BEHAVIORAL PHARMACOLOGY OF ACUTE AND CHRONIC AMPHETAMINE

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A recent survey by NIDA indicates a significant increase in stimulant abuse. This evidence underscores the importance of characterizing in animals the behavioral profiles and corresponding neurochemical system(s) and mechanism(s) associated with different patterns of stimulant abuse. The primary objective of the proposed research is to extend previous work on the various behavioral and neurochemical effects induced by different doses and durations of exposure to amphetamine-like stimulants in rats. Assessments of the behavioral effects induced by single and repeated administration of low to moderate stimulant doses will be extended using our enhanced automated and observational monitoring systems to provide more accurate and thorough characterizations of the stimulant response. In addition to locomotion and focused sterotypies, behavioral measures are now available to evaluate our hypothesis that response perseveration and engagement with the environment represent important behavioral dimensions of the stimulant response. Specific roles for NE, DA, and 5-HT systems in these behavioral dimensions are proposed and studies are designed to test these hypotheses. In addition, a proposed neurochemical mechanism underlying the dose-related transition from stimulant-induced locomotor activation to focused stereotypies will also be assessed. Our previous studies revealed that different patterns and doses of repeated stimulant administration produce alterations in various components of the stimulant response in the form of behavioral augmentation, tolerance, and/or shortened response duration. These phenomena will be further investigated by examining age- and strain-related differences in response to repeated stimulant administration and by assessing the possible involvement of endogenous opioid and monoamine systems and mechanisms in the development of these effects. In addition, we will also examine "emergent" behavioral syndromes produced by high, acute stimulant doses or continuous intoxication regimens and associated with CNS neurotoxicity, particularly with respect to determining the relationship of these syndromes to patterns of stimulant abuse in humans. The proposed research will utilize a variety of behavioral, pharmacological, neurochemical, and electrophysiological techniques to characterize the behaviors and underlying mechanisms associated with different patterns of stimulant administration. These studies may provide important information regarding persistent effects resulting from chronic stimulant administration, interactions between stimulants and other drugs of abuse, and potential treatments for specific adverse effects in humans.