The repeated administration of amphetamine (AMPH) results in a progressive alteration in its behavioral response profile, and the mechanisms underlying these changes may have important implications for drug abuse. The limited success in identifying these mechanisms may be attributable to an incomplete understanding of how stimulant effects on CNS neurotransmitter functions relate to specific components of the behavioral response. Since the effects of stimulants are multiphasic and dynamic, continuous in vivo measures of synaptic neurotransmitter dynamics in freely-moving animals during the drug response may provide a more accurate perspective of neurotransmitter-behavior relationships than has been possiblle with post-mortem techniques. In fact, accumulating data indicate the feasibility and utility of this approach for the study of neurotransmitter dynamics in response to stimulants. One prominent feature of the behavioral response as a function of AMPH dose, chronicity, and individual variation in responsivity is the transition from locomotion to stereotypy. This proposal is aimed at testing our hypotheses that this transition is associated with (1) qualitative changes in striatal dopamine (DA) dynamics, which involve a switch from neuronal impulse-dependent to impulse- independent DA release; (2) an activation of dorsal raphe serotonin (5HT) projections to striatum; and (3) changes in the relative activity of mesostriatal and mesolimbic DA pathways. A complete characterization of the effects of acute AMPH on striatal DA, 5HT and acetylcholine will provide the basis for subsequent experiments designed to assess the hypothesized role of various systems and mechanisms in the behavioral transition. A variety of manipulations will be used to examine the contribution of DA neuronal impulse flow, and to test, in vivo, the validity of the exchange-diffusion model of AMPH-induced DA release. Both in vivo and vitro measures of receptor function will be used to assess the relationship of 5HT and DA receptor activation to components of the behavioral response. Concurrent dialysis of the striatum and nucleus accumbens are aimed at determining if the relative activation of mesostriatal and mesolimbic DA systems contribute to the emergence of stereotypy. The direct evaluation of synaptic neurotransmitter dynamics concomitant with behavioral analysis, and in conjunction with determinants of receptor activation, will provide a fundamental evaluation of stimulant-neurotransmitter interactions, and the basis for subsequent determination of the mechanisms underlying chronic stimulant-induced behavioral change.
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