Mechanisms Mediating Cocaine Abuse in Socially Housed Female and Male Monkeys

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Drug abuse continues to be a major public health problem worldwide, with over 1.5 million Americans confirming current cocaine use and, at present, there are no FDA-approved treatments for cocaine addiction. This research project is a continuation of funded work aimed at understanding the neurobiology of cocaine abuse in a unique nonhuman primate model: intravenous cocaine self-administration 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 drug self-administration in female and male monkeys. Over the previous funding period, we have noted sex- and social-rank related differences in vulnerability to cocaine self-administration (SA) and in response to several acute pharmacological manipulations. In Aim 1, we will extend this characterization to chronic drug treatment in socially housed monkeys self-administering cocaine in the context of an alternative, non-drug, reinforcer (food-cocaine choice). We will also examine how these treatments affect cocaine-induced reinstatement. The studies in Aim 2 will extend these sex- and social-rank differences to impulsive-like behavior by implementing delays to food and cocaine. When food is delayed, we hypothesize that females will be more “impulsive” compared to males and when cocaine is delayed, subordinates will require longer delays to shift preference. The effects of long-term cocaine SA and chronic drug treatment on cognitive performance in socially housed monkeys will be examined in Aim 3. We hypothesize that cognitive performance of females will be more disrupted by cocaine than performance by males and that subordinate monkeys will be more sensitive than dominant animals. We have reported social- rank related differences in brain glucose utilization using [18F]fluorodeoxyglucose and PET and in dopamine D2/D3 receptor availability using [11C]raclopride and most recently in kappa opioid receptor availability using [11C]ECAP. The goal of Aim 4 is to examine how cocaine SA and chronic drug treatment differentially affects these measures 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 drugs will be required to produce a positive outcome in these groups. We are proposing a preclinical personalized-medicine strategy for treating drug abuse that incorporates sex and social variables. Results from these studies should aid in the development of novel and individualized treatment strategies for drug addiction.