NOVEL METHODS TO EXPLORE MECHANISMS OF COCAINE ABUSE

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This proposal was generated in response to RFA DA-93-01 and is designed to establish in vivo neurochemical and electrophysiological correlates of cocaine-seeking behaviors that can then be used to design potential novel treatment drugs for cocaine dependence. These animal models are designed to permit assessment of the neurochemical and physiological basis of cocaine reward magnitude, strength of cocaine-seeking behaviors ("craving"), and the "propensity to relapse" in limited access and the dependent state. Behavioral parameters of various cocaine-seeking behaviors will be established in rats with different histories of cocaine preexposure. Specifically, cocaine-seeking behaviors of rats with a history of daily limited-access cocaine self-administration will be compared to those exhibited by rats given extended access to cocaine. The proposed 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, behavioral parameters of responding for cocaine under different reinforcement contingencies will be established in rats after episodes of extended-access cocaine self- administration using progressive ratio, and multiple schedules. Repeated extinction and spontaneous recovery tests in the presence and absence of environmental cues associated with cocaine availability will provide information about the persistence of cocaine-seeking behaviors. Neurochemical correlates of these behavioral measures will be established using intracranial microdialysis for dopamine and serotonin in various forebrain sites. Neurophysiological correlates of these behavioral methods will be measured using extracellular recording techniques in freely-moving rats at various forebrain sites. Novel pharmacological therapies will be developed by determining effective pharmacological means of reversing the neurochemical (in vivo microdialysis) and electrophysiological (extracellular recording) changes associated with these various components of cocaine-seeking behavior in both limited-access and dependent animals. Treatments effective in modifying these neuropharmacological events will then be tested in the behavioral paradigms for potential pharmacotherapeutic action. These studies will provide important, presently unavailable insights into the neuropharmacological substrate(s) mediating specific cocaine-seeking behaviors as well as information about the relationship between self-administration history and cocaine-seeking behaviors. Finally, the work in this proposal will provide a novel means for the development of specific and novel drugs with therapeutic potential for treating or preventing cocaine abuse and dependence.