Chronic Stress and Cocaine Abuse in Female Monkeys

描述(由申请人提供)：这项建议的主要目标是更好地了解慢性社会压力的影响，以及决定在独特的非人类灵长类药物滥用模型中自我给药可卡因脆弱性的个体差异的因素。之前对群居猴子的研究表明，从属猴子更容易患上包括生殖功能障碍和心血管疾病在内的疾病，这支持了它们比占统治地位的猴子更有压力的假设。使用脑成像程序正电子发射断层扫描(PET)，我们已经证明，社会住房可以改变雄性食蟹猴的多巴胺(DA)D2受体功能。与优势猴子相比，从属猴子的D2受体结合水平较低，而可卡因自我给药率较高。这些研究首次检验了在社会圈养的猴子体内静脉注射可卡因的自我管理，发现社会地位和环境背景可以对可卡因的强化产生深远的影响。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。具体地说，我们建议通过使用PET来测量DA转运体和D2受体水平的变化，以及通过使用微透析技术来研究基础DA和5-羟色胺水平，来更全面地检查DA受体的功能。我们建议利用受试者内部的A-B-A-B设计来检查：1)当猴子被单独安置时，这些神经生物学标记物是否是最终社会等级的预测指标(即，特征标记物)，以及它们是否随着运动活动、冲动和食物维持的操作者反应的测量而变化；2)这些标记物是否随着社会群体的形成而变化；3)这些变化是否是永久性的，或者它们是否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效果。通过这些实验，我们将评估这些雌性猴子的神经内分泌相关性以及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大脑单胺功能的影响方面的性别差异，可能会导致更好的行为和/或药物策略来治疗可卡因滥用。

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.