Mechanisms Mediating Cocaine Abuse in Socially Housed Female and Male Monkeys

这项资助的研究项目，现在已经进入第13个年头，旨在了解可卡因滥用的神经生物学。 在一个独特的非人灵长类动物模型中：在社会圈养的 食蟹猴科学的前提是，不同的机制维持可卡因SA基于社会 等级和性别以及因此不同的药物治疗将需要在这些组中产生积极的结果。 对于这一行政补充，我们建议扩大社会的表型特征， 饲养的雌猴和雄猴，包括睡眠的措施。可卡因引起的睡眠时间的变化， 架构和质量可能会影响认知过程，帮助人们避免继续 可卡因的使用关于可卡因引起的睡眠中断之间的关系， 和认知能力以及它们如何影响治疗结果。我们有一个独特的机会来研究 可卡因-睡眠的相互作用，因为我们目前有可卡因天真的社会安置的女性和男性 在各种认知任务下训练的食蟹猴（n = 4/性别）。我们建议将它们植入 使用遥测设备记录脑电图（EEG）活动，以评估睡眠/清醒状态， 可卡因初治和可卡因SA后。在目标1中，我们将研究认知与 在可卡因未接触过的群居的雄性和雌性食蟹猴中的睡眠/觉醒结构。每只猴子 目前正在接受四项认知任务的训练，这些任务使用剑桥 神经心理测试和电池（CANTAB）设备。在植入遥测装置记录脑电图后 从自由移动的猴子在他们的家笼，我们将研究每一个动物的睡眠-觉醒架构， 它与他们的社会地位有关;这些数据将作为检查可卡因SA在Aim中的作用的基线 2.我们假设性别、月经周期和社会等级在睡眠结构上存在差异， 睡眠周期中断较少的女性和男性将具有更好的认知特征。目标2中的研究 将是第一个确定可卡因SA的获得对睡眠结构的影响， 猴子我们假设，占主导地位的女性和从属男性将获得低于剂量比 其他猴子，当收购发生时，睡眠和认知将被打乱。在目标3中，我们建议 检查可卡因剂量（盐水，0.01 - 0.3 mg/kg/注射）对睡眠结构的影响。我们建议给予 猴子每天都能接触到高剂量的可卡因，以确定是否会对睡眠产生耐受性。 最后，我们将研究可卡因戒断对睡眠/觉醒结构的影响。我们假设睡眠， 如EEG评估，将对可卡因戒断敏感，提供可卡因戒断的证据 动物模型中的症状。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 包括睡眠也为未来药物治疗的评估提供了理论基础。

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.