The proposed research will utilize a non-human primate model to characterize medication effectiveness in reducing cocaine use. The primary objective is to evaluate the ability of selective dopamine transporter inhibitors to attenuate cocaine self-administration in rhesus monkeys. In addition, positron emission tomography (PET) imaging technique will be used as a novel and innovative approach to quantify dopamine transporter occupancy following medication pre-treatments. It is hypothesized that percent occupancy measures will be a direct function of medication, dose, and that a minimal threshold of transporter occupancy will be required for medication effectiveness in reducing cocaine use. The results will have direct clinical relevance regarding the rational selection of dosing regimens in humans. Subsequent studies will manipulate serotonin activity pharmacologically with chronic administration of selective serotonin reuptake inhibitors (SSRIs) to assess potential changes in medication effectiveness. It is hypothesized that SSRI administration will enhance medication efficacy and lower the effective dose required to reduce cocaine self-administration. All experiments will be conducted in adult rhesus monkeys (Macaca mulatta) housed at the Yerkes Center. Two groups of four subjects will be studied, with each subject within a group receiving the same treatments to serve as its own control. Intravenous drug self-administration behavior will be established with a second-order schedule, and daily behavioral performances will e used to evaluate the efficacy of medication pre- treatments in reducing cocaine use. Specificity of pretreatment effects will be assessed during the food-maintained component of a multiple schedule. Collaborators at the Emory PET Center have developed an effective PET ligand, [18]FECNT, for quantifying for quantifying brain dopamine transporter sites. Displacement studies will provide quantitative measures of transporter occupancy by medications shown to be effective in reducing cocaine use. The proposed studies will (1) identify the lead candidate medication to be tested in humans, (2) provide an informed estimate of an appropriate dosing regimen, and (3) determine the utility of SSRI administration in enhancing medication effectiveness.
