The Neurobiology of Addiction 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 drugs 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 drug’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; neurotransmitters; neurotransmission; AOD sensitivity; biological adaptation; brain; dopamine; nucleus accumbens; 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 Psychopharmacology, 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 Psychology and continued drug-seeking behavior by Finally, the article discusses the Psychiatry, 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