University of Florida College of Medicine, Brain Institute, Departments of Neuroscience ... in response to the powerful reward associated with all drugs of abuse.
Journal of Substance Abuse Treatment, Vol. 11, No. 2, pp. 93-97, 1994 Copyright 0 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0740-5472/94 $6.00 + .OO
Pergamon
0740-5472(94)EOO12-F
RESPONSE PAPER
Neurobiology of Addiction and Recovery: The Brain, the Drive for the Drug, and the 12-Step Fellowship MARK S. GOLD, MD University
of Florida
College
of Medicine, Brain Institute, Departments of Neuroscience Health Science Center, Gainesville, Florida
and Psychiatry,
these “feeling states” can be seen as a new drive state, similar to drives for food and sex, that has developed in response to the powerful reward associated with all drugs of abuse. Furthermore, it is my contention that the self-medication hypothesis for drug abuse addiction may be in reality an attempt by the user to satisfy the drive for drug reward.
IN THEIR ANALYSIS of the role of Alcoholics Anonymous (AA) and other 1Zstep fellowships in addiction treatment, Drs. Khantzian and Mack have provided a valuable source of information for all clinicians. Their embrace of the importance of AA in treatment, and their very lucid discussion of how AA employs and augments effective cognitive and behavioral treatment strategies, helps to correct an underlying mistrust between psychiatry and self-groups (Miller & Gold, 1993). However, there are three areas, only tangentially covered by Drs. Khantzian and Mack, that warrant further attention. Specifically, these areas are the importance of the pursuit of reward, the brain as the target for drug taking, and the role of the selfmedication hypothesis in the development and persistence of addiction. According to Drs. Khantzian and Mack, using substances is often a conscious attempt to:
THE ROLE OF REWARD IN ADDICTION Drugs of abuse are self-administered by laboratory animals whether they are living in New York or Florence; whether they are in withdrawal; whether they are drug naive or experienced; whether they have had experience with other drugs; or whether they are taken orally, intravenously, or by other routes. In short, drugs are taken because of their reward and the reinforcement that is associated with their use. All drugs that are addictive in humans are considered reinforcing in that drug use stimulates further drug use. It is their reinforcing properties that is the key element in their addictive nature. The medial forebrain bundle (MFB) region of the brain, together with the nuclei and projection fields of the MFB, have been found to be primarily responsible for the positive reinforcement associated with drugs of addiction. Histofluorescence mapping techniques have revealed a close association between the brain stimulation reinforcement region and the mesolimbic dopamine (DA) system. Additional studies have confirmed the importance of DA neurotransmission to brain reinforcement (Wise & Rompre, 1989).
Avoid feelings and/or distress. At other times, the avoidant, addictive behavior is automatic, beyond awareness. In the former instance, the desire to self-medicate seems to be the main motivation for resorting to substances. . . . In those instances, however, where alcoholics or drug-addicted people are less aware of their feelings, or they experience none, the motivation to “use” or “act” seems more to involve the need to control or alter feeling states that are inaccessible or cannot be put into words. It is the second part of this quote, referring to the drug use that results from “the need to control or alter feeling states that are inaccessible or cannot be put into words” that I wish to address first. It is my belief that
Stimulant Requests for reprints should be addressed to Mark S. Gold, MD, Departments of Neuroscience and Psychiatry, University of Florida College of Medicine, Box 100244 JHM Health Science Center, Gainesville, FL 32610.
Reinforcement
Amphetamine and cocaine achieve positive reinforcement by blocking the reuptake of DA into the presynaptic neuron (Gold & Dackis, 1984; Miller & Gold, 93
M.S.
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1987). By preventing DA reuptake, greater concentrations of DA remain in the synaptic cleft with more DA available at the postsynaptic site for stimulation of specific receptors. The abnormally high levels of DA in the synapse inhibits the firing rate of dopaminergic cells and mediates the process by which synaptic DA is inactivated. Numerous studies have supported the positive reinforcement effects associated with increased synaptic levels of DA. Nicotine has also been found to enhance DA levels and to be a positive reinforcer, although not to the same extent as other stimulants. DA release in the nucleus accumbens (NAc) has occurred in vitro in response to small concentrations of nicotine (Stolerman & Shoaib, 1991). In addition, microinjection of amphetamine into the NAc facilitated stimulation response in the ventral tegmental area (VTA), whereas morphine injections into the NAc did not enhance stimulation response in the VTA. Evidence suggests that cocaine (and possibly all other abused psychoactive compounds) produces its rewarding effect by increasing synaptic DA concentrations and consequently producing a critical increase in the stimulation of NAc DA receptors. Thus, cocaine increases NAc DA concentrations by binding to a DA transporter and thereby inhibiting reuptake of DA into presynaptic neurons. In operant-conditioning experiments where animals have been shown to self-administer large quantities of cocaine and many other compounds abused by humans, the potency of various cocainerelated compounds in maintaining self-administration behavior can be predicted by each compound’s affinity for the DA transporter. In contrast, self-administration behavior is not predictable from drug affinities for norepinephrine or serotonin transporters (Gold, 1993a). Similar studies suggest that amphetamine produces its rewarding effects through activation of NAc DA receptors. Opiate abuse may also be related to the stimulation of NAc DA receptors. However, the data are equivocal (Nakajima, 1989; Pettit, Ettenberg, Bloom, & Koob, 1984). It is also worth noting that nicotine, tetrahydrocannabinol (THC), and alcohol increase NAc DA concentration. Finally, evidence suggests that the DA receptors of the NAc may function as part of a neuronal mechanism responsible for endogenous reward that reinforces behaviors reading to natural stimuli such as food and water. Thus, operant-conditioning experiments with animals indicate that the rewarding properties of food, water, or intracranial brain stimulation may depend on the NAc DA receptor activation. Therefore, the rewarding properties of drugs that lead to excessive self-administration may result from the ability of these compounds to activate this neural substrate for endogenous reward. Cannabis
Reinforcement
Unlike other drugs of abuse, marijuana had previously been thought to lack any pharmacological interaction
Gold
with the brain’s reinforcement system. However, it now appears that marijuana’s principal psychoactive ingredient, delta’-THC, acts as a DA agonist in a manner similar to other noncannabinoid drugs of abuse. In addition, delta’-THC has been shown to bind with the distinct opioid receptor subtype stimulated by morphine and called the p receptor. Chronic p-decreased Locus Coeruleus (LC) activity could cause LC hyperactivity during withdrawal. Chen, Paredes, Smith, and Gardner (1989) demonstrated that delta’-THC administration enhances presynaptic DA levels at brain reinforcement loci and that this increase can be attenuated by the opiate antagonist naloxone. Naloxone’s alteration of delta’-THC effects suggest that marijuana engages endogenous brain opioid circuitry and formulates an essential association between these endogenous opioids and DA neurons in the MFB. Furthermore, this association appears fundamental to marijuana’s positive effects on the brain’s reinforcement system, and ultimately, marijuana’s abuse potential (Gold, 1989). Opiate Reinforcement
Although the primary opiate effect is sedation, opiates have been shown to provoke the dopaminergic cells of the VTA and the substantia nigra, sometimes to the point of exhaustion (Gold, 1993b). As with marijuana, opiate ability to engage endogenous opiate receptors may be associated with the increased DA activity. Opiates produce their analgesia, respiratory depression, hypotension, and axiolytic effects by binding with the delta and p receptors and inhibiting adenylate cyclase. This inhibition results in diminished conversion of adenosine triphosphate to cyclic adenosine monophosphate (CAMP) and decreased phosphoprotein levels. It has been suggested that opiate withdrawal may result in increased CAMP levels (Kosten, 1990). Terwilliger, Neitner-Johnson, Sevarina, Crain, and Nestler (1991) found that chronic morphine decreased the inhibitory G-protein G,, while increasing levels of adenylate cyclase and CAMP-dependent protein kinases activity in the NAc, suggesting that changes in CAMP pathway may lead to drug reward in the NAc. In addition, studies showing that direct injections of opiates into the VTA activate feedings provide additional support for the role of opiate interaction with the DA system in the reinforcement of drive states. In addition, pharmacological inhibition of the DA system in hungry and thirsty animals reduces the reinforcing effects of food and water (Gold & Miller, 1992). Gardner and others have found that the brain reward enhancement produced by drugs of abuse like opiates, cocaine, amphetamine, ethanol, and benzodiazepines is attenuated by opiate antagonists such as naloxone and naltrexone (Gardner, 1992). Naloxoneinduced attenuation of all known classes of abusable drugs and their effects on brain stimulation reward
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supports the importance of endogenous opioid systems in all drugs of abuse and not just opioids. The opioidDA connections are now the focus of scientific study to explain the abuse of all drugs and alcohol. Neuroanatomical study supports the interrelationship between DA and opioid systems because cell bodies, axons, and synaptic terminals of enkephalin-containing and endorphinergic neurons are found throughout the extent of the mesotelencephalic DA reward pathway of the brain. Endogenous opioid peptide neurons synapse directly onto mesotelencephalic DA axon terminals forming an axoaxonic synapse that could modulate the flow of DA and the reward signals through the existing and well-described DA circuitry. Some DA reward neurons may synapse directly on opioid peptide neurons. Alcohol Reinforcement Similar to the stimulants and opiates, ethanol has been shown to stimulate the release of DA in the nucleus accumbens. Furthermore, low-dose ethanol apparently will stimulate neurons in the VTA, suggesting that ethanol activates DA projection from the VTA to the NAc. In addition, alcohol-preferring rats will selfadminister alcohol directly into the stomach, apparently for its reinforcement properties and not because of its taste, smell, or caloric content (Miller & Gold, 1991). Alcohol and drugs, on a basic or primitive level, produce rapid reinforcement described as seeking a sense of well-being. This reinforcement is clearly neurobiological in that the drug use stimulates its own taking and produces a sense of organismic accomplishment similar to species-specific survival behaviors. Drug users feel as if they have acted to preserve the species, when in reality they have simply by-passed the normal behavior reinforcement system. The changes in mood associated with drug reinforcement serve as an unconditioned stimulus. Given frequent association with these changes, a variety of other factors, including the psychological (mood states, cognitive expectations of euphoria, stress, etc.) and environmental (drug paraphernalia, drug-using locations or friends, etc.), can become conditioned stimuli. Exposure to these conditioned stimuli can precipitate withdrawal-like physiological responses that the user interprets as drug cravings and that often lead to relapse. Animal studies using microdialysis show that a conditioned response can provoke an increase in DA levels in the NAc, in effect a “priming dose” that may enhance desire for the drug. O’Brien (1992) studied the responses of cocaine addicts to videos of people using cocaine. These videos have been found to provoke craving and arousal, measured by increases in blood pressure and heart rate and by decreases in skin temperature and skin resistance, that are very similar to the response from using cocaine or another stimulant (O’Brien, 1992).
POSTRECEPTOR SITES OF DRUG ADDICTION Although the discovery of endogenous opiate receptors, THC receptors, as well as the role of DA transporters and neurotransmitter systems6 have greatly enhanced our understanding of the addiction process, they have not accounted for many important aspects of drug addiction (Nestler, 1992). Several years of study have not identified consistent changes in the number of opiate receptors or changes in opiate-ligand affinity associated with opiate addiction (Loh & Smith, 1990). Similar inconsistencies have also been found in long-term changes in specific neurotransmitter or receptor systems associated with stimulant addiction (Peris et al., 1990). As a result, recent research has centered on the role of postreceptor systems in mediating neurotransmission and receptors. These postreceptor systems include intracellular messengers such as G-proteins, and intracellular effector systems consisting of second messengers (i.e., CAMP), protein kinases and protein phosphatases, and phosphoproteins (Nestler, 1992). These postreceptor research efforts stem primarily from the attention devoted to understanding neural plasticity and the molecular process by which gene expression is altered and from the specific molecular probes designed to study such phenomena. Concepts developed in oncogene research have been applied to the study of the nervous system, leading researchers to suggest that the transcription factors capable of oncogenic transformation and implicated in cell growth regulation also act as inducible transcription factors in the stimulus-response coupling in the nervous system (Curran et al., 1990). Regulation of neuronal gene expression may explain the necessity of continued drug exposure in the development of addiction as well as the continuance of addiction long after drug withdrawal. For all drugs, reinforcement may be more important than withdrawal in the persistence of addiction and relapse because successful treatment of withdrawal has not generally improved treatment retention and recovery (Gold, 1993b). All addiction-prone drugs are used, at least initially, for their positive effects and because the user believes the short-term benefits of this experience surpass the long-term costs. Once initiated, drug use permits access to the reinforcement system, which is believed to be anatomically distinct from the negative/ withdrawal system in the LC and elsewhere (Bozarth & Wise, 1984). This reinforcement system, accessed now by exogenous self-administration by drugs of addiction, provides users with an experience their brain equates with profoundly important events like eating, drinking, and sex. Tolerance may occur when the brain environment redefines “normal” and resets neurochemical homeostasis. If a brain affected by 30 mg of methadone or
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a gram of cocaine per day becomes the new neural “normal,” then it should not be surprising that relapse and drug use are the rule rather than the exception. If drugs are taken because of drive states, they develop a life of their own as the brain redefines normal to require their presence in expected quantities (Gold, 1991). THE SELF-MEDICATION HYPOTHESIS AND ADDICTION
Using substances to avoid feelings and/or distress has been labeled the “self-medication hypothesis.” However, this self-medication may actually reflect the drugaddicted individual’s desire to return to the homeostasis of a drug state. In fact, the evidence for a self-medication hypothesis as an etiology or genesis of addictive use of alcohol and drugs is lacking. This hypothesis is an assumption often based on retrospective diagnoses and dogmatic unproven intuitive logic. There are no available objective studies that support the common interpretation that psychiatric disorders predate or are responsible for initiating and sustaining addictive use. Controlled studies show that alcoholics drink despite alcohol-induced depression and anxiety and that drinking and depression/anxiety are negatively correlated in nonalcoholics (Mayfield, 1979; Tamerin & Mendelson, 1969). Controlled studies show further that anxious or depressed people do not prefer to drink more than nonanxious or nondepressed people (Miller & Gold, 1991). Although alcoholics report drinking because of anxiety and depression, under laboratory conditions they become increasingly anxious and depressed in a dosedependent manner as they drink and not before. Similar findings have been reported for cocaine use in cocaine addicts (Gold, 1993a; Miller, Mahler, Belkin, 8z Gold, 1990; Schukit, 1983). Also, no studies show that basic personality structure is irretrievably altered by addiction, and data support that the “personality” often returns to a pre-existing state reflective of the usual personality. Moreover, although anxiety and depressive disorders may arise de novo or be masked by the predominant alcohol and drug use, studies do not support an increased prevalence of these disorders among alcoholics and drug addicts in the abstinent state. The present evidence indicates that addiction is an independent disorder that typically generates anxiety and depression. Studies employing both pharmacological and nonpharmacological agents for depression occurring in the setting of addiction do not demonstrate efficacy in reducing either the depression or the addiction. Antidepressants, antianxiety agents, and psychotherapy, although effective in the treatment of depression, do not possess efficacy in relieving the depression and anxiety induced by alcoholism or drug addiction or the overall course of the addictive use of alcohol and
Gold
drugs. The same findings hold for other psychiatric disorders in which hallucinations and delusions induced by the addictive use of alcohol and drugs do not respond to conventional pharmacotherapies (Gold, 1990; Schukit, 1983). Studies do confirm that specific treatment of the addictive disorders will alleviate the addictive use of alcohol and drugs and often the consequent psychiatric co-morbidity. A period of observation of days to weeks may be necessary to examine important causal links in the genesis of psychiatric symptoms from addictive disorders and to establish independent psychiatric disorders. Instead of drug taking that results from the need to self-medicate an underlying psychiatric condition or to treat withdrawal, drug taking may result, as many 1Zstep fellowships assert, because it feels good (Gold & Miller, 1992). This difference between traditional psychiatry, where drug taking is seen as a response to psychological deficits, and AA, where drug taking is believed to occur because the “addict is an addict,” reflects a fundamental difference between psychiatry and 1Zstep fellowships. Nevertheless, as Drs. Khantzian and Mack admit, this difference is rendered somewhat moot by the fact that the principles of AA are very effective in treatment. AA’s ROLE IN OVERCOMING DRUG REWARD AND ADDICTION
How does someone in the middle of a binge or a longstanding period of drug self-administration stop using drugs? For many people, the 1Zstep fellowships offers the answer. To take the first step, one may have to fail a company drug test, have a caring spouse or loved one initiate a confrontation and intervention, or experience a less desirable hitting bottom. But, while everyone around is focusing on the negative that the drug has wrought, the positive attitude to persist and persevere is provided by the group process of AA and the other 1Zstep fellowships. Psychiatrists may understand AA by relying on their extensive experiences in group treatment. Alcoholics are provided with hope by hearing others recall their experiences and testimonials that there is life after drugs. Rather than feeling alone and isolated, the meetings are full of people with numerous shared and common experiences. There is a relief in talking about their own lives in an arena that is nonjudgmental and available to provide a context as well as related experiences and viable coping skills. The AA fellowship and its 12 steps and 12 traditions assume powerlessness and also provide strength in reliance on the group and the higher power. Simply stated, AA is a fellowship of people who share their experience and derive strength and hope from each other so that they can help themselves and others recover from their addiction. In a relatively
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short time from its beginnings on June 10, 1935 (the date that co-founder Dr. Bob Smith had his last drink), AA has been a mainstay of addiction recovery and relapse prevention. Recovery is related to experiencing the fellowship and allowing the negative effects the priority they deserve in the ongoing risk-benefit ratio that is early abstinence. In a rather complex field, AA tells members that there is hope, that drugs are very powerful and dangerous for them, that without drugs they can and will be normal, and that there is hope and recovery from learning about themselves and the personal experiences of others. AA also helps with relapse and relapse prevention by prescribing that people “keep it simple” and avoid the people, places, and things associated with their drugs and by helping others to develop positive lifestyles and finding new ways to solve old problems. Many of the intuitive core beliefs of the fellowships have had a very positive effect on research in the field from the genetic predisposition thesis, to the children of alcoholics, to the notion that drug-addicted individuals are vulnerable to all drugs and not just the drug they are dependent on at the moment, to the idea that it is the drug that makes addicts depressed and not vice versa. Although fear of the consequences of another positive urine screen or impending loss of a job or loved one is often the necessary stick to get treatment started, it is the fellowship that acts as the carrot in this delicate balance called recovery. Similarly, psychiatry has shown that the effective pharmacological treatment of withdrawal distress is ultimately a pyrrhic victory. Withdrawal pain may be eased, but the rate of relapse remains frustratingly high without the ongoing positive group and life-changing experience commonly felt by addicts in fellowship meetings. AA is more than an alternative treatment program - It is a way of life and a complex relapse prevention program that can work for all drugs of abuse.
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Gold, M.S. (1993a). Cocaine. Drugs of abuse: A comprehensive series for clinicians (Vol. 3). New York: Plenum. Gold, M.S. (1993b). Opiate addiction and the locus coeruleus. Psychiatric Clinics of North America, 16, 61-73. Gold, M.S., & Dackis, C.A. (1984). New insights and treatments: Opiate withdrawal and cocaine addiction. Clin Ther, 7, 6-21. Gold, M.S., & Miller, N.S. (1992). Seeking drugs/alcohol and avoiding withdrawal: The neuroanatomy of drive states and withdrawal. Psychiatric Annals, 22, 430-435. Kosten, T.R. (1990). Neurobiology of abused drugs: Opioids and stimulants. Journal of Nervous and Mentol Disease, 178(4), 217-227. Loh, H.H., & Smith, A.P. (1990). Molecular characterization of opioid receptors. Annu Rev Pharmacol Toxicol, 30, 123-147. Mayfield, D.G. (1979). Alcohol and affect: Experimental studies. In D.W. Goodwin & C.K. Erickson (Eds.), Alcoholism and uffective disorders (pp. 99-107). Miller, N.S., & Gold, M.S. (1987). The relationship of addiction, tolerance, and dependence to alcohol and drugs: A neurochemical approach. Journal of Substance Abuse Treatment, 4, 197-207. Miller, N.S., &Gold, M.S. (1991). Alcohol. Drugs of abuse: A comprehensive series for clinicians (Vol. 2). New York: Plenum. Miller, N.S., & Gold, M.S. (1993). The role of the psychiatrist in integrating pharmacological and nonpharmacological treatments for addictive disorders. Psych Annals, 22(8), 436-440. Miller, N.S., Mahler, J.C., Belkin, B.M., &Gold, M.S. (1990). Psychiatric diagnosis in alcohol and drug dependence. Annals of Clinical Psychiatry, 3(l), 79-89. Nakajima, S. (1989). Subtypes of dopamine receptors involved in the mechanism of reinforcement. Neurosci Biobehav Rev., 13, 123-128. Nestler, E.J. (1992). Molecular mechanisms of drug addiction. Journal of Neuroscience, 12(7), 2439-2450. Nestler, E.J., & Durman, R.S. (1994). G-proteins and cyclic nucleotides in the nervous system. In G.J. Siegel (Ed.), Basic neurochemistry: Molecular cellular and medical aspects (5th ed.). New York: Raven Press. O’Brien, C.P. (1992). Conditioned responses, craving, relapse and addiction: An interview with Charles P. O’Brien. The University of Florida Facts About Drug and Alcohol Newsletter, l(4). 1, 3. Peris, J., Boyson, S.J., Cass, W.A., Curella, P., Dwoskin, L.P., Larson, G., Lin, L-H., Yasuda, R.P., & Zahniser, N.R. (1990). Persistence of neurochemical changes in dopamine systems after repeated cocaine administration. J Pharmacol Exp Ther, 253, 38-44. Pettit, H.O., Ettenberg, A., Bloom, F.E., & Koob, G.E. (1984). Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration. Psychophorm, 84, 167-173. Schukit, M.A. (1983). Alcoholism and other psychiatric disorders. Hospital and Community Psychiatry, 34, 1022-1027. Stolerman, I.P., & Shoaib, M. (1991). The neurobiology of tobacco addiction. Trends in Phormocolog Sci., 12, 467-473. Tamerin, J.S., & Mendelson, J.H. (1969). The psychodynamics of chronic inebriation. Observations of alcoholics during the process of drinking in an experimental group setting. American Journal of Psychiatry, 125(7), 886-899. Terwilliger, R., Neitner-Johnson, D., Sevarina, K.A., Cram, S.M., & Nestler, E.J. (1991). A general role for the adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. Brain Res, 548, 100-110. Wise, R.A., & Rompre, P.P. (1989). Brain dopamine and reward. Annu Rev Psychol, 40, 191-225.
