This proposal is to examine the dependence produced by chronic cocaine administration using a rat model of behavioral dependence. The significant increases in cocaine abuse over the past decade is reflected in the increased numbers of individuals seeking help with cocaine related medical and behavioral problems. These increases have, in turn, served to emphasize the paucity of data concerning cocaine abuse and dependence and potential treatment approaches. The scientific and lay community alike have come to recognize the powerful dependence liability of the drug, however there is much to be learned concerning the dependence which occurs to cocaine. This proposal includes the development of a rodent model of dependence using operant behavior to quantify the effects of drug administration and drug withdrawal. Such a model will allow the manipulation of a number of variables which may be involved in cocaine dependence. Complete characterization of cocaine dependence will include determining, the nature of the abstinence syndrome, and the relationship of dose and duration of drug administration on the severity of withdrawal. The effects of various pharmacological interventions during cocaine dependence and withdrawal will be studied to determine cross-tolerance with other compounds and potential therapeutic interventions. Additionally, basic neuropharmacological manipulations involving the use of selective agonists and antagonists will be used to determine the relative contributions of the dopamine, norepinephrine, and serotonin systems in cocaine dependence. The research in this proposal will also assess the environmental contributions such as the schedule of reinforcement, type of contingencies and degree of stimulus control to the development of tolerance and dependence on cocaine. The effects of cocaine delivered as discrete bolus injections will be compared to the effects of the drug delivered as a slow, continuous infusion. The research outlined in this proposed project will provide a) a rodent model for assessing drug abstinence, even in the absence of observable effects, b) important information which will help us understand the nature of cocaine tolerance and dependence and c) information on neurochemical systems which may mediate tolerance and dependence, suggesting potential psychotherapeutic approaches to treatment of cocaine abstinence and dependence.
