ronmental factors shape that genetic potential. That is, environmental exposures (e.g., a drug or stress) alter the brain in different ways depending on the genetic template of the brain. Particularly powerful environmental exposures (e.g., high levels of a drug of abuse) may lead to the same types of changes in the brain despite genetic differences (Nestler, 1992). Together, genetic and environmental factors combine to set an individual's responses to drugs of abuse. Identification of the specific genetic and environmental factors that influence the actions of drugs of abuse in animal models can provide insight into the types of genetic factors that contribute to an individual vulnerability for drug dependence in humans (Hilbert et al., 1991).

Neural Substrates of Drug Abuse

Neural Substrates of Reinforcement

A multineurotransmitter system called the medial forebrain bundle, which courses from the ventral midbrain to the basal forebrain, has long been associated with reinforcement and reward (Olds and Milner, 1954; Olds, 1962; Stein, 1968; Wise, 1989). Electrical stimulation through electrodes implanted along this bundle is considered to be pleasurable or rewarding because animals will perform certain tasks repeatedly (e.g., pressing a bar) to trigger the stimulation (self-stimulation). Thresholds for that intracranial self-stimulation are lowered by drugs of abuse, suggesting that they ''sensitize" the brain reward system. Recent advances exploring the neurobiological basis for the positive reinforcing effects of drugs of abuse have focused on specific neurochemical systems that make up the medial forebrain bundle reward system.

Psychomotor stimulants, such as cocaine and amphetamine, appear to depend on an increase in the synaptic release of dopamine in the mesolimbic dopamine system (Koob, 1992b). This system has its cell bodies of origin in the ventral tegmental area and projects to the nucleus accumbens, olfactory tubercle, frontal cortex, and amygdala. Cocaine is thought to act mainly to block reuptake of dopamine by binding to a specific protein, the dopamine transporter protein, involved in reuptake; amphetamines both enhance dopamine release and block its reuptake. Three of the five cloned dopamine receptor subtypes have been implicated in the reinforcing actions of cocaine (Woolverton, 1986; Koob, 1992b; Caine and Koob, 1993).

Opiate drugs bind to opioid receptors to produce their reinforcing effects.2 The mu receptor appears to be most important for the reinforc-


Three known receptor subtypes have been cloned: mu, delta, and kappa.

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