This proposal is designed to establish a reliable animal model of cocaine dependence for the evaluation of the therapeutic efficacy of potential treatment drugs. The animal model will permit assessment of treatment drug effects on separate aspects of cocaine dependence, including the rewarding value of cocaine, craving, and propensity to relapse. Initially, behavioral parameters of responding for cocaine under different reinforcement contingencies will be established using progressive ratio, concurrent, and multiple schedules . Repeated extinction and spontaneous recovery tests in the presence or absence of environmental cues associated with cocaine availability will provide information about the persistence of cocaine-seeking behavior. The characteristic patterns of responding observed in these behavioral tests will serve as measures of (1) reward magnitude, operationally defined as the """"""""breaking point"""""""" for responding for cocaine on a progressive ratio schedule, (2) degree of preference for cocaine in a drugs vs. food choice situation, (3) craving, operationally defined as the magnitude and duration of extinction responding on a non-reinforced multiple schedule component, and (4) propensity to relapse, operationally defined as the facilitation of spontaneous recovery after introduction of a conditioned stimulus. The behavioral parameters serve as reference points against which the effects of potential treatment drugs will be evaluated. Initial compounds to be tested include agents that act on monoamine and opioid neurotransmission. As other agents become available, subsequent compounds will include neuropeptide analogues and drugs that act on non-monoaminergic systems. These studies have important clinical implications with regard to new drugs that may be effective in treating or preventing cocaine abuse and dependence, and may aid in determining which of the various neuropharmacological actions of cocaine are involved in different components of cocaine dependence.
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