Neurochemistry of Cocaine Reinforcement

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DESCRIPTION (provided by applicant): Cocaine has been reported to have stimulant, reinforcing and addictive properties, among others. A consensus exists that mesocorticolimbic dopamine is involved in cocaine self-administration in rats and there are studies suggesting that corticosterone may be involved in cocaine reinforcement. Several studies have demonstrated that the context of cocaine delivery can alter the behavioral and neurochemical responses to the drug, emphasizing the importance of using appropriate behavioral models when assessing neural mechanisms of reinforcement. The hypothesis to be tested in this application is that drug-seeking behavior associated with cocaine self-administration triggers a sequence of events involving the interaction of dopaminergic systems in the brain with the hypothalamo-pituitary-adrenal (HPA) axis, which depends on the context of drug presentation, i.e., whether the drug is actively administered or infused passively. To test this hypothesis, it will be necessary to successfully combine the complex behavioral experiment (self-administration and yoked infusions) with the complex neurochemical procedure, in vivo microdialysis from different brain areas thought to be involved in the mediation of cocaine-seeking behavior. First, in vivo microdialysis coupled with high performance liquid chromatography (HPLC) will be used to determine the concentrations of dopamine and corticosterone in the microdialysates collected from the medial prefrontal cortex of rats in response to several doses of cocaine. In the second experiment, a limited dose response will be performed using in vivo microdialysis with the HPLC analysis of dopamine and radioimmunoassay of corticosterone in the microdialysis samples collected from the central nucleus of the amygdala. The results of this study will determine the role of mesolimbic and mesocortical dopaminergic projections in drug addiction, demonstrating whether or not the neurochemical response to self-administered cocaine is different from that observed after the passive infusions of cocaine. Using the combination of microdialysis with the yoked-triad model will allow us to distinguish the activating effect of cocaine on the HPA axis from the activation of the HPA axis related to drug-seeking behavior (i.e., self-administration vs. passively infused cocaine). Thus, the results of these experiments will demonstrate how control over drug delivery can affect the influence of a hormonal input on the functional characteristics of specific anatomical projections of the neural system. These results will also provide evidence of the role that is played by steroid hormones in shaping the functional activity of the brain.