Neurobiology of Disease 7, 543–545 (2000) doi:10.1006/nbdi.2000.0351, available online at http://www.idealibrary.com on
Drug Addiction Adapted from a Presentation by George Koob The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Much of the most revealing research in drug addiction has been performed in rodent models. Researchers study the interaction of the drugs with transmitter messenger systems in specific brain regions. Drugs can interfere with the normal activation, storage, uptake, and release of these crucial systems.
Large portions of the general population will not only experience a form of mental illness during the course of their lifetime, but will also experience some form of addiction. Drug addiction is a chronic relapsing disorder characterized by compulsive uncontrollable use of a drug. Addiction occurs in three stages: the preoccupation and anticipation stage; the stage of “binge,” or intoxication stage; and the withdrawal negative affect stage. These stages of addiction also occur with legalized drugs like tobacco and alcohol. The greatest functional impairment occurs among chronic users of tobacco or among repeatedly binging or chronic users of alcohol. Of course, heroin addiction can also produce functional impairment, but the number of people estimated to have ever used heroin in the United States is 1.5 million, while alcohol users, for example, number 91.5 million (Table 1). Therefore, these drugs, being more accessible, negatively affect a far larger population. Drug addiction has been categorized as a brain disease, much like eating disorders or depression. The major dysfunction and deregulation associated with addictive disorders involve the brain’s natural reward system, a system presumably important for guiding homeostatic regulating behavior, e.g., seeking and obtaining food and shelter and reproducing. In other words, all drugs of addiction, when taken acutely or in a one-time high dosage, activate brain systems involved in processing natural rewards. When taken chronically or regularly over a period, they deregulate these reward systems. Neurochemical systems activated by drugs of addiction and responsible for the acute pleasurable effects of drugs include those activated by dopamine, opioid peptides (enkephalins and endorphins), serotonin (5-HT), and ␥-aminobutyric acid (GABA). Chronic administration of addictive drugs compromises the function of these reward transmitters but also recruits activation of brain stress systems such as corticotropin-releasing factor (CRF). Thus, the disorder actually becomes more acute over time with escalating drug use. 0969-9961/00 $35.00 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
NEUROBIOLOGICAL BASIS FOR ACUTE DRUG REINFORCEMENT A classic experiment using a rodent animal model exposed to cocaine or alcohol administration demonstrates the acute reinforcing effects of addictive drugs. In the experiment, the rat self-administers cocaine or ethanol by pressing a lever, and thereby injects the drug via an intravenous catheter. Dopamine release is measured by inserting a microdialysis probe into the nucleus accumbens. The probe has a very small semipermeable membrane at the tip, through which dopamine can pass, accumulate, and be measured. One of the major actions of cocaine is on monoamine transporter mechanisms to block the reuptake of dopamine in an area called the nucleus accumbens, part of the mesolimbic dopamine system. Following cocaine administration, more dopamine is allowed into the synapse, and the brain experiences amplified and extended effects of this neurotransmitter, resulting in an amplified pleasurable experience. In the case of ethanol administration, numerous transmitters including dopamine undergo changes in the nucleus accumbens and the amygdala (Table 2). The above experiment proves the obvious: people use drugs based on a pleasurable activation of the brain’s reward system. But how does this lead to addiction? How does this model change with chronic administration of drugs? Clearly, not all 91.5 million people who have used alcohol at least once in their lifetime become addicted. The major questions are where the vulnerability lies—why some people become addicted and others do not and how the brain
TABLE 1 Estimated Prevalence among 15- to 54-Year-Olds of Nonmedical Use and Dependence among Users (1990 –1992) (NCS)
Tobacco Alcohol Illicit drugs Cannabis Cocaine Stimulants Anxiolytics Analgesics Psychedelic drugs Heroin Inhalants
Prevalence of dependence
Dependence among users
75.6 91.5 51.0 46.3 16.2 15.3 12.7 9.7 10.6 1.5 6.8
24.1 14.1 7.5 4.2 2.7 1.7 1.2 0.7 0.5 0.4 0.3
31.9 15.4 14.7 9.1 16.7 11.2 9.2 7.5 4.9 23.1 3.7
Source. Anthony, J. C., Warner, L. A., & Kessler, R. C. (1994) Exp. Clin. Psychopharmacol. 2, 244 –268. FIG. 1. Extracellular dopamine and serotonin concentrations during cocaine self-administration and withdrawal.
changes with addiction. The answer is perhaps to be found in an area of the brain called the medial forebrain bundle, the site of action for this effect.
NEUROBIOLOGICAL BASIS FOR THE MOTIVATIONAL EFFECTS OF DRUG WITHDRAWAL Researchers believe that a catalyst for addiction may be attributable to events occurring in the reward areas of the brain during the withdrawal stage on removal of the drug after chronic use. Over a 12-h period of cocaine self-administration in rats, extracellular dopa-
TABLE 2 Neurobiological Substrates for the Acute Reinforcing Effects of Drugs of Abuse Drug of abuse Cocaine and amphetamines Opiates Nicotine
Neurotransmitter Dopamine Serotonin Dopamine Opioid peptides Dopamine Opioid peptides Dopamine Opioid peptides Dopamine Opioid peptides Serotonin GABA Glutamate
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mine and serotonin levels increased dramatically in the nucleus accumbens. When the rats were then prevented from self-administering the cocaine, the levels of those neurotransmitters plummeted below baseline (Fig. 1). Is this decrease in dopamine levels below control or baseline values enough to cause addiction? The dysphoria, or negative mood state, and anxiety-like disorders associated with withdrawal from drugs of abuse may be required to set the stage for future addiction. But more appears to be involved. During the aforementioned 12-h cocaine binge, extracellular levels of the major stress hormone CRF show little change in the amygdala of the rat brain (Fig. 2). However, when the withdrawal stage is induced, extracellular CRF increases in the amygdala substantially. It is
Site Nucleus accumbens Amygdala Ventral tegmental area Nucleus accumbens Ventral tegmental area Nucleus accumbens Amygdala Ventral tegmental area Ventral tegmental area Nucleus accumbens Amygdala FIG. 2. Extracellular CRF levels in the amygdala during cocaine self-administration (SA) and subsequent withdrawal.
speculated that this increase in CRF in the amygdala during withdrawal may contribute to the changes in mood during this period and to subsequent addiction.
CHRONIC RELAPSING DISORDER Clearly the stage is set for addiction, but the aforementioned research still does not indicate what brain changes lead to a chronic, relapsing disorder and where the vulnerability to relapse is mediated. Scientists have suggested that withdrawal and protracted abstinence and the changes in the brain that occur during this period lead to an escalation in compulsive use. Another experiment, once again using rats and selfadministration of cocaine, lends valuable insight into this theory of addiction. Two groups of rats were used: one was allowed only an hour of cocaine access per day; the other, 6 h a day. This experiment continued for 22 days. The group allowed only 1 h of cocaine per day never, throughout the entire period, increased their intake (Fig. 3). For that 1-h period, the rats selfadministered the same amount of cocaine every day. However, the binge group, who were given 6 h a day to self-administer, continued increasing the amount throughout the experiment (Fig. 3). A similar experiment using ethanol was done with two groups of rats. One group of rats was trained to administer 10% ethanol orally for 30 min per day over a period of 2 weeks. They were then deprived for 5 weeks. When allowed access once again, they showed what is called the “alcohol deprivation effect.” Initially, they increased their alcohol intake, as if they were making up for lost time. Yet they then returned to their baseline level. The other group of rats was placed into ethanol vapor chambers for 2 weeks, to hold their blood alcohol levels at 200 mg%. Thus, in contrast to the initial group, this group was given a history of ethanol dependence. When taken off the
FIG. 4. A prior history of chronic ethanol exposure enhances the alcohol deprivation effect in rats.
ethanol for 5 weeks and allowed during this time to self-administer, they increased their ethanol intake dramatically. Thus it appears that prior history of continuous alcohol intake to the point of dependence enhanced alcohol self-administration, thereby setting the stage for binge drinking (Fig. 4). What does this mean? It is speculated that this effect can be attributed to a theory called “allostasis” that is derived from the concept of homeostasis. This theory states that an organism must vary all the parameters governing its internal milieu and match them appropriately for the anticipated demands to maintain the stability of its physiological balance. Simply put, a subject suffering from drug addiction may attempt to maintain an apparent stability of its reward function at a new pathological “set point.” Allostasis has been hypothesized to occur also in eating and anxiety disorders. Any small challenge to an allostatic state may lead to a major regulatory breakdown. Scientists argue that this “set point” reflects the kind of pathological neuroadaptation that leaves the organism in a very fragile state. Until all of these systems, which have become disrupted from the molecular level and lead to compulsive behavior, can reequilibrate, homeostasis cannot be reinstated. Once again, drug addiction is a brain disorder. It involves enormous changes in how the central nervous system organizes itself at many different levels of analysis. The future challenge for neuroscientists in this field will be relating the changes in molecules to the changes in clinical condition and determining how they can reverse the changes that have occurred in chronic administration.
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