PERSISTENT COCAINE-INDUCED CHANGES IN DOPAMINE RELEASE

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This is a request for an ADAMHA RSDA (Level II). The proposed experiments will investigate whether enhanced dopamine (DA) overflow and D-1 DA receptor function contribute to the behavioral sensitization observed following repeated cocaine administration. Specifically, we hypothesize that following withdrawal from repeated cocaine administration, evoked DA overflow from nerve terminals will be increased only when a cocaine challenge is given but that the functionality of terminal release- modulating autoreceptors and postsynaptic D-1 DA receptors will be greater whether or not a cocaine challenge is given. In vivo voltammetry in anesthetized rats and in vitro slice preparations will be used to investigate the DA transporter and evoked DA overflow following withdrawal from repeated cocaine administration. Results in the nucleus accumbens (NAc) and striatum will be compared. Local challenge with DA or cocaine and systemic challenge with cocaine will be utilized. The results will indicate (1) whether cocaine challenge is required to increase evoked DA overflow, (2) whether the change in overflow is observed when the stimulus is restricted to the terminal or whether it is dependent on the cell body and/or impulse flow and (3) whether changes in vesicular release and/or the DA transporter are involved. In vitro binding and second messenger assays will be used to investigate changes in agonist interactions with D-1 and D- 2 DA receptor subtypes in these same brain regions. To test further the relationship of the observed neurochemical changes with behavioral sensitization, the time course and dose-dependency of the neurochemical and behavioral changes will be compared. Pretreatment with SCH-23390, a D-1 DA receptor antagonist, or with MK-801, an N-methyl-D-aspartate receptor antagonist, both of which have been reported to block stimulant-induced behavioral sensitization, will also be used to test the relationship between the neurochemical and behavioral observations. The results of these studies will enhance our understanding of persistent changes in DA neurochemistry and regulation of the mesolimbic and nigrostriatal DA systems that occur as a result of repeated cocaine administration. It is our hope that understanding these changes will enhance our ability to predict the long-term consequences of low-level, intermittent use of cocaine on central DA systems. The importance of this RSDA to my professional growth will be (1) the opportunity to focus on this cocaine research project, (2) the opportunity to learn new techniques in other scientists' labs that will enhance the scope of the proposed research and (3) the opportunity to interact with experts in this field in order to extend the breadth of my own research into new areas. The four major areas that would be assimilated into my cocaine research program as a direct consequence of an RSDA include in vivo electrochemical recording in behaving rats, serotonin systems, molecular biological approaches and pharmacogenetics.