Chronic Stress and Vulnerability to Cocaine Abuse in Female Monkeys

雌性猴子的慢性压力和对可卡因滥用的脆弱性

• 批准号: 8238940
• 负责人: Michael A Nader
• 金额: $ 37.21万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8238940
• 关键词: Acute; Affect; American; Animal Model; Animals; Antidepressive Agents; Attenuated; Behavior Therapy; Brain; Brain imaging; Chronic; Chronic stress; Cocaine; Cocaine Abuse; Data; Development; Dopamine; Dopamine Receptor; Dose; Drug Addiction; Drug abuse; Environment; Etiology; Female; Food; Funding; Goals; Grant; Housing; Human; Image; Imaging Techniques; Individual Differences; Intravenous; Laboratories; Lead; Maintenance; Measures; Modeling; Monkeys; Neurobiology; Performance; Pharmaceutical Preparations; Pharmacological Treatment; Positron-Emission Tomography; Predisposition; Prevention; Primates; Psychological reinforcement; Public Health; Reaction Time; Reporting; Research; Research Project Grants; Schedule; Self Administration; Sex Characteristics; Social Behavior; Social Environment; Social Functioning; Social Hierarchy; System; Training; Work; base; behavior influence; cocaine exposure; cocaine use; dopamine transporter; drug reinforcement; environmental enrichment for laboratory animals; environmental stressor; improved; intravenous drug use; male; nonhuman primate; novel; receptor; receptor function; response; social; social group; social stress; treatment strategy

DESCRIPTION (provided by applicant): Drug abuse continues to be a major public health problem worldwide, with an estimated 1.6 million Americans confirming current cocaine use. There is evidence of sex differences in vulnerability to cocaine abuse, although males are disproportionately represented in research. This research project is a continuation of funded work aimed at understanding the neurobiology of cocaine abuse in a unique nonhuman primate model: intravenous cocaine self-administration in socially housed female monkeys. We have successfully 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. Specific Aim 1 will examine the effects of chronic cocaine self-administration on dopamine (DA) D2/D3 receptors and DA transporters (DAT), brain systems that have been well characterized in males, but not females. Specific Aim 2 will examine whether acute social stress differentially affects cocaine self- administration as a function of social rank and whether dominant and subordinate females respond similarly to chronic drug treatment. Finally, in Specific Aim 3, we will combine environmental enrichment and chronic drug treatment in an effort to decrease the reinforcing strength of cocaine in dominant and subordinate monkeys. We hypothesize individual differences, based on social rank-induced differences in D2/D3 and DAT availability, in response to environmental challenges and drug treatments. The combination of social rank and PET imaging studied over years, in female monkeys, will allow for a better understanding of the interactions between social context and DA receptor function, which will be critical to developing behavioral and pharmacological treatment strategies. PUBLIC HEALTH RELEVANCE: Individual differences in vulnerability to drug abuse is a hallmark of human drug addiction. These studies will further explore factors related to etiology and maintenance of drug abuse in socially housed female monkeys, which should aid in the development of novel treatment strategies.

药物滥用仍然是全球主要的公共卫生问题，估计有160万美国人确认目前使用可卡因。有证据表明，在易受可卡因滥用影响方面存在性别差异，尽管研究中男性所占比例过高。该研究项目是资助工作的延续，旨在了解独特的非人灵长类动物模型中可卡因滥用的神经生物学：在社会圈养的雌性猴子中静脉注射可卡因自我管理。我们已经成功地将灵长类动物社会行为的研究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）相结合，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。具体目标1将检查长期可卡因自我给药对多巴胺（DA）D2/D3受体和DA转运蛋白（DAT）的影响，这些脑系统在男性中得到了很好的表征，但在女性中没有。具体目标2将研究急性社会压力是否不同地影响可卡因自我给药作为社会等级的函数，以及占主导地位和从属地位的女性是否对慢性药物治疗有类似的反应。最后，在具体目标3中，我们将联合收割机环境富集和慢性药物治疗相结合，努力降低可卡因在优势和从属猴子中的强化强度。我们假设个体差异，基于社会等级引起的D2/D3和DAT可用性的差异，以应对环境挑战和药物治疗。多年来在雌性猴子中研究的社会等级和PET成像的组合将允许更好地理解社会背景和DA受体功能之间的相互作用，这对于开发行为和药理学治疗策略至关重要。 公共卫生相关性：药物滥用易感性的个体差异是人类药物成瘾的标志。这些研究将进一步探索与社会圈养的雌性猴子中药物滥用的病因学和维持相关的因素，这将有助于开发新的治疗策略。