There is an estimated 5.7 million Americans that are current cocaine users and, at present, there are no FDA- approved treatments for cocaine use disorders. This research project is a continuation of funded work aimed at understanding the behavioral, pharmacological and neurobiological variables influencing the reinforcing effects of cocaine in a unique nonhuman primate model: intravenous cocaine self-administration (SA) in socially housed cynomolgus monkeys. The goals of the present application are to continue using this homologous animal model to examine the mechanisms of action mediating the interactions between social hierarchy and environmental and pharmacological modulation of cocaine self-administration in female and male monkeys. Using PET imaging, over the previous funding period, we have noted sex- and social-rank related differences in dopamine (DA) D2/D3 receptor (D2/D3R) and kappa opioid receptor (KOR) availability in cocaine-naïve monkeys through long-term cocaine SA. Consistent with these sex- and social-rank differences, we noted individual differences in response to several pharmacological manipulations. In Aim 1, we propose to extend the characterization of sex- and social-rank differences in cocaine SA to examine several behavioral interventions. For these studies, monkeys will choose between cocaine and food and the following interventions will be examined: delay discounting involving both food and cocaine delays; changes in the magnitude of the food reinforcer, to better model contingency management; and punishment, using a KOR agonist (positive punishment), which will be important since we have measures of KOR availability in these monkeys, as well as using response-contingent timeouts (negative punishment). The studies in Aim 2 will examine the effects of chronic drug treatments in socially housed monkeys self-administering cocaine in the context of an alternative, non-drug, reinforcer (food-cocaine choice). We will also combine chronic pharmacological treatments with behavioral interventions in an effort to further decrease cocaine choice. Importantly, cognitive performance will be assessed to better determine if the intervention has unwanted side effects. The goals of Aim 3 are to examine how cocaine SA and chronic drug treatment differentially affects D2/D3R and KOR availability, using a within-subjects design, in socially housed female and male monkeys. The scientific premise is that different mechanisms maintain cocaine SA based on social rank and sex and thus different intervention strategies (both behavioral and pharmacological) will be required to produce a positive outcome in these groups. We are proposing a preclinical personalized-medicine strategy for treating cocaine abuse that incorporates sex and social variables.

Relevance: Individual differences, social factors and sex are variables that influence vulnerability, maintenance and treatment outcomes in human drug addiction. The research proposed in this application will utilize socially housed female and male monkeys self-administering cocaine to further explore behavioral (alternative reinforcers, impulsive choice, punishment, cognition), pharmacological (chronic drug treatments) and brain changes using positron emission tomography. Results from these studies should aid in the development of personalized medicine strategies for cocaine use disorders.