This proposal is a continuation and extension of work begun during the previous funding period which was aimed at the development of valid behavioral tests modeling cocaine-seeking behaviors for the evaluation of the therapeutic efficacy of potential treatment drugs for cocaine dependence. These animals models were designed to permit assessment of treatment drug effects on cocaine reward magnitude, strength of cocaine- seeking behaviors (""""""""craving""""""""), and the """"""""propensity to relapse"""""""". Results indicate that reliable measures of these behaviors can be established using progressive ratio and multiple schedules of reinforcement combined with tests of extinction and recovery. The objective of this application is to extend the scope of the previous proposal in three important respects: First, using the using the behavioral models established during the administration will be compared to those exhibited by rats given extended access to cocaine. Second, while the behavioral models will continue to be applied to the testing of potential treatment drugs with diverse pharmacological profiles, treatment drug tests will focus on the evaluation of agents that directly or indirectly interact wit mesocorticolimbic dopaminergic (DA) neurotransmission, in particular DA, D1, D2, and D3, agonists and antagonists, serotonin 5-HT, 5-HT2, 5-HT3 agonists and antagonists, cholecystokinin CCKa and CCKb agonists and antagonists, as well as a competitive NMDA glutamate antagonist. Third, the propose studies will examine whether the behavioral manifestations of cocaine """"""""craving"""""""" are subserved by the same or different neuropharmacological substrates as the acute reinforcing effects of cocaine. To accomplish these goals, the relative efficacy and nature of the modification by neurotransmitter-specific and receptor subtype- selective pharmacological agents of individual cocaine-seeking behaviors in both the limited-and extended-access situations will be evaluated. Finally, the baseline behavioral performance and test drug effects of rats trained under limited cocaine access conditions will be compared to that of rats receiving repeated exposure to extended-access cocaine self- administration. These studies will provide important, presently unavailable, insights on the relationship between self-administration history and cocaine cocaine-seeking behaviors, as well as information about the neuropharmacological substrate(s) mediating specific cocaine- seeking behaviors. Finally, the work in this proposal has valuable clinical implications with regard to the therapeutic potential of specific drugs in treating or preventing cocaine abuse and dependence.
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