The primary goal of this proposal is to achieve a better understanding of the effects of chronic social stress and the factors that determine individual differences in the vulnerability to self-administer cocaine in a unique nonhuman primate model of drug abuse. Previous research with socially housed monkeys has shown that subordinate monkeys are more susceptible to disease states, including reproductive dysfunction and cardiovascular disease, supporting the hypothesis that they are more stressed than dominant monkeys. Using the brain imaging procedure positron emission tomography (PET), we have shown that social housing can alter dopamine (DA) D2 receptor function in male cynomolgus monkeys. Subordinate monkeys had lower levels of D2 receptor binding compared to dominant monkeys and higher rates of cocaine self-administration. These studies were the first to examine intravenous cocaine self-administration in socially housed monkeys and found that social status and environmental context can have profound effects on cocaine reinforcement. The studies proposed in this application are designed to extend these findings to female macaques and to evaluate the plasticity of the DA system to changes in the environment. Specifically, we propose to more fully examine DA receptor function by using PET to measure changes in DA transporter levels, as well as D2 receptors, and by using microdialysis techniques to study basal DA and serotonin levels. We propose to utilize a within-subjects, A-B-A-B design to examine: 1) whether these neurobiological markers, when measured while monkeys are individually housed, are predictors of eventual social rank (i.e., are trait markers) and if they vary with measures of locomotor activity, impulsiveness and food-maintained operant responding; 2) whether these markers change in response to social group formation; 3) whether these changes are permanent or whether they continue to be influenced by current environmental conditions; and 4) whether these changes impact the reinforcing effects of cocaine. Throughout these experiments we will assess the neuroendocrine correlates and consequences of drug self-administration and social interactions in these female monkeys. A better understanding of sex differences in regards to the effects of chronic stress on cocaine reinforcement and brain monoamine function, may lead to better behavioral and/or pharmacological strategies for the treatment of cocaine abuse.
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