This proposal requests funds to extend preliminary work on the development of new reliable microdialysis and analytical methods for the recovery and detection of neuropeptides in freely-moving rats during cocaine withdrawal. The work in this proposal will focus on two neuropeptides of high-molecular weight: corticotropin-releasing factor (CRF) and neuropeptide Y (NPY). These neuroactive peptides are involved in physiological, emotional, and behavioral responses to stress and are present in high concentrations in limbic brain regions that are also densely innervated by ascending dopaminergic neurons, and that have been previously implicated in psychostimulant reinforcement, dependence, and withdrawal. Thus, their functional role as well as their localization suggests that these neuropeptides may independently, or by interaction with dopaminergic neurotransmission, contribute to the cocaine withdrawal syndrome. To test this hypothesis, CRF and NPY levels will be monitored in the centrolmedial amygdala, bed nucleus of the stria terminalis, and shell of the nucleus accumbens (i.e., the """"""""extended amygdala"""""""") of freely moving rats during withdrawal from cocaine after unlimited-access intravenous cocaine self-administration. To accomplish these goals, we will initially refine recently developed original microdialysis and radioimmunochemical methods with which detectable basal and stimulated release of CRF was obtained in the mediobasal hypothalamus of awake rats. These procedures will then be extended to NPY with careful and extensive in vitro and in vivo validation. These experiments will provide important insights about the role of stress-related limbic neuropeptides in the behavioral and neurochemical effects of cocaine withdrawal.
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