Phencyclidine abuse has persisted at a constant rate throughout the 1980s. There is increased public concern for the practice of smoking PCP with cocaine base (space base). There is increased scientific interest in PCP as an NMDA receptor antagonist. PCP-like drugs may prevent damage to the cerebral cortex resulting from stroke, cardiac arrest, asphyxia and brain injury. Progress on this grant has focused on developing a behavioral profile of PCP in monkeys. The models of PCP self-administration have extended the PCP self-administration research to other drugs and other routes of administration (i.e., cocaine smoking). There are two overall goals of this competing renewal application. The first is to devise strategies for preventing and reducing drug self-administration and the aversive effects of withdrawal. Environmental strategies (arranging contingencies of other rewarding events in the environment and applying a behavioral economic analysis) and pharmacological strategies (pretreatment with drugs that have shown to be promising candidates for the clinical management of drug abuse) will be tested for their effects on PCP self- administration and withdrawal. The second is to expand the oral PCP model to new areas of research, such as development of an animal model of relapse and the application of behavioral economics to drug abuse. The PCP model will also be extended to other drugs and routes of administration. There are four specific aims. The first two are extensions of current work and the last two represent new directions.
The first aim i s to examine environmental and pharmacological methods for reducing self-administration of orally-delivered PCP. A behavioral economic analysis will compare FR size (price) of PCP and an alternative reinforcer to consumption of these substances, and cross-price elasticity coefficients will be obtained as a quantitative index of change in demand for drug due to price and the availability of the alternative substance. Behavioral history with an alternative reinforcer will also be evaluated. Pharmacological methods will include injections of buprenorphine and antidepressants (fluoxetine, sertraline) before self-administration sessions.
The second aim i s to test environmental and pharmacological strategies for reducing behavioral disruptions resulting from PCP withdrawal. The behavioral economics of presenting a nondrug alternative reinforcer during PCP withdrawal as well as a history of exposure to that substance will be investigated. Pharmacological treatments to be tested are buprenorphine, sertraline or fluoxetine. The sensitive behavioral dependence model developed with PCP will also be used to study withdrawal effects from self-administration of buprenorphine and MK-801 (a potent NMDA antagonist).
The third aim i s to develop a model of relapse and investigate environmental and pharmacological factors that initiate and suppress relapse. Environmental factors will be the presence and absence of alternative reinforcers such a food and preferred liquids. Pharmacological factors will be other drugs of abuse (e.g., opiates, ethanol) and pharmacotherapeutic drugs (e.g., buprenorphine).
The fourth aim i s to extend the oral self-administration of PCP to other drugs and routes of administration. Buprenorphine and a related NMDA antagonist, MK-801 will be smoking. Heart rate, blood pressure and activity (by telemetry) will be continuously monitored during PCP self-administration, withdrawal, relapse, and reinitiation of drug- taking behavior. The effects of environmental and pharmacological interventions on these measures will be analyzed. The significance of comparing a range of environmental and pharmacological interventions across critical phases of the addition process, is that it will provide important information on the most effective intervention strategy for a specific behavioral event (e.g., maintenance, withdrawal and relapse). The health related consequence of this research is that it will provide animal models of prevention and reduction of drug abuse.
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