The proposed research will utilize a nonhuman primate model to characterize the effectiveness of selective dopa-mine transporter (DAT) inhibitors to reduce cocaine use. A second-order schedule of I.V. drug self-administration in rhesus monkeys will characterize changes in drug-maintained behavior following pretreatment with DAT inhibitors (Specific Aim 1). In addition, DAT inhibitors will be substituted for cocaine to assess their abuse liability. Positron emission tomography (PET) neuroimaging techniques will quantify DAT occupancy following drug pretreatments shown to be effective in reducing cocaine use (Specific Aim 2). It is hypothesized that DAT occupancy will be a direct function of drug dose, and that a minimum threshold of DAT occupancy will be required for effectiveness in reducing cocaine use. In vivo microdialysis will quantify drug-induced changes in extracellular dopamine associated with different levels of DAT occupancy (Specific Aim 3). It is hypothesized that doses of DAT inhibitors that effectively reduce cocaine use will produce significant elevations in extracellular dopamine. While the behavioral effects of cocaine have been attributed primarily to an interaction with the dopa-minergic system, evidence indicates that serotonin is an important modulator of the behavioral effects of cocaine. Accordingly, studies will manipulate serotonin activity pharrnacologically to assess changes in the effectiveness of DAT inhibitors to reduce cocaine use (Specific Aim 4). It is hypothesized that co-administration of selective serotonin reuptake inhibitors (SSRI) will lower the effective dose required for DAT inhibitors to decrease cocaine self-administration. A final objective is to continue the development and implementation of cocaine self-administration protocols during dynamic neuroimaging of regional cerebral blood flow (rCBF) as a model of brain activation (Specific Aim 5). The direct pharrnacological effects of cocaine on rCBF will be compared to those induced by environmental stimuli associated with cocaine self-administration. It is hypothesized that the pattern of brain activation will differ significantly under the two conditions. Collectively, the proposed research will provide an innovative preclinical model to evaluate the use of selective DAT inhibitors as pharmacotherapies for cocaine abuse.
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