PHARMACOTHERAPIES OF COCAINE ADDICTION IN RATS

Research Triangle Institute, Durham NC

Investigators

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Abstract

Project 3 is one in the series of well-coordinated studies representing multiple disciplines aimed at evaluating potential pharmacotherapies for cocaine addiction and written in response to SPIRCAP RNA DA 00-001. This series of studies will examine novel 3-phenyltropane analogs of cocaine developed by the Principal Investigator, Dr. F. Ivy Carroll. These compounds posses properties suggestive of pharmacotherapeutic value; they bind potently and selectively to the dopamine transporter, a well- recognized site involved in the behavioral effects of cocaine, and have a slow-onset and long-duration of action, attributes believed to be necessary for effective medications for cocaine addiction. Project 3 will examine the effects of a set of these compounds on intravenous cocaine self- administration in rats and provide information for the primate self- administration studies (Project 4). Our laboratory is experienced in this procedure and is currently running such studies. The first aim of Project 3 is to evaluate six compounds (two doses each) selected for their ability to generalize to the cocaine discriminative cue with minimal disruption of response rates (results obtained from Project 2). We will examine whether these compounds alter maintenance of cocaine self-administration. Results will lead to selection of four compounds to be tested in Project 4. Compounds selected would provide a downward shift in the cocaine dose response function as this is the best indicator of an effective pharmacotherapeutic agent for cocaine addiction based on self- administration data obtained in animals. The second aim of Project 3 is to examine two compounds for their effects on cocaine-induced reinstatement of responding after extinction of lever-press responding for cocaine. This procedure, a well-establishment model of "relapse", is set- up and running in our laboratory. The specific outcomes of aim 2 of Project 3 are to determine whether the compound block-induced reinstatement or cause reinstatement. Data obtained from this aim will be used, in conjunction with results from Projects 2 and 4, to inform the decision to proceed with studies in humans. (Projects 5 and 6).