Social Stress: Vulnerability to Cocaine Abuse in Monkeys

描述(由申请人提供)：这项研究的首要目标是利用一种独特的非人类灵长类药物滥用模型，更好地了解可卡因强化效应的易感性和脆弱性的个体差异。为了实现这一点，我们将灵长类社会行为的研究与静脉给药和非侵入性脑成像程序正电子发射断层扫描(PET)相结合，以研究环境和药物变量如何影响可卡因的行为和增强效应。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受体的功能，这些变化与主导和从属猴子之间自我给药的不同脆弱性有关。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。我们还发现，长期接触可卡因可以减弱社会地位对DA受体功能的影响，并导致社会安置的猴子的自我管理率相似。在这项竞争性更新申请中提出的研究旨在进一步评估DA、社会等级和可卡因强化效果之间的相互作用。具体地说，我们建议1)进一步检验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)确定自我给予可卡因的社会后果对药物强化效应和冲动测量的影响；3)进一步考察急性和慢性环境应激源和丰富对DA受体功能的相互作用以及作为社会等级函数的可卡因强化效应。建议使用新的和相应的非人类灵长类可卡因滥用模型，应该有助于理解环境和药理学变量如何导致涉及滥用药物的易损性、维持、复发和选择行为。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.