The goal of the research in this subproject is to use a novel model of cocaine self-administration in monkeys, several pharmacological tools developed in the Center, combined with the non-invasive imaging procedure of PET, to broaden our understanding of the neural and behavioral mechanisms that mediate the transition from recreational cocaine use to cocaine addiction. More specifically, in Specific Aim 1 we propose to establish, in monkeys, a model of cocaine self-administration that assess reinforcing efficacy of cocaine, while also allowing the monkey to self-administer cocaine in a """"""""binge"""""""" pattern. We hypothesize that the opportunity to binge will increase the reinforcing efficacy of cocaine. The experiments proposed in Specific Aim 2 will examine how long-acting, indirect-acting dopamine and serotonin compounds (DAT- and SERT-selective, respectively) alter the reinforcing effects of cocaine and food. We hypothesize that SERT-selective drugs will attenuate the reinforcing efficacy of cocaine and decrease binge performance at doses that do not alter daily food-reinforced responding. Finally, in Specific Aim 3 we will study DAT and SERT function using PET imaging in monkeys. Initial baseline levels will be assessed in cocaine-na'l've subjects to determine how basal DAT and SEPT levels correlate with reinforcing efficacy of cocaine. Next, we will examine, longitudinally, how DAT and SERT levels vary and co-vary as a function of cocaine exposure and rate of recovery during abstinence. Finally, we will examine how treatment with a DAT- or SERT-selective compounds affects levels of each transporter, as well as cocaine self-administration. These studies will use a within-subjects design and PET imaging to examine long-term changes in the brains of monkeys self-administering cocaine under conditions that model """"""""loss of control"""""""" and during cocaine abstinence. Although the vast majority of research has focused on dopamine neurotransmission in cocaine abuse, we hypothesize that the neuronal adaptation that mediates the transition from recreational drug use to compulsive binge taking, is a functional interaction between dopamine and serotonin systems. A better understanding of these neuronal adaptations, as well as how these systems respond to various pharmacological treatments, will lead to a better understanding of the mechanisms that mediate the transition from drug use to addiction.
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