Chronic Stress and Cocaine Abuse in Female Monkeys

描述（由申请人提供）：本提案的主要目标是更好地了解慢性社会压力的影响，以及在独特的非人灵长类药物滥用模型中确定自我管理可卡因脆弱性的个体差异的因素。以前对社会圈养猴子的研究表明，从属猴子更容易受到疾病状态的影响，包括生殖功能障碍和心血管疾病，支持它们比主导猴子更紧张的假设。使用脑成像程序正电子发射断层扫描（PET），我们已经表明，社会住房可以改变多巴胺（DA）D2受体功能的雄性食蟹猴。与占主导地位的猴子相比，下属猴子的D2受体结合水平较低，可卡因自我给药率较高。这些研究是第一个研究社会圈养猴子静脉注射可卡因自我管理的研究，发现社会地位和环境背景对可卡因强化有深远的影响。本申请中提出的研究旨在将这些发现扩展到雌性猕猴，并评估DA系统对环境变化的可塑性。具体而言，我们建议更全面地检查DA受体的功能，通过使用PET来测量DA转运蛋白水平的变化，以及D2受体，并通过使用微透析技术来研究基础DA和5-羟色胺水平。我们建议利用受试者内A-B-A-B设计来检查：1）当猴子单独圈养时测量这些神经生物学标记物时，是否是最终社会等级的预测因子（即，是特征标记），以及它们是否随运动活动、冲动和食物维持的操作性反应的测量而变化; 2）这些标记是否随社会群体的形成而变化; 3）这些变化是永久性的还是继续受到当前环境条件的影响;以及4）这些变化是否影响可卡因的强化作用。在这些实验中，我们将评估这些雌性猴子的神经内分泌相关性和药物自我给药和社会互动的后果。更好地了解慢性应激对可卡因强化和脑单胺功能的影响方面的性别差异，可能会导致更好的治疗可卡因滥用的行为和/或药理学策略。

DESCRIPTION (provided by applicant): 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.