145.

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Derivation of the Equation Nernst-Aibassov in a Magnetic Field Aibassov Yerkin, Yemelyanova Valentina, Tussupbayev Nessipbay, Shakieva Tatyana, Yerzhanova Zhadyra Research Institute of New Chemical Technologies and Materials, Kazakh National University Al-Farabi, Almaty, Kazakhstan

Abstract We offered the new formula Nernst equation in a magnetic field. Our proposed formula takes into account the influence of the magnetic field on the redox processes. Keywords Nernst equation, Magnetic field, Redox processes 1. Introduction At present, the rapid development of science and technology and equipment allows us to look at the classical equations with new perspectives. The actual problem is the question of how to lead the Nernst equation in the presence of a strong magnetic field. Addressing these issues is scientific and practical value. The purpose of the work to consider how to behave in the Nernst equation under the action of a magnetic field. 2. Theory Nernst equation - an equation that relates the redox potential of the system with active substances included in the electrochemical equation, and standard electrode potentials of redox couples under the influence of a magnetic field. Conclusion Nernst equation Nernst studied the behavior of electrolytes by passing an electric current and discovered the law. The law establishes the relationship between the electromotive force (potential difference) and ion concentration. Nernst equation to predict the maximum operating potential, which may be prepared


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by the electrochemical interaction where the pressure and temperature are known. Thus, this law relates to the thermodynamics of electrochemical theory in solving problems related to very dilute solutions. E = E0 + RT/nF ln aOx/aRed, (1) where: E – electrode potential; E0 - standard electrode potential, V; R — universal gas constant equal, 8.31 J/(mol•K); T - absolute temperature, K; F Faraday constant, 96,485.35•mol-1; n - the number of electrons involved in the process; aOx and aRed - activity respectively oxidized and reduced forms of the substances involved in the half reaction. If the Nernst formula to substitute the numerical values of the constants R and F, and go from natural logarithms to decimal, when T = 298 K we obtain: E = E0 + 0,0592/n lg aOx/aRed (2) 3. Results and Discussion To display the Nernst equation in a magnetic field is necessary to consider the Lorentz force. Lorentz force - the force with which the electromagnetic field according to the classical (non-quantum) electrodynamics operates on a point charge. Lorentz force called the force acting on moving with velocity ν charge q only by the electromagnetic field of the electric E and magnetic B fields. F = q(E + [ν xB]) (3) The direction of the Lorentz force and the direction of its deviation caused by a charged particle in a magnetic field depends on the sign of the charge Q of the particle. We assume that the magnetic field is uniform and the particle electric fields do not work. If a charged particle moving in a magnetic field with velocity v along the lines of magnetic induction, the angle a between the vectors a v and В is 0 or p. Then the formula (3) the Lorentz force is equal to zero, i.e. the magnetic field on the particle does not work and it is moving uniformly and rectilinearly. If a charged particle moving in a magnetic field with the velocity v, perpendicular to the vector B, the Lorentz force F = Q [vB] is constant in magnitude and normal to the trajectory of the particle. According to second Newton's law, this force creates a centripetal acceleration. Hence it follows that

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the particle will move in a circle, the radius r is determined from the condition QvB = mv2/r where r = m/Q v/B. (4) The period of rotation of the particle, i.e. the time T for which it makes one complete revolution, T = 2πr/ν. Substituting the expression (3), we obtain T = 2π/B m/Q

(5)

t. e. the period of rotation of a particle in a uniform magnetic field is determined only by the reciprocal of the specific charge (Q/m) particles and the magnetic induction field, but does not depend on its velocity (when v 0, but not as a result of expended efforts, but as a result of circumstances beyond the control of the subject. Suppose that beforehand the forces necessary to achieve the result were estimated by the magnitude of OV3, and the available resource was equal to AV3, where OY3 = AV3> 0, i.e. what happened was first estimated as impossible. Then there will be an emotion of joy of magnitude E = F (Vg, Oy3 - Dyz). In the particular case for a fixed second argument, the force of emotion will depend only on Vg. 4. Conclusions Thus, we studied the influence of various factors on the equation of happiness. We have shown that the equation of happiness in chemical form is written down: Hyper Happines =2π k[Serotonine][DOPA][Glycine][I], (8) where k is информация.

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Taking into account the influence of hyperinformation, the equation of happiness has the form: Hyper Happiness = 2π[P+5*E+3*H"]t + I, (9) where H is happiness, P is personal traits (гибкость, способность к адаптации, жизненная позиция), E is existence needs характеризует "потребности низшего порядка" (здоровье, деньги, наличие друзей), Н is higher order needs (чувство юмора или самоуважение), t – время, I is information. REFERENCES [1]

Simonov P.V. Motivated brain. Moskau: Science, 1987.

[2]

Sushko E.I. The formula of love: theory and methodology of application. Minsk, 2007.


413

Conclusions We believe that without the development of pico- and femto-technologies it is impossible to understand the chemistry of the brain, thinking, consciousness and behavior. Chemistry of the brain is the most complex and interesting science that studies the chemical and cellular mechanisms of the nervous system. In this review compiled theoretical and practical material on brain chemistry, hyper thinking, consciousness and behavior. Earlier the authors were discovered four new Aibassov - Dorfman, Aibassov-Yuriev, Aibassov-Ugi, Aibassov-Savizky reactions, and a new approach to finding the modification 26 reactions: Atherton-Todd, Betti, Mannich, Doebner, Michaelis-Arbuzov, Allen Milobendzky-Shulgin, Michaelis-Becker, Raymond, Petasis, Passerini, Hantzsch, Kabachnic-Fields, Ugi and etc. The authors proposed four new Klopman-Dorfman-Aibassov, Nernst-Aibassov, Goldman–Hodgkin–Katz-Aibassov, and Sonnon-Aibassov equations for solving the magnetic and relativistic effects in catalysis and chemistry of Brain. The authors proposed a new magnetic isotope theory of the origin of life on Earth, theory of vision "of white and blue of the tunnel" in people who have clinical died. The authors proposed a new approach to the theory Chemistry of Brain, Hyper-Information, Hyper Thinking, Hyper-Consciousness, and Behavior. We assume that hyper-thinking transforms industry, agriculture, transport and communications. More details with these works can be found in the literature [1-25]. REFERENCES [1]

Aibassov Yerkin, Aibassova S.M., Aralov A.A., Zamzin N. Methodology of qualitative and quantitative analysis of poisonous agents and means of their detoxification, Almaty, 2009, 172 p.

[2]

Aibassov Yerkin, Aibassova S.M., Aralov A.A. Environmental ecology: Environmental safety in the areas of impact of separating parts of rocket

414


launchers and soil detoxification using “Muhamedzhan-1” catalyst, Almaty, 2010, 210 p. [3]

Aibassov Yerkin, Aibassova S.M., Aralov A.A. Treatment of uranium industry liquid radioactive wastes using modified Chankanai field zeolite, Almaty, 2010, 240 p.

[4]

Aibassov Yerkin, Aibassova S.M. Treatment of soil, waste water, and gases from toxic phosphorus using “Muhamedzhan-1” catalyst at the Novodzhambul Phosphorus Plant, Almaty, 2010, 242 p.

[5]

Aibassov Yerkin, Aibassova S.M. Applied ecology: treatment of soil, waste water, and gases from toxic contaminants using “Muhamedzhan-1” catalyst, Almaty, 2010, 248 p.

[6]

Aibassov Yerkin, Aibassova S.M. Organic chemistry and catalyses of uranium. Thorium and uranium catalysts. Almaty, 2010, 240 p.

[7]

Aibassov Yerkin, Aibassova S.M. New reaction involving the oxidative O-, C-phosphorylation of organic compounds by phosphine in presence of complexes Pt(IV) and Pt(II), oxidation of U(IV) to U(VI) used of catalyst “Muhamedzhan-1”, “Gitel Publishing House, Inc.”, New York, 2011, 62 p.

[8]

Aibassov Yerkin, Aibassova S.M. New reaction of Arsine. Introduction to Organic Chemistry of Arsenic, Actinides, Lanthanides, Os187 and Re. “Gitel Publishing House, Inc.”, New York, 2011, 100 p.

[9]

Aibassov Yerkin, Aibassova S.M. How to open a new chemical reaction, Almaty, 2011, 264 p.

[10] Aibassov Yerkin, Aibassova S.M. Oxidation of U(IV) and U(VI) in solutions using “Muhamedzhan-1” catalyst, Almaty, 2011, 250 p. [11] Aibassov Yerkin, Baiguzhin A., etc. The chemical thermodynamics of inorganic compounds of uranium, “Infiniline” Publishing House, Inc.”, Almaty, 2013, 210 p. [12] Aibassov Yerkin, Baiguzhin A., etc. The Mechanisms named reactions in modern organic chemistry, “Infiniline” Publishing House, Inc.”, Almaty, 2013, 410 p. [13] Aibassov Yerkin, Baiguzhin A., etc. The search for new reactions in organometallic chemistry of uranium, arsenic, antimony and bismuth, “Infiniline”


415

Publishing House, Inc.”, Almaty, 2013, 230 p. [14] Aibassov Yerkin, Bulenbayev M., etc. The new reactions in organometallic chemistry of arsenic, antimony and bismuth and uranium catalysts, “Infiniline” Publishing House, Inc.”, Almaty, 2014, 230 p. [15] Aibassov Yerkin, Yemelianova V., etc. Magnetic and relativistic effects in catalysis and uranium catalysts, “Infiniline” Publishing House, Inc.”, Almaty, 2014, 184 p. [16] Aibassov Yerkin, Yemelianova V., etc. Spin Chemistry and Magnetic of Uranium-Thorium Catalysts, “Scientific & Academic Publishing”, USA, 2015, 232 p. [17] Aibassov Yerkin, Yemelianova V., etc. Spin Catalytic Reactions in the presence of Nitric Oxide and the New Reactions of Arsenic, Antimony and Bismuth, “Scientific & Academic Publishing”, USA, 2015, 346 p. [18] Aibassov Yerkin, Yemelianova V., etc. The Neutron Magnetic Isotope Catalysis and Fermi Surface, “Scientific & Academic Publishing”, USA, 2015, 164 p. [19] Aibassov Yerkin, Yemelianova V., etc. The Complexes of Uranium of with DNA, “Scientific & Academic Publishing”, USA, 2015, 166 p. [20] Aibassov Yerkin, Savizky R., Yemelianova V. Magnetic effects in Brain Chemistry, “Scientific & Academic Publishing”, USA, 2015, 246 p. [21] Aibassov Yerkin, How to open a new chemical reaction or equation? “Infiniline” Publishing House, Inc.”, Almaty, 2016, 210 p. [22] Aibassov Yerkin, Yemelianova V., Introduction to Brain Chemistry, “Infiniline” Publishing House, Inc.”, Almaty, 2016, 212 p. [23] Aibassov Yerkin, Yemelianova V., etc. Organic chemistry and thermodynamics of actinides (U, Th, Pu, Np, Am), “Infiniline” Publishing House, Inc.”, Almaty, 2016, 220 p. [24] Aibassov Yerkin, Yemelianova V., etc. The search for new multicomponents catalytic reactions, “Scientific & Academic Publishing”, USA, 2016, 258 p. [25] Aibassov Yerkin, Yemelianova V., etc. “Chemistry of Brain, Hyper Thinking, Consciousness and Behavior”, “Scientific & Academic Publishing”, USA, 2017, 240 p.


417

Figure 1. Satpayev University 2009. Professor Alya Baikonurova, Ph.D Maxat Bulenbayev, Ph.D Galina Usolcyeva

Figure 2. University of Notre Dame 2013. Department of Civil & Environmental Engineering & Earth Sciences. Ph.D Maxat Bulenbayev, Ph.D Adelani Pius and Ph.D Bagdat Altaibayev

418


Figure 3. University of Notre Dame 2014. Department of Civil & Environmental Engineering & Earth Sciences, Ph.D Maxat Bulenbayev

Figure 4. Nobel Prize Laureate in Chemistry 2016 Sir James Fraser Stoddart and Bakhytzhan Alzhanuly


419

Figure 5. Cleaning soil from heptyl by catalyst “Mukhamedzhan-1» on Baikonur cosmodrom

Figure 6. Pilot Uranium plant “Uvanas”, Suzak raion, Kazakhstan

420


Figure 7. Department of Inorganic Chemistry of Oxford University, United Kingdom

Figure 8. Laboratory of Professor Ruben Savitsky, Cooper Union

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