BEHAVIORAL PHARMACOLOGY OF ACUTE AND CHRONIC AMPHETAMINE

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Thorough behavioral characterization of the acute and chronic amphetamine profiles in experimental animals is a necessary prerequisite for elucidating the psychological and neurobiological processes implicated in amphetamine abuse liability and those affected by various patterns of usage in humans. Several experimental approaches may facilitate the identification of specific behaviors that are clinically relevant. In addition to the use of dosage regimens which simulate various abuse patterns, comparisons of psychomotor stimulants that produce effects in humans similar to amphetamine (e.g., cocaine) with those that do not (e.g., caffeine) may also provide useful behavioral and neuro- chemical information. Another approach involves the identification of behavioral dimensions that transcend species- specific responses. Two such dimensions that are apparent in virtually all animals given amphetamine-like stimulants are the perseverative quality of the response and the corresponding decreases in environmental interaction. Some evidence suggests that mesostriatal dopamine and serotonin systems may play a role in perseveration whereas the degree of environmental engagement may be regulated by a balance in the activities of the dorsal noradrenergic system and the mesolimbic serotonergic system. Studies with selective monoamine lesions are designed to test these hypotheses. Converging evidence indicates that the appearance of specific components of the behavioral response to stimulants are intimately related to the experimental conditions, exhibit strict temporal patterns, and vary dramatically between animals. However, most biochemical studies have used pharmacologically, but not necessarily behaviorally relevant experimental conditions and time points, and have ignored individual differences in response. More relevant biochemical data would be obtained in studies of individual animals whose behavioral profiles have been assessed. In addition, because of the limitations associated with post-mortem biochemical analyses, studies are also planned using push-pull perfusion techniques to measure synaptic transmitter levels in freely moving animals. This approach provides a continuous measure of neurotransmitter dynamics throughout the behavioral time course, and allows each animals to serve as its own control. Our ongoing and proposed studies represent a multidisciplinary approach aimed at characterizing the spectrum of stimulant effects produced by the range of dosage regimens associated with various patterns of stimulant abuse.