Social Stress: Vulnerability to Cocaine Abuse in Monkeys

描述（由申请人提供）：本研究的总体目标是使用独特的非人灵长类药物滥用模型，更好地了解可卡因强化作用的易感性和脆弱性的个体差异。为了实现这一目标，我们结合了灵长类动物的社会行为与静脉注射药物自我管理和非侵入性脑成像程序正电子发射断层扫描（PET）的研究，以研究环境和药理学变量如何影响可卡因的行为和强化作用。在之前的资助期间，我们发现社会住房改变了雄性食蟹猴的多巴胺（DA）D2受体功能，这些变化与显性和从属猴子之间自我管理可卡因的差异脆弱性有关。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。我们还发现，长期暴露于可卡因可以减弱社会地位对DA受体功能的影响，并导致社会圈养的猴子之间类似的自我管理率。这项竞争性更新申请中提出的研究旨在进一步评估DA、社会地位和可卡因的强化作用之间的相互作用。具体而言，我们建议：1）进一步研究可卡因戒断期间和社会群体重组后DA系统的可塑性，并评估这些操纵对可卡因强化的影响; 2）确定自我施用可卡因的社会后果对药物强化效果和冲动性措施的影响; 3）进一步研究急性和慢性环境应激源之间的相互作用以及对DA受体功能和可卡因的强化作用的富集，作为社会等级的函数。使用新的和同源的非人灵长类动物模型的可卡因滥用，如建议，应有助于了解环境和药理学变量如何有助于脆弱性，维护，复发和选择行为，涉及药物滥用。这些信息将导致更好的治疗和预防战略。

DESCRIPTION (provided by applicant): The overarching goal of this research is to achieve a better understanding of the individual differences in the susceptibility and vulnerability to the reinforcing effects of cocaine using a unique nonhuman primate model of drug abuse. To accomplish this, we have combined the study of primate social behavior with intravenous drug self-administration and the noninvasive brain imaging procedure positron emission tomography (PET) to examine how environmental and pharmacological variables influence the behavioral and reinforcing effects of cocaine. In the previous funding period we found that social housing altered dopamine (DA) D2 receptor function in male cynomolgus monkeys and these changes were associated with differential vulnerability to self-administer cocaine between dominant and subordinate monkeys. 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. We also found that chronic exposure to cocaine could attenuate the effects of social rank on DA receptor function and result in similar rates of self-administration among the socially housed monkeys. The studies proposed in this competing renewal application are designed to evaluate further the interactions between DA, social rank and the reinforcing effects of cocaine. Specifically, we propose to 1) examine further the plasticity of the DA system during cocaine abstinence and following social group reorganization and assess the impact of these manipulations on cocaine reinforcement; 2) determine the effects of social consequences of self-administering cocaine on the reinforcing effects of the drug and on measures of impulsivity; and 3) examine further the interactions between acute and chronic environmental stressors and enrichment on DA receptor function and on the reinforcing effects of cocaine, as a function of social rank. The use of novel and homologous nonhuman primate models of cocaine abuse, as proposed, should aid in understanding how environmental and pharmacological variables contribute to vulnerability, maintenance, relapse and choice behavior involving drugs of abuse. Such information will lead to better treatment and prevention strategies.