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Home , Neuropharmacology

The Neurobiology of An Overview

AMANDA J. ROBERTS, PH.D., AND GEORGE F. KOOB, PH.D.

Addiction can be defined in part as a compulsion to use alcohol or other and the occurrence of withdrawal symptoms when long-term consumption ceases. In addition to physical symptoms related to nervous system hyperexcitability, withdrawal includes changes in mental state that may motivate renewed AOD consumption. The manifestations of addiction are associated with changes in nerve cell function by which the brain attempts to adapt to a ’s presence. These functional changes modulate a person’s initial response to a drug, the establishment of long-term craving for the drug (i.e., addiction), and the persistent sense of discomfort that leads to relapse after abstinence has been achieved. Research is beginning to reveal how specific brain regions may be integrated to form neural circuits that modulate aspects of addiction. KEY WORDS: AOD dependence; compulsion; AOD withdrawal syndrome; AOD craving; positive reinforcement; AODD (alcohol and other drug disorders) relapse; AOD abstinence; neurobiological theory; ; ; AOD sensitivity; biological adaptation; brain; ; ; literature review

ddiction can be defined from a Research over the past two decades of neural connections involving sev- behavioral viewpoint as repeat- has increased our understanding of the eral adjacent brain regions. This arti- Aed self-administration of alco- neural processes that underlie drug- cle is not an exhaustive overview, but hol or other drugs (AOD’s) despite seeking behavior. This article summa- a sampling of some topics of interest knowledge of adverse medical and rizes some of the molecular and to researchers studying addiction social consequences and attempts to cellular events in the brain that appear neurobiology. abstain from AOD use. Typically, an to be associated with addiction. The AMANDA J. ROBERTS, PH.D., is a addicted person’s daily activities are article first discusses some observable manifestations of addiction and basic research associate in the Department centered on obtaining and consuming mechanisms involved in initiating and of Neuropharmacology, The Scripps the drug at the expense of social and maintaining addictive behavior. The Research Institute, La Jolla, California. occupational commitments. Many hypothesized roles of various chemical GEORGE F. KOOB, PH.D., is a factors contribute to the development communication systems of the brain of addiction. A person’s initial deci- professor and director of the Division (i.e., neurotransmitters and receptors) of , Department sion to use a drug is influenced by are explored, followed by a discussion of Neuropharmacology, The Scripps genetic, psychosocial, and environ- of the interactions between these sys- Research Institute, La Jolla, Califor- mental factors. Once it has entered the tems within brain regions thought to nia, and adjunct professor in the body, however, the drug can promote be involved in addiction. Departments of and continued drug-seeking behavior by Finally, the article discusses the , University of California. acting directly on the brain. suggested role of an integrated system San Diego, California.

VOL. 21, NO. 2, 1997 101 BASIC MECHANISMS Reinforcement Scientists believe that ICSS directly OF ADDICTION activates the brain’s reward centers, Several sources of reinforcement may thus providing a unique tool for inves- Two characteristics are common to contribute to addiction. In positive tigating reinforcement processes. most definitions of AOD addiction: the reinforcement, a rewarding stimulus AOD’s appear to make ICSS more compulsion to use a drug, leading to its (e.g., AOD-induced euphoria) directly rewarding by decreasing the amount increases the probability of a response excessive and uncontrolled consump- of current required by the animal to (e.g., continued AOD use). In negative tion, and the appearance of a cluster of achieve the same level of reward. This reinforcement, the incentive for AOD symptoms when the drug is withheld ability corresponds closely to a drug’s use is relief of a painful or unpleasant after a period of its continuous con- potential for abuse. state (i.e., the physiological and motiva- sumption (i.e., withdrawal syndrome). A third behavioral paradigm used tional symptoms of withdrawal). In Physiological symptoms of alcohol to test the reinforcing actions of addition to their direct reinforcing ef- withdrawal begin from 6 to 48 hours AOD’s is place conditioning (figure fects, drugs can motivate behavior after the last drink and include tremors, C). In a simple place-conditioning elevated blood pressure, increased indirectly through environmental stim- uli with which the drugs have become test, an animal is alternately placed in heart rate, and seizures. AOD with- two distinct environments, neither of drawal also includes changes in mental associated (i.e., conditioned reinforce- ment). For example, the locations which initially elicits any apparent state (e.g., anxiety, negative emotional behavioral response (i.e., neutral envi- state, and craving) that may motivate where drugs are taken or the parapher- nalia used for their administration may ronments). The animal is conditioned renewed AOD consumption. These themselves elicit a druglike state of to associate one of the environments signs may both precede and outlast the euphoria in the absence of the drug (i.e., with the effects of the drug under physiological symptoms. For the pur- conditioned positive reinforcement). study. For example, the animal may pose of this article, addiction is defined Conversely, exposure to stimuli associ- be placed in a dark chamber with a as a loss of control over AOD use and ated with periods of abstinence may rough-textured floor after receiving a the appearance of a withdrawal syn- produce symptoms of withdrawal (i.e., drug injection, and placed in a light drome—with motivational aspects— conditioned negative reinforcement). chamber with a smooth-textured floor upon cessation of such use. Researchers can examine the rein- after receiving an injection of drug- Two factors that modulate behav- forcing effects of AOD’s by measuring free saline solution. This procedure is ior—reinforcement and neuroadapta- the behavior of animals exposed to repeated several times. Later, the tion—contribute to the addictive drugs in the laboratory (see figure). A animal is allowed to enter and explore process. Reinforcement is a theoretical commonly employed method is direct either environment in the absence of construct by which a stimulus (e.g., an self-administration whereby an animal the drug. A greater amount of time unconditioned stimulus, such as the is either allowed free access to AOD’s spent in the drug-associated environ- drug itself or drug withdrawal, or a (e.g., given a bottle containing alcohol ment appears to reflect positive rein- conditioned stimulus, such as drug- to drink) or required to perform a spe- forcing effects of the drug. In the taking paraphernalia) increases the cific behavior to obtain AOD’s (e.g., aforementioned example, a greater probability of a response (e.g., contin- trained to press a lever for a small vol- time spent in the dark, rough-textured ued use of the drug). Neuroadaptation ume of alcohol). Changes in the pat- environment, compared with the light, refers largely to the processes by which terns of self-administration that occur smooth-textured environment, would initial drug effects are either enhanced with long-term AOD exposure or fol- suggest that the administered drug had (i.e., sensitization) or attenuated (i.e., lowing the experimental manipulation positive reinforcing effects. counteradaptation) by repeated AOD of a particular neural system may reveal Whereas the acute positive reinforc- exposure. Drug-related responses (i.e., underlying mechanisms of reinforce- ing effects of drugs may be investi- reinforcement) are modulated by the ment (figure A). gated using these paradigms, negative neuroadaptive changes that occur with A second behavioral test used to reinforcing effects can be examined by AOD exposure. Working together, measure the reinforcing effects of testing animals in the withdrawal or these factors appear to motivate the AOD’s is intracranial self-stimulation abstinent state. These paradigms also initial, short-term (i.e., acute) response (ICSS). In this procedure, electrodes can be used to examine conditioned to a drug and the establishment of the are implanted in the brain of a rat. The positive and negative reinforcement. long-term (i.e., chronic) craving for the rat is subsequently allowed to press a For example, a rat can be trained to drug that characterizes addiction. In lever to receive mild electrical pulses associate the presentation of alcohol addition, some neuroadaptive changes through the electrodes (figure B). with a light. The experimenter can then may be permanent, producing the Animals will self-administer electrical measure the frequency with which the persistent sense of discomfort during stimulation to certain brain regions at rat presses a lever to turn on the light in abstinence that leads to reinstatement extremely high rates, indicating that the absence of alcohol (i.e., condi- of drug use (i.e., relapse). such stimulation is reinforcing. tioned positive reinforcement).

102 ALCOHOL HEALTH & RESEARCH WORLD The NeurobiologyRunning of Addiction Heads

Neuroadaptation Although the positive reinforcing AB effects of drugs are critical for estab- Alcohol lishing addictive behavior, both posi- Computer Water Stimulator tive and negative reinforcing effects interface are probably important for maintain- Computer interface ing drug use following the develop- ment of addiction. Neuroadaptive Lever changes that occur with chronic drug use lead to increased positive and negative reinforcing effects. Thus, as Rotating mentioned previously, neuroadapta- Wheel Fluid tion is a modulatory process that can receptacle lead to increased reinforcement with repeated AOD exposure. C Sensitization is an increased re- Drug ? sponse to a drug effect following re- Saline peated administration of the drug. Sensitization of drug effects that sup- port further intake (such as the motiva- tional state of “wanting” or “craving” Phase 1 Phase 2 Phase 3 (test) and/or the physiological state of arousal) may contribute to the process of addic- tion. A recent conceptualization of the Animal behavioral paradigms used to explore the positive and negative reinforcing role of sensitization in drug depen- actions of alcohol and other drugs. (A) Oral alcohol self-administration paradigm, in dence posits that a motivational state which the animal is trained to press a lever to obtain alcohol instead of water. Rats described as “wanting” is progressively will readily self-administer enough alcohol in daily 30-minute sessions to become increased by repeated exposure to drugs mildly intoxicated. (B) Intracranial self-stimulation paradigm, in which the animal is trained to spin a wheel to receive a current through electrodes implanted in the of abuse (Robinson and Berridge brain. (C) Place-conditioning paradigm, in which injection of a drug is paired 1993). As “wanting” increases across repeatedly with one environment and injection of a nondrug control solution (e.g., repeated AOD exposures, the likeli- saline) is paired repeatedly with a different environment. The animal subsequently is hood of relapse following periods of allowed access to both environments in the drug-free state, and the amount of time abstinence may increase, ultimately spent in each environment is recorded. A greater amount of time spent in the drug- leading to compulsive drug use. paired environment indicates a positively reinforcing drug effect. Counteradaptation refers to pro- cesses that are initiated to counter the acute effects of drugs. For example, released and subsequently bound by The general reward circuitry of the tolerance is the reduction in a drug’s receptive elements on neurons. This brain centers around connections be- effect after repeated use of the drug. process leads to a cascade of intracellu- tween the and the Tolerance to the desired effect of an lar events that changes the excitability basal forebrain (which includes the AOD could stimulate increased AOD of the cell and ultimately alters neu- nucleus accumbens, olfactory tubercle, use in an attempt to re-experience the ronal circuit activity. A circuit can be frontal cortex, and amygdala). An im- intensity of the drug’s initial effect. defined as a group of connected neu- portant component of this system in- Withdrawal is another counteradap- rons that pass information related to a volves the transmitter dopamine; tive process. In this case, the processes specific function. AOD’s hypothetically however, opioid, , and gamma- initiated to counter acute AOD effects possess acute positive reinforcing ef- aminobutyric (GABA) systems are also are expressed when the drug is removed; fects because of their interactions with involved. Evidence for a role of these thus the symptoms are often opposite in individual transmitter systems within systems in AOD addiction is discussed nature to the original drug effects. the general reward circuitry of the in the sections that follow. This discus- brain. The intracellular events elicited sion is not exhaustive, however: Other by AOD’s can lead to changes in many systems besides those discussed may NEURAL CIRCUITRY OF ACUTE other neural processes, including those play crucial roles in drug addiction DRUG REINFORCEMENT that trigger the long-term AOD effects processes. Moreover, individual systems which eventually lead to tolerance, interact with one another in complex Information is passed between neurons dependence, withdrawal, sensitization ways that are beyond the scope of this by chemical transmitters, which are and, ultimately, addiction. overview.

VOL. 21, NO. 2, 1997 103 Dopamine Systems tions between mesolimbic dopamine MECHANISMS OF and opioid systems are important in NEUROADAPTATION The mesolimbic dopamine system con- the addictive process. (For review, see necting the ventral tegmental area and the Koob and Nestler in press.) Neuroadaptations in the reward system basal forebrain appears to be critical to accompany the development of addic- the self-administration of psychomotor tion and can involve the same systems stimulants (i.e., and amphe- Serotonin Systems underlying acute drug reinforcement tamine) (Koob 1992). The cell bodies of The serotonin helps (within-system adaptation) or different this dopamine system originate in the regulate such functions as bodily systems (between-systems adaptation). ventral tegmental area and send projec- rhythms, appetite, sexual behavior, and These changes in the reward circuitry tions to the nucleus accumbens and basal emotional states. Evidence indicates that promote compulsive drug use in part forebrain, transmitting information to the serotonin systems are important in alco- by increasing a drug’s positive (e.g., dopamine receptors in these brain areas. hol consumption. For example, increas- sensitization) and negative (e.g., This system also is important, but per- ing the level of serotonin in synapses or counteradaptation) reinforcing effects. haps not critical, for reinforcement of blocking certain serotonin opiate, nicotine, and alcohol use (Koob subtypes can decrease alcohol consump- Sensitization 1992; Pich et al. 1997). For example, tion (LeMarquand et al. 1994a, 1994b). alcohol consumption increases dopamine Repeated administration of stimulants, release in the nucleus accumbens from Serotonin systems also may be im- opiates, or alcohol can result in sensi- ventral tegmental neurons, and dopamine portant in the acute reinforcing effects of tization, which appears to be mediated receptor antagonists1 reduce lever press- drugs other than alcohol. For example, by the mesolimbic dopamine system ing for alcohol in rats. However, virtually although reinforcement of cocaine use is (Wise and Leeb 1993). The process of complete destruction of dopamine nerve attributed primarily to the dopamine sensitization, whereby an enhanced terminals in the nucleus accumbens failed system, cocaine strongly inhibits re- activation of dopamine function oc- to alter lever pressing for alcohol. moval of serotonin from synapses, curs in the mesolimbic system, may thereby facilitating increased binding of represent a within-systems mechanism Opioid Systems serotonin to its receptors (White and of neuroadaptation. For example, Wolf 1991). Antagonism of a specific injections of opiates or amphetamine Endogenous opioids are morphinelike directly into the ventral tegmental area serotonin receptor (i.e., 5-HT2) appears neurotransmitters. Considerable evi- to decrease consumption of cocaine by that change the function of the dopa- dence shows that the endogenous opioid rats (McMillen et al. 1993), and experi- mine neurons produce sensitization to systems have roles in the positive rein- later injections of these drugs in the mental activation of the serotonin 5-HT1B forcing effects of opiates (e.g., heroin). receptor increases reinforcement by periphery (White and Wolf 1991). As is the case with tolerance, sensitization For example, Ettenberg and colleagues dopamine (Parsons et al. 1996). (1982) administered an opioid antago- may develop to one particular effect of nist to rats previously trained to self- a drug and not to another. GABA Systems administer heroin. The animals reacted Another system that may have an to this treatment by increasing their Gamma-aminobutyric acid (GABA) is important role in sensitization, repre- heroin intake, suggesting an attempt to the primary inhibitory neurotransmitter senting a between-systems mechanism compensate for the decreased efficiency in the brain. Sedative-hypnotic drugs of neuroadaptation, involves corti- of opioid neurotransmission. including alcohol, benzodiazepines (e.g., cotropin-releasing factor (CRF). This The opioid system also appears to Valium¨), and barbiturates have long hormone is released by the hypothala- mus and the amygdala in response to be important for the reinforcing effects been hypothesized to modulate recep- stress. CRF causes the release of addi- of both alcohol and nicotine. For ex- tors in GABA systems. Supporting this tional stress hormones into the blood- ample, the opiate receptor antagonists concept, experimental drugs that de- naloxone and naltrexone reduce both stream from the pituitary gland crease the function of GABA receptors (located at the base of the brain) and alcohol and nicotine reinforcement in reduce alcohol consumption by rats. several animal models. Naltrexone has the adrenal cortex (located atop the Microinjections of GABA antagonists kidneys). This stress-response system also shown success in decreasing alco- into various rat brain regions suggest hol consumption, frequency of relapse, is called the hypothalamic-pituitary- that an important brain area for alcohol- and craving for alcohol in humans adrenal (HPA) axis. The amygdala GABA interactions is the central nucle- (O’Malley et al. 1992; Volpicelli et al. release may be responsible for behav- us of the amygdala, a structure that 1992). These data suggest that interac- ioral responses to stress. Exposure to a communicates with the basal forebrain variety of stressors can promote sensi- 1For a definition of this and other technical structures and is associated with emo- tization to drug effects, and the CRF- terms used in this article, see central glossary, tion and stress. (For review, see Deitrich mediated stress-response system has pp. 177Ð179. and Erwin 1996.) been implicated in this sensitization.

104 ALCOHOL HEALTH & RESEARCH WORLD The NeurobiologyRunning of Addiction Heads

For example, stress hormones released drawal is associated with increased EXTENDED AMYGDALA: by the adrenal cortex (i.e., corticos- levels of CRF in this brain region INTEGRATIVE CONCEPT teroids) have been implicated in the (Merlo-Pich et al. 1995). Altered corti- increased locomotor response ob- costeroid activity also has been associat- Although the mesolimbic dopamine served in mice following repeated ed with both alcohol and benzodiazepine system is clearly important in drug administration of low doses of alcohol withdrawal. In mice, administration of addiction, its activity alone does not (Roberts et al. 1995). corticosteroids exacerbated withdrawal appear to account for the diversity of Excitatory neurotransmitter sys- convulsions, whereas a steroid synthesis drug-reinforcement processes. Recent tems also may represent a source of inhibitor diminished them (Roberts and data suggest that the reinforcing between-systems sensitization for Keith 1995). actions of AOD’s may involve a neu- AOD’s. The major excitatory neuro- ral circuit within the basal forebrain, transmitter in the brain is glutamate. termed the “extended amygdala” Administration of an antagonist of a PROTRACTED ABSTINENCE (Heimer and Alheid 1991). The ex- specific glutamate receptor subtype AND RELAPSE tended amygdala comprises several can block the development of sensiti- basal forebrain structures—for exam- zation to psychomotor stimulants, Perturbations in AOD reward pathways ple, the medial part of the nucleus suggesting a role for brain glutamate persisting after the acute withdrawal accumbens and the centromedial systems in sensitization (Wise 1988). phase may promote vulnerability to amygdala. The extensive connections relapse of drug-taking behavior. The of this system to and from brain scarcity of relevant animal models Counteradaptation regions that are critical in various limits the study of the neurobiology aspects of reinforcement support a Repeated AOD exposure also can lead of relapse. In one study, cocaine was role for the extended amygdala as the to adaptations in the reward circuitry withheld from animals trained to lever overall reward center of the brain. that oppose and neutralize a drug’s press for cocaine until the lever- The extended amygdala may regu- effects (i.e., counteradaptation). The pressing behavior was extinguished. late the acute reinforcing actions of persistence of these opposing effects The rats were then treated with drugs AOD’s as well as neuroadaptations after a drug has left the body may that activate the mesolimbic dopamine associated with addiction. Actions of produce the motivational withdrawal system and a rapid reinstatement of the drugs of abuse on components of response that possibly contributes to lever-pressing for cocaine was ob- the extended amygdala are described renewed drug use. As with sensitiza- served. (Stewart and deWit 1987). above. Additional evidence includes tion, both within- and between-system Acamprosate, a medication that may the observation that acute administra- adaptations appear to underlie counter- modify glutamate action, is being mar- tion of AOD’s produces increases in adaptation. Researchers have found keted in Europe to prevent relapse in extracellular levels of dopamine in the decreased levels of dopamine in the alcoholics. This drug has been shown to medial nucleus accumbens (Pontieri et nucleus accumbens during withdrawal block the increase in drinking observed al. 1995). Also, neurons in the medial from cocaine, opiates, and alcohol (Di in rodents after forced abstinence nucleus accumbens contain high levels (Spanagel et al. 1996; Heyser et al. in Chiara and North 1992; Rossetti et al. of dopamine D1 and D3 receptor sub- 1992; Weiss et al. 1993); these results press ). Similarly, opioid antagonists types. Furthermore, the central nucleus are opposite to those produced by can prevent animals’ increased alcohol of the amygdala appears to be impor- acute exposure to these drugs. In addi- consumption caused by exposure to tant in acute alcohol reinforcement, as tion, GABA transmission decreases stress and have shown some success in microinjection of GABA or opioid and glutamate transmission increases preventing relapse in detoxified human peptide antagonists into this brain during alcohol withdrawal, again re- alcoholics (O’Malley et al. 1992; region diminish lever pressing to ob- flecting the opposite effects of acute Volpicelli et al. 1992). Finally, a recent tain alcohol (Hyttia and Koob 1995). exposure (Koob et al. 1994). study has found that of a spe- Even more intriguing is the possibili- As is the case with sensitization, the cific dopamine receptor subtype (i.e., ty of a role for the extended amygdala in brain CRF systems and HPA axis may the D1 receptor) can prevent “relapse” counteradaptive processes associated represent a between-systems source of in abstinent rats previously trained to with chronic drug exposure. A recent counteradaptation. Rats exhibit a stress- press a lever to obtain cocaine (Self et observation showed that microinjections like response when repeated administra- al. 1996). Although these studies sug- of a GABA into the central tion of cocaine, opiates, or alcohol is gest a role for dopamine, opioid, and nucleus of the amygdala in alcohol- terminated. In addition, alcohol-with- glutamate systems in protracted absti- dependent rats decreased alcohol self- drawalÐinduced increases in anxietylike nence and relapse, additional research administration, whereas this treatment responses in rats were reversed by mi- using animal models is needed to pro- had no effect in non-alcoholÐdependent croinjection of a CRF antagonist into vide a better understanding of the neu- animals (Roberts et al. 1996). These the central nucleus of the amygdala robiological mechanisms underlying results suggest that the GABA system is (Koob et al. 1994), and alcohol with- the role of these systems in addiction. altered significantly during the course of

VOL. 21, NO. 2, 1997 105 dependence. In addition, the interaction KOOB, G.F. Dopamine, addiction and reward. ROBERTS, A.J., AND KEITH, L.D. Corticosteroids of CRF systems with alcohol withdraw- Seminars in 4:139Ð148, 1992. enhance convulsion susceptibility via central mineralocorticoid receptors. Psychoneuro- al appears to involve the central nucleus KOOB, G.F., AND BLOOM, F.E. Cellular and of the amygdala (Koob et al. 1994). molecular mechanisms of drug dependence. endocrinology 20:891Ð902, 1995. Science 242:715Ð723, 1988. Thus, the extended amygdala may be ROBERTS, A.J.; LESSOV, C.N.; AND PHILLIPS, T.J. involved in both acute AOD actions and KOOB, G.F., AND NESTLER, E.J. Neurobiology of Critical role for glucocorticoid receptors in various motivational aspects of addic- drug addiction. Journal of and stress- and ethanol-induced locomotor sensi- tion (Koob and Bloom 1988). Clinical , in press. tization. Journal of and Experi- mental Therapeutics 275:790Ð797, 1995. 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Biological A focus is developing on a brain re- Psychiatry 36:326Ð337, 1994a. phine, cocaine and amphetamine abstinence in ward circuit that links the mesolimbic rats. European Journal of Pharmacology 221: dopamine system and amygdala and LEMARQUAND, D.; PIHL, R.; AND BENKELFAT, C. 227Ð234, 1992. Serotonin and alcohol intake, abuse, and on the neuroadaptive changes in neu- dependence: Findings of animal studies. SELF, D.W.; BARNHART, W.J.; LEHMAN, D.A.; rotransmission that occur with chronic Biological Psychiatry 36:395Ð421, 1994b. AND NESTLER, E.J. Opposite modulation of drug administration. Researchers also cocaine-seeking behavior by D1- and D2-like are investigating the genetic and envi- MCMILLEN, B.A.; JONES, E.A.; HILL, L.J.; dopamine receptor agonists. Science 271: WILLIAMS, H.L.; BJÖRK, A.; AND MYERS, R.D. 1586Ð1589, 1996. ronmental factors that may act on this Amperozide, a 5-HT2 antagonist, attenuates circuit to influence individual differ- craving for cocaine by rats. 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