The primary thesis of this research proposal is that the central nervous system alterations that underlie drug taking behaviors involve long-term adaptive phenomena, both within-systems adaptations and between-systems adaptations. Thus, an analysis of drug effects that includes but also extends beyond the primary action of the drug will be fruitful in furthering our understanding of the cellular aspects of drug abuse. Within this framework, we propose a thorough analysis of the effects of amphetamine, a highly abused psychomotor stimulant, upon the neurochemistry of a circuit that includes basal ganglia and associated thalamocortical structures. This circuit potentially is capable of strong influence over psychomotor behaviors. Since the primary action of amphetamine in brain is the release of the neurotransmitter dopamine, the hypothesized within-systems adaptations in this circuit would involve dopamine neurons directly whereas between-systems adaptations would extend to the neurochemical circuits in which dopamine operates. The present experiments make use of the technique of in vivo microdialysis to monitor, in behaving rats, the extracellular concentration of the neurotransmitters dopamine and acetylcholine at several points in this circuit First, we propose to document the impact of amphetamine upon striatal dopamine/acetylcholine dynamics. We will extend our analysis to include the effects of amphetamine on the release of extra-striatal dopamine in substantia nigra pars reticulata and in medial prefrontal cortex. It is hypothesized that amphetamine-induced alterations in dopamine release in these latter structures may influence striatal neurochemistry indirectly by affecting the activity of the corticostriatal glutamatergic pathway. Finally, we will incorporate these findings into an analysis of neurochemical adaptations in basal ganglia circuitry in response to repeated amphetamine administration. The results will provide basic information regarding neurochemical interactions in the basal ganglia and also will reveal how these interactions are altered by amphetamine abuse. Such an understanding surely will provide insight into novel strategies for intervention in the pharmacological treatment of drug abuse.
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