The proposed research will characterize interactions between monoamine transporter inhibitors and cocaine in nonhuman primate models of i.v. drug self-administration, neuroimaging with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), and in vivo microdialysis. Emphasis will be directed toward combined inhibition of the dopamine transporter (DAT) and the serotonin transporter (SERT) in the context of cocaine self-administration. A second-order schedule of i.v. drug self-administration in rhesus monkeys will be used to evaluate the effectiveness of combined inhibition of DAT and SERT to reduce cocaine self-administration, and to maintain self-administration when substituted for cocaine (Aim 1). Similarly, extinction conditions will be used to evaluate the effectiveness of combined inhibition of DAT and SERT to attenuate cocaine-induced reinstatement, and to induce reinstatement in the absence of cocaine (Aim 2). PET neuroimaging techniques will be used to quantify DAT and SERT occupancy at drug doses shown to be effective in drug self-administration and reinstatement studies (Aim 3). In addition, in vivo microdialysis techniques will be used to correlate DAT and SERT occupancy measures with drug-induced changes in dopamine, serotonin and their primary metabolites (Aim 4). Lastly, fMRI protocols will be implemented in awake, behaving monkeys in order to characterize functional changes in CNS activity during self- administration of cocaine or selective DAT inhibitors. Studies conducted during the previous funding period documented the effectiveness of selective DAT inhibitors to reduce or eliminate cocaine self-administration, but only at high levels of DAT occupancy. Moreover, selective DAT inhibitors reliably maintained drug self- administration and induced reinstatement of extinguished cocaine self-administration behavior. It is hypothesized that combined inhibition of DAT and SERT will lower the level of DAT occupancy required to reduce cocaine self-administration, and limit the reinforcing and reinstatement effects of DAT inhibitors. It is also hypothesized that selective DAT inhibitors will induce a pattern of brain activation similar to that observed for cocaine. In contrast, combined inhibition of DAT and SERT will limit brain activation induced by cocaine and DAT inhibitors, and by drug-associated stimuli. Collectively, the integration of behavioral pharmacology, functional neuroimaging and in vivo neurochemistry will enhance our understanding of the neurobiological mechanisms involved in cocaine self-administration and reinstatement in nonhuman primates. The results obtained will also evaluate the effectiveness of monoamine transporters as potential targets for cocaine medications development. ? ? ?
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