These studies propose to isolate differences in the metabolism of a major drug of abuse, cocaine, using two distinct but genetically related rat strains, the spontaneously hypertensive rat (SHR) and it normotensive control, the Wistar-Kyoto rat (WKY). Relationships between conversion of cocaine to norcocaine and differences between SHR and WKY in pharmacodynamic and toxic responses to administrations of cocaine and norcocaine will be determined. Experimental observations will focus on the relative effects of cocaine and norcocaine on neurological and cardiovascular responses that are mediated by dopaminergic neurons. This emphasis is prompted by evidence that pharmacological sequelae to cocaine ingestion involve actions on dopaminergic neurons. In addition, major differences between SHR and WKY in dopaminergic function are known. Neurological, cardiovascular and toxic effects of acute and subacute administration of cocaine and norcocaine will be observed and correlated with the degree of bioconversion of cocaine to norcocaine in the two strains, by determination of brain and liver N-demethylase activities and levels of cocaine and norcocaine. Concentrations of dopamine (DA) and DA-metabolites, activities of tyrosine hydroxylase and monoamine oxidase and the characteristics of DA and cocaine receptors from isolated membrane preparations will be determined in specified brain regions. Finally, intracerebroventricular injections of DA or DA receptor antagonists will be used to assess, in vivo, specific contributions of dopaminergic neuronal systems to the behavior, cardiovascular and toxic actions of cocaine and norcocaine. The results will significantly extend knowledge of mechanisms underlying individual differences in the mechanism of action of and toxic responses to cocaine.
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