Mechanisms Mediating Cocaine Abuse in Socially Housed Female and Male Monkeys

社会饲养的雌性和雄性猴子中调节可卡因滥用的机制

• 批准号: 10265791
• 负责人: Michael A Nader
• 金额: $ 9.98万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265791
• 关键词: Abstinence; Administrative Supplement; Affect; Animal Model; Animals; Architecture; Behavioral; Brain; Brain imaging; Catheters; Chronic; Clinical; Cocaine; Cocaine Abuse; Cocaine Users; Cognition; Cognitive; Data; Development; Devices; Dopamine; Dose; Drug Addiction; Drug Modelings; Drug abuse; Evaluation; Female; Food; Funding; Future; Goals; Grant; Home; Human; Imaging Techniques; Implant; Impulsivity; Individual Differences; Injections; Intravenous; Knowledge; Macaca fascicularis; Maintenance; Measures; Mediating; Menstrual cycle; Modeling; Monitor; Monkeys; Neurobiology; Neuropsychological Tests; Outcome; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Positron-Emission Tomography; Primates; Psychological reinforcement; Recovery; Research; Research Design; Research Project Grants; Saline; Same-sex; Schedule; Self Administration; Sex Differences; Sleep; Sleep Architecture; Sleep disturbances; Social Behavior; Social Characteristics; Social Hierarchy; Telemetry; Training; Translational Research; Treatment outcome; Withdrawal Symptom; base; behavior influence; cocaine exposure; cocaine self-administration; cocaine use; cognitive performance; cognitive process; cognitive task; environmental enrichment for laboratory animals; male; nonhuman primate; personalized medicine; pre-clinical; programs; receptor; reinforcer; response; sex; social; social factors; social group; social stress

This funded research project, now in its 13th year, is aimed at understanding the neurobiology of cocaine abuse in a unique nonhuman primate model: intravenous cocaine self-administration (SA) in socially housed cynomolgus monkeys. The scientific premise is that different mechanisms maintain cocaine SA based on social rank and sex and thus different drug treatments will be required to produce a positive outcome in these groups. For this Administrative Supplement, we are proposing to extend the phenotypic characteristics of socially housed female and male monkeys to include measures of sleep. Cocaine-induced changes in sleep duration, architecture and quality could impact cognitive processes that would aid someone in refraining from continuing cocaine use. There is a gap in knowledge related to the relationship between cocaine-induced sleep disruptions and cognitive performance and how those affect treatment outcomes. We have a unique opportunity to study cocaine-sleep interactions because we currently have cocaine-naïve socially housed female and male cynomolgus monkeys (n=4/sex) being trained under various cognitive tasks. We propose to implant them with telemetry devices to record electroencephalographic (EEG) activity to assess sleep/wake states while cocaine-naïve and following cocaine SA. In Aim 1, we will examine the relationship between cognition and sleep/wake architecture in cocaine-naive socially housed male and female cynomolgus macaques. Each monkey is currently being trained on four cognitive tasks that assess different cognitive domains using the Cambridge Neuropsychological Test and Battery (CANTAB) apparatus. After implanting telemetry devices to record EEG from freely-moving monkeys within their home cage, we will examine each animal’s sleep-wake architecture as it relates to their social rank; these data will serve as a baseline for examining the effects of cocaine SA in Aim 2. We hypothesize sex, menstrual cycle and social rank differences in sleep architecture and that monkeys (females and males) with a less disrupted sleep cycle will have better cognitive profiles. The studies in Aim 2 will be the first to determine the effects of acquisition of cocaine SA on sleep architecture in socially housed monkeys. We hypothesize that dominant females and subordinate males will acquire at lower doses than the other monkeys and that when acquisition occurs, sleep and cognition will be disrupted. In Aim 3, we propose to examine the effects of cocaine dose (saline, 0.01-0.3 mg/kg/injection) on sleep architecture. We propose to give monkeys access to high cocaine doses daily, in order to determine if tolerance develops to the effects on sleep. Finally, we will examine the effects of cocaine abstinence on sleep/wake architecture. We hypothesize that sleep, as assessed with EEG, will be sensitive to cocaine abstinence, providing evidence of cocaine withdrawal symptoms in an animal model. Future studies will examine how drug treatments affect sleep/wake architecture and cognition, during cocaine abstinence and following re-exposure to cocaine. Expanding our research to include sleep also provides rationale for the evaluation of future drug treatments.

该资助的研究项目现已进入第 13 个年头，旨在了解可卡因滥用的神经生物学 在独特的非人类灵长类动物模型中：在社会饲养中静脉注射可卡因自我给药（SA） 食蟹猴的科学前提是不同的机制维持可卡因SA基于社会。 等级和性别，因此需要不同的药物治疗才能在这些群体中产生积极的结果。 对于本行政补充，我们建议扩展社会的表型特征 饲养雌性和雄性猴子以测量可卡因引起的睡眠时间变化， 架构和质量可能会影响认知过程，从而帮助人们避免继续 可卡因使用引起的睡眠中断之间的关系存在知识空白。 和认知表现以及它们如何影响治疗结果。我们有一个独特的研究机会。 可卡因与睡眠的相互作用，因为我们目前有未接触过可卡因的女性和男性 我们建议对食蟹猴（n=4/性别）进行各种认知任务的训练。 使用遥测设备记录脑电图 (EEG) 活动以评估睡眠/觉醒状态 在目标 1 中，我们将研究认知与可卡因 SA 之间的关系。 未吸食可卡因的社会饲养的雄性和雌性食蟹猴的睡眠/觉醒结构。 目前正在接受四项认知任务的培训，这些任务使用剑桥评估不同的认知领域 植入遥测设备记录脑电图后的神经心理测试和电池（CANTAB）装置。 从笼子里自由活动的猴子身上，我们将检查每只动物的睡眠-觉醒结构： 它与他们的社会等级有关；这些数据将作为检查可卡因 SA 在 Aim 中的影响的基线 2. 我们研究了睡眠结构中的性别、月经周期和社会等级差异，并且猴子 目标 2 中的研究表明，睡眠周期中断较少的（女性和男性）将具有更好的认知能力。 将是第一个确定获取可卡因 SA 对社会住房中睡眠结构的影响的人 我们追求的是，​​占主导地位的雌性和从属雄性的感染剂量低于雄性猴子。 在目标 3 中，我们建议： 检查可卡因剂量（生理盐水，0.01-0.3 mg/kg/注射）对睡眠结构的影响。 猴子每天接触高剂量的可卡因，以确定是否会对睡眠影响产生耐受性。 最后，我们将研究可卡因戒断对睡眠/觉醒结构的影响。 根据脑电图评估，将对可卡因戒断敏感，提供可卡因戒断证据 未来的研究将研究药物治疗如何影响睡眠/觉醒结构。 和认知，在可卡因戒断期间和重新接触可卡因后将我们的研究扩展到 包括睡眠也为评估未来的药物治疗提供了依据。