Molecular mechanisms of nicotine dependence - IOS Press

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Journal of Pediatric Biochemistry 1 (2010) 75–89 DOI 10.3233/JPB-2010-0015 IOS Press

Molecular mechanisms of nicotine dependence Marcelo O. Ortellsa,∗ and Hugo R. Ariasb a

Facultad de Medicina, Universidad de Morón – Consejo Nacional de Investigaciones Cient´ıficas y Técnicas (CONICET), Morón, Argentina b Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, Glendale, AZ, USA

Received 4 May 2010 Accepted 4 May 2010

Abstract. Nicotine is the main psychoactive substance present in tobacco, targeting neuronal nicotinic acetylcholine receptors (AChRs). The main effects of nicotine associated with smoking are AChR activation, desensitization, and upregulation, with the subsequent modulation of the mesocorticolimbic dopaminergic system. However, there is a lack of a comprehensive explanation of their roles that effectively makes clear how nicotine dependence might be established on those grounds. Receptor upregulation is an unusual effect for a drug of abuse, because theoretically this implies less need for drug consumption. Receptor upregulation and receptor desensitization are commonly viewed as opposite, homeostatic mechanisms. We here review the available information on smoking addiction, and drugs employed as aids in smoking cessation, especially under a recently presented model of nicotine dependence. In this model both receptor upregulation and receptor desensitization are responsible for establishing a biochemical mechanism of nicotine dependence, which have an important role in starting and maintaining tobacco addiction. Basically, a conclusion of this model is that those drugs used for smoking cessation should inhibit preferentially α4β2-containing AChRs and to have a low or null ability to upregulate AChRs, as this characteristic allows the smoker to achieve downregulation without abstinence symptoms. Keywords: Nicotinic receptors, nicotine addiction, neurotransmitter release, AChR upregulation, AChR desensitization

1. Introduction According to the World Health Organization, tobacco addiction is a global health problem affecting onethird of the population. Around half of the smoking population dies from a smoking associated disease. The evidence points to the alkaloid nicotine as the principal psychoactive substance present in tobacco [1]. Nicotine is so powerful that adolescent smokers already present the first symptoms of nicotine dependence such as withdrawal, craving, and relapse, within the first weeks of smoking [2]. More∗ Correspondence:

Marcelo O. Ortells, Facultad de Medicina, Universidad de Morón, Machado 914, 4◦ piso, 1708 Morón, Argentina. Tel.: +54 11 4502 9460; Fax: +54 11 4502 9460; E-mail: mortells @retina.ar.

over, tobacco smoke also contains minor quantities of harman, norharman, anabasine, anatabine, and nornicotine. Some of these compounds significantly decrease the activity of monoamine oxidases, enzymes that are involved in the catabolism of bioamines including, dopamine (DA), norepinephrine, and serotonin (5HT) [3]. Since DA is the main neurotransmitter of the “brain reward circuitry”, these compounds might have additional consequences in the process of tobacco addiction. A full and clear understanding of the mechanisms by which nicotine promotes tobacco addiction is lacking. Nicotine is an agonist of nicotinic acetylcholine receptors (AChRs), which are important neuronal modulatory proteins that also mediate muscle activation in vertebrates and present pleiotropic functions in nonneuronal tissues [4]. They are pentameric ion chan-

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M.O. Ortells and H.R. Arias / Nicotine addiction and nicotinic receptors

nels belonging to the Cys-loop ion channel superfamily including type A and C GABA, type 3 or 5-HT, and glycine receptors [5]. With 17 different subunits (α1-α10, β1-β4, γ or ε, and δ), the AChR variability is potentially large supporting the evidence of different physiological functions throughout the body [6]. Several processes have been related to tobacco addiction. Albeit initially nicotine can activate AChRs, it can subsequently produce AChR desensitization and AChR upregulation. The combination of these pharmacological and biological effects finally modulates the dopaminergic, glutamatergic, and GABAergic systems that form part of the “brain reward circuitry”.

2. AChR activation (-)-Nicotine is the predominant isomer present in tobacco smoke, producing the majority of its pharmacological effects. It is an unspecific agonist at several AChRs including those expressed in the autonomic ganglia, adrenal medulla, neuromuscular junction, brain, and non-neuronal tissues. The stimulation of these AChRs produce some of the side effects elicited by nicotine including, high blood pressure, tachycardia, and indirectly cancer [4]. There are two prominent AChR subtypes in the brain that can be discriminated by its sensitivity to nicotine: AChRs that are efficiently activated by nicotine including the α4β2 subtype, and those AChRs that are not efficiently activated by nicotine including the α7 subtype. Nicotine is a weak base and it readily cross cell membranes and the blood – brain barrier at physiological pH. Considering that each cigarette may deliver 1–2 mg of nicotine, plasma levels of 10–50 ng/mL are obtained after multiple cigarettes during the day, which are decreased during sleep. After inhalation, nicotine takes ∼10 s to reach the brain, and peak concentrations of ∼0.3 µM can be attained after ∼5 min [7]. This concentration is sufficient to activate AChRs and in the mesocorticolimbic pathway this activation produces an increase in DA release (see more details below).

nous ligands including Lynx1 [7,8]. The accumulation of nicotine during a smoking day is enough to produce AChR desensitization. Thus, AChRs can exist in vivo in at least three basic physiologic states: resting activated and desensitized. In the resting state, the receptor channel is closed; the two agonist binding sites are empty and present low affinity for ligands. Upon ligand binding at high agonist concentrations, the channel transiently opens. This activated state is followed by a desensitized or inactive conformation where the binding sites are occupied with high affinity. This closed conformation is structurally different from that in the resting state [9,10]. Although this basic scheme is true for different AChR subtypes, there are still differences among them. For example, at > 0.5 µM nicotine, α7 AChRs desensitize faster (millisecond timescale) than α4β2 AChRs (second timescale) [7]. In addition, the α4β2 AChR is desensitized more quickly when contains a higher number of β2 subunits [8]. After agonist removal, the receptor goes back to the resting state and is ready for a new activation cycle. This recovery process depends on the AChR subtype and agonist used [8] as well as on intracellular (e.g., phosphorylation) and extracellular (e.g., catabolism of ACh by acetylcholinesterase) mechanisms. For example, the time constant for the slow recovery component of nicotine in the rat α4β2 AChR is 40 s, whereas the time constant for ACh is 17 s, indicating that the overall recovery from desensitization by ACh proceeds much more rapidly than that by nicotine [11]. In addition to the classical desensitization process, low agonist concentrations can induce desensitization even without AChR activation, a process named “highaffinity desensitization” [8]. This is a slow process that in the prolonged presence of low concentrations of nicotine affects preferentially α4β2 receptors compared to α7 AChRs [12]. For instance, at nicotine concentrations present in chronic smokers’ brain (∼20–80 nM), α4β2 AChRs are desensitized and upregulated, but not α7 receptors. Although our understanding of the desensitization process has been improved in the last years, we do not have a clear distinction of the desensitizing effects of nicotine between pre- and postsynaptic AChRs.

3. AChR desensitization After an initial activation, the AChR, in the prolonged presence of agonists including nicotine, becomes desensitized [8]. Although desensitization is an intrinsic property of the receptor, it can also be modulated by external signals like phosphorylation and endoge-

4. AChR upregulation The classical idea is that AChR upregulation results from an increase in receptor number after a chronic exposure to agonists [13,14]. This view was challenged


by the interpretation that the number of receptors remains unchanged, but the functional condition is altered to a “high-affinity state”, easier to activate and with a larger single-channel conductance [15]. More recently, the classical idea was reinforced by considering that nicotine acts as a molecular chaperone stabilizing assembly intermediates and increasing the half-life of AChRs, with the consequent AChRs upregulation [16, 17]. Concomitantly, the “high-affinity state” hypothesis was reinterpreted as an increase in the proportion of the (α4)2 (β2)3 vs. the (α4)2 (β2)2 stoichiometry. Interestingly, it was also proposed that desensitization triggers the process of AChR upregulation [18]. Upregulation by nicotine is not the same for different AChR subtypes. There is clear cut evidence indicating that nicotine preferably upregulates α4β2 AChRs. For example, mice lacking the β2 subunit do not show upregulation of nicotine binding sites [19]. Interestingly, nicotine-induced α4β2 AChR upregulation has been referred as a central mechanism somehow related to nicotine addiction [20]. α4β2 AChRs are the most abundant AChRs in the brain and are directly involved in tobacco addiction. They have high affinity for nicotine [21] and high-affinity nicotine binding sites in most brain regions are formed from α4β2 AChRs [22,23].

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tization (a mechanism for nicotine tolerance) have no direct relationship with a mechanism of nicotine dependence; rather they make emphasis on their independent roles as putative corrective mechanisms. Moreover, only one can represent a problem that the brain must compensate as these phenomena go in opposite directions. If nicotine-induced AChR activation is a problem and needs to be balanced by desensitization, then upregulation, going in the opposite direction, should not be needed. However, if desensitization is the main disruptive process, then upregulation does make sense as a way to compensate the lost signaling capability. However, none of these scenarios fully explains how nicotine dependence is initiated in the first place. An intrinsic problem is that nicotine triggers both desensitization and upregulation, and this is the reason these mechanisms have been involved in nicotine dependence. This dual role of nicotine, activation and desensitization of AChRs, was recently described in the context of tobacco addiction [7], showing that a coordinated activation and desensitization of different nAChRs on different neuronal subtypes occurs in response to nicotine administration during smoking.

6. AChR-induced modulation of the dopaminergic and glutamatergic systems 5. Physiological roles of desensitization and upregulation in tobacco addiction Because nicotine promotes both, upregulation and desensitization are thought to be central to nicotine addiction. Desensitization is an intrinsic feature of the molecular structure of AChRs [8] and nicotine is highly effective in promoting it, especially on the α4β2 receptor. Upregulation on the other hand, has only been observed after external administration of agonists, especially nicotine. Upregulation by nicotine is at first view paradoxical [24], because the number of receptors is increased in a sort of positive feedback, contrary to what is normally expected (i.e., tolerance) for a drug of abuse. One possible explanation is that this increment is a homeostatic response to desensitization [20, 25]. This idea is supported by the evidence that AChR upregulation is only produced after AChR desensitization [18,26]. In contrast, others have proposed that desensitization might represent a cellular basis of nicotine tolerance [27], especially in the presence of upregulation. These two potential explanations for upregulation (homeostatic response to desensitization) and desensi-

The combined activation and desensitizing properties of nicotine finally modulate DA release in the mesocorticolimbic system, and thus, the rewarding properties of nicotine. Since AChRs are more desensitized at higher nicotine plasma concentrations, this dual activation/desensitization mechanism will be different between light and heavy smokers. In agreement with this cyclic mechanism, positron emission tomography (PET) results indicate that β2-containing AChRs are ∼88% occupied after a single cigarette at concentrations producing ∼50% α4β2 AChR desensitization [10]. The modulation of DA release by AChRs has been well documented and it is very important for the development of tobacco addiction [1,27,28]. The mesocorticolimbic dopaminergic system, the so called “brain reward circuitry”, is central to reinforcing behaviors, reward and the development of drug abuse and dependence. This system comprises cell bodies from the ventral tegmental area (VTA) and their projections to the nucleus accumbens (NAc). Drugs of abuse increase DA levels in the NAc, producing their behavioral effects [29]. Nicotine concentrations that are obtained by

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smokers [27] are sufficient to stimulate AChRs in DA neurons in the VTA, with the concomitant increase of DA release in the NAc. The most important AChRs expressed in the mesocorticolimbic pathway are α4α5β2 (with and without the α6 subunit) and α7 AChRs in the VTA as well as α4β2, α4α5β2, and α6β2β3 (with and without the α4 subunit) in the NAc [30]. However, we do not know whether these different assemblies are present in the same terminal or not. Systemic nicotine also increases the activity of DA neurons in the VTA via N-methyl-D-aspartate (NMDA)-type glutamate receptors located on the cell bodies from DA neurons [31]. This increase is mediated by α7 AChRs present on the glutamatergic terminals, facilitating glutamate release [32,33]. The corticolimbic system is also regulated by a second reward pathway, the habenulo-interpeduncular pathway, and vice versa. Details of these connections are in Arias’ minireview in this special issue.

7. AChR-induced modulation of the GABAergic system In addition to the modulation of the dopaminergic and glutamatergic systems by nicotine-induced AChR activation and/or desensitization, nicotine activates transiently non-α7 AChRs at the preterminal, somatic and dendritic regions of GABAergic neurons increasing inhibitory GABAergic inputs to DA neurons in the VTA. However, this initial effect fades away after nicotine-induced AChR desensitization. In other words, nicotine can first inhibit DA release and then enhance (disinhibit) DA release by modulating GABAergic neurons. More importantly, the relative balance between the stimulation of dopaminergic neurons and the inhibition of GABAergic neurons by non-α7 AChRs will produce the final DA-mediated output. Although we do not know with certainty which nonα7 AChRs are the most important in this process, β2[most probably (α4)2 (β2)3 ; (30,7)] and α6-containing AChRs [34] are expressed in these GABA neurons. VTA GABA neurons also express α7 AChRs but in less proportion than in glutamatergic neurons [30]. α4β2 AChRs expressed in GABAergic neurons desensitize faster than those more complex AChR assemblies expressed in DA neurons, finally decreasing the inhibitory influence of GABA. This effect in addition to the α7 AChR activation on glutamatergic neurons switches the DA neurons from phasic to burst firing, with the final increase of DA release in the NAc. This increased

DA release is substantially larger than regular spiking and has been associated with anticipatory phases of nicotine reward. The role of β2-containing AChRs in this neuronal switching mechanism is supported by the decreased effect in mutant mice which is restored after the re-expression of this subunit in the animal [35]. Moreover, the α7 AChR also plays a role by fine tuning the response of these DA neurons.

8. Nicotine dependence and tobacco addiction As with other drug addictions, a difference between the mechanisms underlying tobacco addiction and nicotine dependence exists [36]. The former has a broader connotation, including complex behavioral components. The latter could be restricted to a specific biochemical alteration triggered by nicotine, an alteration that would promote the physical need for more nicotine to compensate the disarrangement. Clearly, a behavioral component in tobacco addiction is essential. Subjects need to relate the experienced pleasure with its origin (i.e., nicotine self-administration devices, tobacco cigarettes, puffs). In other words, smokers are addicted to cigarettes not to nicotine, but only because cigarettes and the various associated behaviors result in nicotine administration. 8.1. Desensitization and upregulation as the basis for nicotine dependence The initial and intrinsic biochemical basis of tobacco addiction should be found in the abnormal mechanisms that nicotine promotes on AChRs (i.e., but not promoted by the normal neurotransmitter ACh). These mechanisms, according to a recent model of smoking addiction and nicotine dependence [37], are not surprisingly AChR upregulation and desensitization. The proposed biochemical mechanism gives a molecular basis to the habit-forming properties of nicotine, in the same way the inhibition of DA reuptake by cocaine explains a part of its dependence properties [38]. In this model desensitization and upregulation are compatible molecular processes that effectively cause nicotine dependence. That is, they are not considered just opposing homeostatic processes. As a starting point, this model assumes from a logical point of view, that what is essential for nicotine dependence is nicotine based AChR inactivation, not AChR activation (which of course does occur simultaneously). Why this conclusion is achieved is explained below.


8.2. Can be nicotine activation of nAChRs the basis of nicotine dependence? Under this assumption nicotine exacerbates AChR activation, and by increasing DA release in the mesocorticolimbic dopaminergic system, it promotes all the rewarding mechanisms associated with addiction. There are well described neuronal circuits in which AChR activation enhances DA release. However, nicotine also triggers desensitization which cancels what in principle we assumed promotes addiction. Stopping the reasoning here, then it would be logical that smokers need more nicotine to receive again the same rewarding stimuli, albeit they would only need to wait until the receptors go from the desensitized to the resting state. Although desensitization recovery depends on the AChR subtype, in human receptors it is produced in the minute time regime [39]. However, nicotine also promotes upregulation, and the level and kinetics of upregulation depend on the AChR subtype [40]. Considering all these variables, we can still generalize by stating that in a time span of several days the brain would develop an exacerbated capacity of AChR response (positive feedback) when the receptors are not desensitized. If so, an immediate need for more nicotine would be lacking, as the normal concentration of the natural agonist ACh would be sufficient to elicit a response similar to the first nicotine stimulus. Moreover, without an immediate need for more nicotine, no reinforcing behavioral mechanisms are developed. Under this circumstances only when upregulation is reversed, nicotine consumption might be eventually wanted, but not needed in a dependence way. That is, the assumption that AChR activation by nicotine is the nucleus of the addiction process is logically inadequate. 8.3. Nicotine inactivation of AChRs is the basis of nicotine dependence In a second scenario, the assumption is that AChR inactivation, by nicotine desensitization, initiates the dependence mechanism and eventually addiction. In this case AChR inactivation enhances DA release. A typical example would be the desensitization of AChRs present on inhibitory GABAergic neurons. Independently of the mechanisms triggered by AChR desensitization to enhance DA release, the logical consequence is that the upregulation that follows desensitization completes the mechanism of nicotine dependence. Effectively, upregulation makes more difficult to achieve rewarding because it strengthens the mechanisms that should

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be inactivated for that purpose. Consequently, upregulation promotes the need of higher or faster nicotine consumption. Therefore, in this hypothesis nicotine provokes both the rewarding stimulus (via desensitization) and the need for more nicotine consumption (via upregulation). 8.4. Nicotine activation of rewarding: Disrupting a negative feedback mediated by α4β2 AChRs A central conclusion of the model [37] is that in order to conciliate desensitization and upregulation as the bases of nicotine dependence, nicotine has to be able to elicit its rewarding properties by inactivation of AChRs. The model explicitly proposes that what desensitization inactivates is an inhibition mechanism of rewarding stimulus mediated by α4β2 AChRs. This circuit of nicotine dependence is schematically shown in Fig. 1. Starting with a normal or physiological number of AChRs, endogenous ACh normally stimulates all AChR subtypes and activates or inhibits rewarding stimulus depending on the neuronal circuit. Regarding this, the model distinguishes three basic neuronal processes related to rewarding [37]. These are Long Term Rewarding Activation (LTRA), Short Term Rewarding Activation (STRA), and Long Term Rewarding Inhibition (LTRI). An essential assumption is that the increase in DA release correlates with rewarding activation, while inhibition of DA release means rewarding inhibition. According to the model [37] LTRA is associated with glutamatergic systems [31]. Because ACh or nicotine activates an indirect complex system of DA release, the removal of these agonists does not cause an immediate stop of rewarding activation. Figure 2 shows a diagrammatic representation of this and other neuronal systems described in this review. STRA (Fig. 2) is mediated by AChRs present on cell bodies and terminals of DA neurons in the VTA. These AChRs are of the α4β2, (α4)2 α5(β2)2 , α4α6α5(β2)2 and α7 subtypes [30,41], and when activated by ACh or nicotine promote the liberation of DA. Dopamine release stops as soon as ACh or nicotine is removed or AChRs are desensitized. LTRI is central to the model of nicotine dependence [37]. An example of LTRI is the important GABAergic system involved in the regulation of DA release in the VTA. This system inhibits DA neurons (Fig. 2), and is activated by α4β2 receptors [30,42]. The activation of these systems by endogenous ACh is the normal physiological way. However, if these sys-

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Fig. 1. Schematic representation of the mechanisms by which nicotine dependence is established. The model distinguishes three neuronal processes related to rewarding: LTRA, Long-Term Rewarding Activation; STRA, Short-Term Rewarding Activation; LTRI, Long-Term Rewarding Inhibition. LTRA is associated with glutamatergic (GL) neuronal circuits, where nicotine increases the activity of dopaminergic (DA) neurons in the VTA, via facilitation through presynaptic (Pr) α7 AChRs on glutamatergic neurons. The target NMDA glutamate receptors are present on the cell bodies of DA neurons. This rewarding path is long-lasting because it is indirectly activated and the removal of the agonist has no immediate consequences, and α7 receptors are not desensitized by nicotine. STRA is mediated by somatic (So) AChRs localized on DA neurons cell bodies in the VTA. The AChR subtypes involved are less or not sensitive to nicotine desensitization and when activated enhance the release of DA. Dopamine release stops as soon as the agonist is removed. The essential feature of LTRI is that is mediated by the α4β2 AChR subtype, with high propensity to desensitization by nicotine. A basal number of all types of resting AChRs are stimulated by endogenous ACh in a normal physiological path (left), and depending on the neuronal circuit and subunits involved, activates or inhibits rewarding stimulus. After an acute administration of nicotine, the normal functioning of the nicotinic cholinergic circuit is disrupted (right). Transitorily, nicotine has the same effects of the endogenous ACh. However, nicotine is not cleaved as ACh and consequently (solid arrows represent causal relationships) it remains for a longer period at low concentration (chronic state). Nicotine, at this low concentration, has different consequences in the three neuronal processes. As α7 is not desensitized by nicotine, the effect on LTRA is a prolonged activation. Because STRA is not based on the α4β2 subtype, it is either continuously activated, or partially inhibited (dashed lines). LTRI, based on α4β2, is fully (solid line) inhibited by desensitization. The overall result is an exacerbation of the rewarding system by the three neuronal processes. However, desensitization of α4β2 in LTRI promotes their upregulation. Therefore, in the subsequent population of resting AChRs, the α4β2 subtype increases its number enhancing the inhibitory circuit. What follows depends on the smoker behavior. The easiest way to recover a normal rewarding level is to administer more nicotine (bottom right). However, this is a transient solution, as it also reinforces the disrupted path through a new cycle of α4β2 desensitization-upregulation, increasing rewarding inhibition. The alternative choice is to wait unpleasantly until α4β2 receptors down regulate to normal levels (bottom left).


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Fig. 2. Schematic representation of neuronal systems involved in nicotine addiction. This diagram shows how dopamine release (rewarding) is modulated by neuronal circuits involved in nicotine addiction. Actual receptor neuronal localization and their modulatory relationships are represented (positive and negative feedbacks). Neuronal circuits described in subsequent Figures are indicated. LTRA: Long Term Rewarding Activation; STRA: Short Term Rewarding Activation; LTRI: Long Term Rewarding Inhibition; ACh: cholinergic neuron; DA: dopaminergic neuron; GABA: gabaergic neuron; Glu: glutamatergic neuron. For other references see the inset.

tems receive an acute exposure to nicotine (“disrupted path”), the same results are obtained but transitorily (Fig. 1). As nicotine is not degraded as ACh, it remains for longer periods at low concentrations. After the normal recovery of AChRs, the chronic exposure to the residual low nicotine concentration desensitizes preferentially α4β2 AChRs [12], the proposed subtype involved in rewarding inhibition. This provides a long lasting rewarding stimulus not present in the normal path, because nicotine is abolishing the action of a LTRI path. Because low nicotine concentrations preferentially desensitize α4β2 AChRs compared to other receptors, LTRA and STRA can remain active. The rewarding effects end when the inhibited α4β2 AChRs are upregulated and exit the desensitized state after nicotine removal [16]. The result of having exposed the cholinergic pathways to nicotine is that the smoker ends with an exacerbated (upregulated) rewarding inhibition system, even under normal conditions when nicotine is not longer present. The smoker faces two alternatives at this stage. The harder choice is to suffer the consequences of the abstinence symptoms until AChRs are downregulated, interrupting the addiction process and eventually quitting smoking. The easy choice is to consume more nicotine, which rapidly disrupts by de-

sensitization the exacerbated rewarding inhibitory system. This option has the malicious consequence of a further and long lasting α4β2 upregulation, favoring addiction and the subsequent pernicious effects of smoking. In short, under this new concept of nicotine dependence [37], desensitization and upregulation are not viewed as regulatory mechanisms, but as abnormal consequences of nicotine exposure and necessary participants in starting and in the development of smoking addiction.

9. Neuronal circuits compatible with the desensitization-upregulation hypothesis There are several neuronal circuits matching the desensitization-upregulation hypothesis. Nicotine can disrupt these neuronal circuits simultaneously and therefore nicotine dependence can be initiated and reinforced in different brain regions. 9.1. Cholinergic-GABAergic-DA system The inhibitory GABAergic neuronal circuit shown in Figs 2 and 3 is an important example compatible with

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Fig. 3. Schematic representation of the mechanisms by which nicotine dependence is established by inhibition of a GABAergic neuronal circuit. The well documented inhibitory mechanism based on the GABAergic (GA) hyperpolarization of DA neurons is represented as an example of the general LTRI of Fig. 1. Although nicotine transiently enhances the inhibitory GABAergic transmission on DA neurons via α4β2 activation (for abbreviations see Fig. 1), a long-term rewarding stimulus follows through α4β2 desensitization. However, the initial transient inhibition become stronger (hyperpolarization is enhanced) with each cycle of upregulation.

the desensitization-upregulation hypothesis [37]. In this circuit, the inhibitory mechanism is the hyperpolarization of DA neurons by GABAA receptors. Although nicotine transiently enhances the inhibitory GABAergic transmission on DA neurons via α4β2 AChR activation (thus reducing the liberation of DA), a longer rewarding stimulus follows via α4β2 AChR desensitization [42]. This desensitization promotes an enhanced release of DA in the NAc. In spite that AChRs on DA neurons can be also transiently activated (STRA) but subsequently inhibited, the long-lasting effects of canceling LTRI prevail. First, many of the AChRs in DA neurons that compose a STRA circuit are of the α7,

α4α6α5(β2)2 and (α4)2 α5(β2)2 types [30,41]. This means a null or a reduced desensitization promoted by nicotine because the β2 subunit is either not present or present in less proportion in these receptors. This view is supported by the experimental evidence showing that AChRs on GABAergic neurons are upregulated, but not those on dopaminergic neurons [43]. Second, the majority of the cholinergic neurons in the VTA project to GABAergic neurons [44]. Thus, the eventual inactivation of AChRs on DA neurons is probably physiologically less relevant. During the period of α4β2 AChR desensitization, α7 mediated LTRA circuits remain capable of nicotine and


endogenous ACh activation [42]. However, with time, upregulation of α4β2 AChRs reinforces the inhibitory pathway. Thus, as a consequence of upregulation, a sustained and probably increased exposure to nicotine is needed not just to enhance but to maintain DA release within the normal levels. The easier decision for a smoker to alleviate the unpleasant symptoms of nicotine withdrawal is to smoke again, but subsequent exposures to nicotine reinforce this mechanism. In other words, a biochemical mechanism for the initial phase of tobacco addiction is established. 9.2. Cholinergic-Glutamatergic-DA system A second neuronal circuit compatible with the desensitization-upregulation hypothesis is the glutamatergic path involved in LTRA (see Figs 2 and 4). Activation of α7 AChRs by nicotine promotes dopaminergic activity via facilitation of glutamatergic pathways, but this fact alone does not explain nicotine dependence. Their upregulation (if any), which would eventually reinforce DA release, does not explain a need for more nicotine as described for the GABAergic system. While activation by acute doses is important transiently, the key point to develop addiction in the hypothesis [37] is the assumption that the main effect of nicotine in nicotine dependence is inactivation of AChRs via desensitization. In this case the inhibitory mechanism which would be inactivated by nicotine is a negative feedback on ACh release (LTRI). This mechanism which hinders the release of DA, is proposed to be situated in cholinergic fibers that activate α7 AChRs on glutamatergic neurons [37] (see Fig. 2). It is known that presynaptic α4β2 (ionotropic) receptors normally have a positive feedback role on ACh release while muscarinic (metabotropic) receptors are involved in a negative feedback [45]. In the nervous system, there are several registered cases of positive feedback on ACh release [46–49]. Interestingly, the muscarinic negative feedback seems to be activated only after an overflow of ACh release and to be mediated by activation of presynaptic α4β2 AChRs [47]. The effects of the muscarinic type last for longer periods, considering it is a metabotropic receptor. If α4β2 AChRs are desensitized by nicotine, then the negative muscarinic feedback cannot start because it depends on the prior activation of the α4β2 nicotinic type. However, the activation of α7 AChRs is still enhanced. The main result of the positive feedback mediated by α4β2 AChRs is an overflow of ACh. Consequently, the lack of this overflow suppresses both, the negative feedback and

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a massive and simultaneous activation of postsynaptic α7 AChRs. However, without a negative feedback, the activation of the cholinergic fibers is still capable of producing a longer and continuous (tonic) activation of postsynaptic α7 AChRs, which are not desensitized at low nicotine concentrations. Likewise the GABAergic neuronal circuit, rewarding activation remains whilst rewarding inhibition is abolished. In the GABAergic path, both endogenous ACh and acute nicotine exposure have the same effects (Fig. 3). Here, an acute exposure to nicotine does not per se enhance ACh release unless concomitant with the activation of the cholinergic fiber. Even if it does promote some ACh release by activating presynaptic α4β2 AChRs, it most probably does not activate the negative feedback mediated by muscarinic receptors without the presence of an action potential. The important fact in this neuronal circuit is that α7 AChRs, which promote DA release, are not desensitized and upregulated by nicotine. Figure 4 shows that both effects mediated by α4β2 AChRs are enhanced, the positive feedback on ACh release targeted to postsynaptic α7 AChRs, and the negative feedback on ACh targeted to muscarinic receptors. At first glance, it can be thought that these effects cancel each other and hence there is no influence of nicotine dependence. However, the effect of the enhanced positive feedback on ACh release is not directly proportional to the level of α4β2 AChRs upregulation as it is limited to the activation of a “fixed” number of α7 AChRs (represented by a dashed line in Fig. 4). On the contrary, the enhanced negative feedback on ACh is directly proportional to the levels of presynaptic α4β2 AChRs, which are upregulated, and of ACh release, which is highly increased. Thus, the higher the concentration of ACh the faster the onset time of the negative feedback. In this system, with a large population of upregulated α4β2 AChRs, the net effect of an action potential is a full but very short activation of postsynaptic α7 AChRs, and a very fast (and probably longer) activation of the muscarinic negative feedback of ACh release. As with the GABAergic system, the initial rewarding effect of nicotine ends with a long lasting reduction in the activation of the DA system. This reduction of DA release eventually ends when α4β2 AChRs are downregulated. However, as before, smokers might reduce this time to avoid abstinence symptoms by means of nicotine consumption, neutralizing the upregulated α4β2 AChRs via desensitization. This will in turn maintain in the long term a great proportion of α4β2 AChRs in the upregulated state perpetuating nicotine use.

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Fig. 4. Schematic representation of the mechanisms by which nicotine addiction is established by inhibition of a negative feedback that modulates a Glutamatergic neuronal circuit (Case I). The LTRI suppressed by nicotine in this instance is a negative feedback on ACh release based on α4β2 receptors. This ACh release is involved in the activation of postsynaptic α7 receptors situated on glutamatergic neurons, which in turn facilitates dopamine release. Presynaptic regulation of ACh release is usually positive by nicotinic (NC) α4β2 receptors, and negative by muscarinic (MC) receptors (for other abbreviations and further explanations see Fig. 1 and the text). Muscarinic inhibition of ACh release is triggered by both, an activation of α4β2 receptors and by an overflow of ACh (which in turn is also facilitated by the activation of α4β2 receptors). The arrows within the boxes show the dual effect of the presynaptic α4β2 receptors. On the one hand, they enhance ACh release and consequently they increase the simultaneous activation of α7 receptors on the glutamatergic postsynaptic side (indirect increase of dopamine release via facilitation of glutamatergic transmission). On the other hand, they allow a subsequent activation of the negative feedback mediated by the muscarinic receptors as a side effect of the increased ACh release (reduced activity of glutamatergic neurons, decrease of dopamine release). After an acute administration of nicotine, ACh release is highly enhanced if concomitant with an action potential, but also an early activation of the muscarinic inhibition is launched. Without an action potential, α4β2 receptors might induce the liberation of some ACh and activate α7 receptors on the glutamatergic neurons, without triggering muscarinic inhibition. As before, α7 are also directly activated by nicotine. Dashed lines indicate this conditional or reduced modulation. With chronic nicotine α4β2 receptors are desensitized, the positive feedback on ACh release and the overflow of this neurotransmitter are abolished, and consequently the negative feedback is not activated. The result of these events is a lower but continuous or prolonged activation of postsynaptic α7 receptors which facilitates glutamatergic and subsequently DA transmission. α4β2 upregulation promotes an enhanced modulation (bold arrows) that is asymmetrical in its consequences. Upregulated α4β2 receptors now trigger the muscarinic negative feedback faster; proportionally to their increased number and to the increased ACh overflow (see also the text). However, the enhanced activation of glutamatergic neurons is still limited by the number of postsynaptic α7, which are not upregulated.


In spite of the initial theoretical nature, there is experimental support for the proposed mixed nicotinicmuscarinic modulation of ACh release in a cholinergic system related to glutamatergic transmission. In the NAc, excitatory postsynaptic currents (EPSCs) mediated by AMPA/kainate (KA) and NMDA receptors are inhibited when ACh or carbachol are added to the superfusing medium [50]. In contrast, in the presence of the muscarinic antagonist atropine, these neurotransmitters increase by 35% the AMPA/KA and NMDA receptor-mediated EPSCs. These excitatory effects were blocked by the noncompetitive antagonist mecamylamine, which is more potent blocking α4β2 AChRs compared with α7 AChRs [51,52]. The possible involvement of muscarinic receptors in nicotine dependence can be even more complex. Metabotropic D2 autoreceptors and nicotinic α4β2 heteroreceptors can form heteromeric complexes [53]. At the interface of these aggregates, there is a direct or indirect involvement of the nicotinic β2 subunit. If this type of association is widespread, then muscarinic and nicotinic receptors might also form heteromeric complexes. Consequently, muscarinic receptors can be also modulated by conformational changes of AChRs in the complex and upregulated with AChRs. However, a direct evidence of this co-upregulation is still lacking. A third probable case is a variant of the previous case where the negative feedback mechanism on ACh release is directly mediated by the same presynaptic α4β2 AChRs [for more details see [37]].

10. Desensitization or blocking of α4β2 AChRs and smoking It is known that nicotine self-administration in nicotine sensitized rats is reduced by pretreatment with α4β2 but not with α7 AChR antagonists [54]. According to the desensitization-upregulation hypothesis, in those conditions blocking α4β2 AChRs reduce nicotine self-administration by emulating nicotine, not by blocking its effects. α4β2 AChR antagonists themselves cannot induce self-administration because they lack the dual property of activation/inactivation of nicotine. The same happens in nicotine sensitized rats, but in this case the α4β2 AChR antagonist helps in decreasing the number of upregulated and active α4β2 AChRs thus, reducing the number of nicotine infusions taken. It was proposed that smokers tend to enjoy the first cigarette of the day because AChRs would not be in

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a state of prolonged desensitization [27,55], where desensitization is considered a cellular mechanism of nicotine tolerance. An alternative explanation of the desensitization-upregulation hypothesis is that during nicotine abstinence at sleeping time and after upregulation, α4β2 AChRs go back to the resting state allowing the activation of the negative feedback on ACh release thus, reducing DA levels. Therefore, the enjoyment (rewarding effect) of the “first cigarette of the day” derives from nicotine inactivation of LTRI and transient activation of STRA. Non-smoking intervals during the day allow a subpopulation of α4β2 AChRs to return to the resting state. A persistent consumption of nicotine during the day is needed to keep most α4β2 AChRs desensitized and inactive.

11. Exposure to nicotine: Alterations in reward sensitivity and reward tolerance Nicotine can increase the sensitivity to rewarding brain stimulation by lowering brain reward threshold (BRT) [56–58], a feature common with other drugs of abuse. DA is involved in this process [59], and thus this enhanced reward sensitivity could be a consequence of nicotine based liberation of this neurotransmitter. There are experiments reporting this changes where nicotine is directly injected [57] or selfadministered [58]. With an acute dose of nicotine [57], it is plausible that the elevation of DA concentration is due to STRA, i.e. a direct activation of dopaminergic neurons by nicotine. With self-administered nicotine two different results were obtained, depending on the available time that the rats have for nicotine selfadministration, i.e. restricted (1 h) or extended (12 h). With 12 h exposure, the basal BRT remained unaltered during the experiment. With 1 h exposure, the preexposure BRT downward shifted daily. Because this effect was not observed immediately but it started on the ninth day of treatment, plausibly AChR desensitization plays a role. The lower exposure to nicotine in 1 h exposed rats might have favored a subsequent desensitization of α4β2 AChRs in LTRI systems. When nicotine is delivered chronically via subcutaneous osmotic mini-pumps [60], control and nicotine exposed rats do not differ in their BRT as with selfadministration. Additionally, nicotine withdrawal, by means of pump extraction or precipitated by dihydroβ-erythroidine (DHβE, an α4β2 specific antagonist), induces the elevation of BRT above pre-nicotine baseline. These differences were explained based on the

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higher nicotine concentration delivered by mini-pumps compared to the obtained by self-administration [58]. The same authors proposed that volitional nicotine intake may trigger adaptations in reward circuitries different from those generated by passively administered nicotine, involving LTP and the glutamatergic system [31,58]. The desensitization-upregulation hypothesis is congruent with their explanations. Under these chronic conditions (self-administered or passively injected) α4β2 AChRs are upregulated. When nicotine is present, a balance between a direct activation of AChRs present on DA neurons (elevation of DA baseline → reduction of BRT), and the activation of α4β2 AChRs on inhibitory GABA neurons (reduction of DA baseline → elevation of BRT) is possible. As AChRs on DA neurons are not fully desensitized by nicotine, they can be continuously activated. On the other hand, α4β2 AChRs on GABA neurons are desensitized and afterward upregulated, so this inhibitory system continues working with a mixed population of desensitized and active AChRs. When nicotine is removed, the balance is lost because the inhibitory system is exacerbated as all α4β2 AChRs on GABA neurons become active, with the consequence of a reduction of DA concentration and the elevation of the BRT. However, in the self-administration experiments, where there is a difference between pre- and postexposure BTR, a behavioral component is added that probably promotes the activation of a cholinergicglutamatergic circuit [58]. This additional activation might explain not only the differences observed between pre- and post-exposure BTR, but also the posterior reinforcement of this circuit (LTP) responsible for the long-lasting low BTR. According to the description of LTRA, this glutamatergic circuit is not facilitated by acute nicotine unless concomitant with a behavioral activation of the afferent cholinergic fiber. The increase of reward sensitivity due to acute nicotine exposure is blocked by mecamylamine [57] or reversed by DHβE [58,61], which is congruent with the blocking of STRA mechanisms. Yet, if we consider the proposed negative feedback role of α4β2 AChRs in LTRI, nicotine and DHβE should have the same effect via desensitization or competitive inhibition, respectively. However, if DHβE displaces nicotine from its binding site (and this effect depends on the concentration of both ligands), α4β2 AChRs exit the desensitized state promoted by nicotine, and enter earlier in the resting state. Consequently, the negative feedback is gradually activated and DA concentration reduced. Although experimental evidence suggests that DHβE

stabilizes the open state [62], there is no direct proof supporting an endogenous mutual exclusive interaction between nicotine and DHβE in terms of the desensitized or resting states, respectively.

12. Chronic nicotine and decrease of dopamine release Nicotine increases DA in the NAc, however, chronic nicotine reduces basal extracellular DA levels [63,64]. Nicotine self-administered rats have a slightly lower level of basal extracellular DA compared to their partners (nicotine yoked group), which receive simultaneously but involuntarily the same doses of nicotine [64]. Additionally, a reduction in the elevation of DA in the NAc after a nicotine challenge (24 to 48 h after the last nicotine self-administration) was observed in both the self-administered group (112%) and the nicotine yoked group (121%) compared to controls (154%). These lower levels of DA in the NAc were partially justified by an observed increase in DA reuptake as the result of chronic nicotine. Independently of this explanation, the desensitization-upregulation hypothesis expects a reduction in DA release after a chronic exposure to nicotine, because LTRI systems in basal conditions are exacerbated by upregulation. The chronic nicotine treatment enhances, via α4β2 AChR upregulation, the negative feedback of the GABAergic circuit, and additionally in the nicotine self-administered rats, the α4β2 – muscarinic negative feedback system associated to LTRA. According to this, it is expected a stronger reduction in DA levels in nicotine self-administered rats. However, if the basal DA reduction due to chronic nicotine is mainly the result of an enhanced reuptake, then the differences due to a lower DA release might be negligible, and this seems to be the case. However, the expected differences between control, nicotine self-administered and the nicotine yoked groups are reflected in the reduction of the elevation of DA after a nicotine challenge, where reuptake is not involved. In this case, nicotine self-administered rats had the lower increase in DA (112%) as expected.

13. Nicotine dependence and drugs used in smoking cessation In the desensitization-upregulation hypothesis [37], nicotine dependence is central in triggering smoking addiction. Subsequently, behavioral components help


in maintaining upregulation of α4β2 AChRs, albeit in advanced stages upregulation itself would not be the main factor in smoking addiction. However, once the decision of quitting has been made, nicotine biochemical dependence becomes an obstacle. Therefore, to overcome this problem and take the “normal path” instead of the “disrupted path” (Figs 1, 3, and 4), any drug used for smoking cessation aid should have the same rewarding properties as nicotine (i.e., inhibiting α4β2 AChRs) without inducing α4β2 AChR upregulation. This seems to be the case for some of the current and emerging drugs. 14. Conclusions The idea that AChR inactivation is the basis of nicotine dependence was the basis of the desensitizationupregulation hypothesis. Initially proposed on logical grounds, it has experimental sustain in neuronal circuits in which different AChR subtypes are involved and matched the requirements of the hypothesis. In the view of this hypothesis, the pathology in smoking addiction is a cholinergic system with an upregulated negative feedback system on ACh release, and the drive for cigarette consumption is to reduce its effects. Under this hypothesis, drugs used for smoking cessation should ideally inhibit preferentially but not upregulate α4β2.

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Acknowledgement [16]

This review was supported by grants from the CONICET, Argentina (to M.O.O.), and from the Science Foundation Arizona and Stardust Foundation and the College of Pharmacy, Midwestern University (to H.R.A.).

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