Drug addiction: A model for the molecular basis of neural plasticity

Although some aspects of drug addiction can occur relatively rapidly in response to acute administration of a drug of abuse, most changes in brain function associated with addiction occur gradually over time in response to prolonged drug exposure. These gradually developing changes can persist for a long time after cessation of chronic drug administration. Such adaptive changes are described by the terms tolerance, sensitization, dependence, and withdrawal. Tolerance represents a reduced effect upon repeated exposure to a constant drug dose, or the need for an increased dose to maintain the same effect. Sensitization, or “reverse-tolerance,” describes the opposite situation, in which a constant drug dose elicits increasing effects. Dependence is defined as the need for continued drug exposure to avoid a withdrawal syndrome, characterized by physical or psychological disturbances, when the drug is withdrawn. The traditional distinction between physical and psychological dependence is artificial, because both are mediated by the brain, possibly even by similar neural mechanisms, as will be seen below. Addiction can be defined as the accumulated effects of tolerance, sensitization, and dependence. However, the most useful clinical definition of addiction is the compulsive use of a drug despite adverse consequences, which is presumably due to certain adaptive changes that arise in specific brain areas. The prominence of delayed, progressively develop ing, and persistent adaptations in brain function during drug addiction suggests that long-term changes in the brain are important in mediating addictive phenomena. Drug addiction can thus be viewed as druginduced neural plasticity and as such can serve as a model system to investigate the types of neurobiological mechanisms involved in plasticity. Drug addiction can also serve as a model system to establish the biological basis of a complex and clinically relevant behavioral abnormality. This is because prominent features of drug addiction can be reproduced accurately in laboratory animals, enabling detailed investigations of the molecular and cellular mechanisms underlying addictive phenomena. An improved understanding of the molecular neurobiology of drug addiction must include two types of information: mechanisms of pathophysiology-identification of the changes that drugs of abuse produce in the brain that lead to addiction, and mechanisms of individual risk-identification of specific genetic and environmental factors that predispose certain individuals to addiction. In this review, weoutline an experimental approach bywhich the neurobiological mechanisms underlying the neural plasticity responsible for drug addiction can be investigated. This approach focuses on two anatomically well-defined brain regions known from behavioral and pharmacological studies to mediate aspects of drug addiction: the locus ceruleus, which plays an important role in physical opiate dependence and withdrawal (Aghajanian, 1978; Redmond and Krystal, 1984; Koob et al., 1992; Nestler, 1992), and the mesolimbic dopamine system, which plays an important role in psychological dependence to opiates and many other drugs of abuse (Bozarth, 1989; Wise, 1990; Kuhar et al., 1991; Fibiger et al., 1992; Koob, 1992; Dworkin and Smith, 1993). These brain regions have served as useful models for biochemical studies of drug addiction, based on their prior electrophysiological and behavioral characterizatian. The approach we outline here has three aims: to identify molecular and cellular adaptations that are induced in these regions by drugs of abuse; to relate the altered biochemical phenotype of cells in those regions to the altered electrophysiological phenotype of the cells and to the altered behavioral phenotype of the organism; and to elaborate the detailed molecular mechanisms by which the drugs produce the altered biochemical and electrophysiological phenotypes. Information concerning the molecular basis of drug action can then be used to identify genetic and environmental factors that determine individual differences in responsiveness to the drugs, including predilection for drug addiction.