Role of orexin receptors in the abuse- and sleep-related effects of methamphetamine

项目摘要 有兴奋剂使用障碍的人表现出睡眠问题的高发，睡眠中断可能 影响药物成瘾的进程。在这种双向相互作用下，理解神经生物学机制- 将睡眠障碍和兴奋剂滥用联系在一起的失调症可能为发展广泛的疗效提供关键信息。 积极的治疗。我以前的研究表明，甲基苯丙胺损害了rhe-hE基于动作图的睡眠。 刺激猴子和在猴子恢复模型中呈现与甲基苯丙胺相关线索 复发导致睡眠障碍。最近的研究表明，食欲素(下丘脑)系统是一种关键的 增强过程以及睡眠-觉醒状态的调节器，以及食欲素-1(OX1)和 食欲素-2(OX2)受体可能调节睡眠和兴奋剂滥用之间的关系。工作人员- 这一应用的假设是，食欲素介导的机制在相互作用中发挥着重要作用。 在服用甲基苯丙胺、与甲基苯丙胺相关的复发诱因和睡眠损害之间- 门槛。我的研究策略是围绕三个具体目标在雌性和雄性恒河猴身上进行的 猴子。目标1(K99阶段)将评估这样的假设，即实验者日间注射的甲烷- 扑热息痛会减少慢波(N3)睡眠和快速眼球运动的时间，从而扰乱夜间睡眠。 OX2受体调节甲基苯丙胺引起的睡眠障碍。我会投资- 多导睡眠图检测不同亚型选择性食欲素受体拮抗剂对睡眠-觉醒周期的影响 基于electroencephalography/electromyography/electrooculography的遥测记录 (EEG/EMG/EOG)和定量行为观察。目标2(R00阶段)将评估假设 OX1受体调节甲基苯丙胺的增强作用，而OX2受体调节睡眠 在甲基苯丙胺自我给药方面的损害。我会调查亚型-Se-的影响 静脉注射选择性食欲素受体拮抗剂。甲基苯丙胺自我给药，并对睡眠进行评估 使用动作记录仪。AIM 3(R00阶段)将评估OX1受体与 甲基苯丙胺的复发效应，而OX1和OX2受体都参与恢复- 诱发性睡眠障碍。我将在植入EEG/EMG/EOG Telem的动物身上进行恢复研究- 试金术。我将研究OX1或OX2拮抗剂对甲基苯丙胺和/或线索诱导的反应的影响。 声明，以及药物和/或线索诱导的睡眠障碍，在猴子自我给予甲基-2-甲基-2-甲基-2，4-二甲基苯丙氨酸-1，2，4，4，5，6，5，5，5，5，5，5，5，5，5，6-二恶英 扑热息痛。对于所有的研究，将使用定量药理学来评估潜在的OX1和OX2受体 甲基苯丙胺作用中的相互作用。总体而言，缺乏对兴奋剂使用的治疗是 秩序和兴奋剂引起的睡眠障碍在美国和美国是一个重要的未得到满足的公共卫生需求 全世界。这些结果可能为食欲素受体拮抗剂作为潜在靶点提供信息。 对兴奋剂滥用和兴奋剂所致睡眠障碍的认识和治疗。

Project Summary Individuals with stimulant use disorder show a high prevalence of sleep problems, and sleep disruption may affect the course of drug addiction. Given this bidirectional interaction, understanding the neurobiological mech- anisms linking sleep impairment and stimulant abuse may provide key information for developing broadly effec- tive treatments. My previous studies have shown that methamphetamine impairs actigraphy-based sleep in rhe- sus monkeys and that presentation of methamphetamine-associated cues in a monkey reinstatement model of relapse resulted in sleep impairment. Recent research has implicated the orexin (hypocretin) system as a critical regulator of reinforcing processes as well as sleep-wake states, and an interplay between orexin-1 (OX1) and orexin-2 (OX2) receptors may regulate the relationship between sleep and stimulant abuse. The working hy- pothesis of this application is that orexin-mediated mechanisms play a major role in the interplay be- tween methamphetamine taking, methamphetamine-associated triggers of relapse, and sleep impair- ment. My Research Strategy is organized around three Specific Aims to be conducted in female and male rhesus monkeys. Aim 1 (K99 Phase) will evaluate the hypothesis that experimenter-administered daytime metham- phetamine will disrupt nighttime sleep by decreasing time spent in slow-wave (N3) sleep and rapid eye move- ment (REM) sleep, and that OX2 receptors modulate methamphetamine-induced sleep impairment. I will inves- tigate the effects of subtype selective orexin receptor antagonists on sleep-wake cycles using polysomnography based on telemetric recording of electroencephalography/electromyography/electrooculography (EEG/EMG/EOG) and quantitative behavioral observations. Aim 2 (R00 Phase) will evaluate the hypothesis that OX1 receptors modulate the reinforcing effects of methamphetamine, whereas OX2 receptors mediate sleep impairment in the context of methamphetamine self-administration. I will investigate the effects of subtype-se- lective orexin receptor antagonists on i.v. methamphetamine self-administration, and sleep will be evaluated using actigraphy. Aim 3 (R00 Phase) will evaluate the hypothesis that OX1 receptors are associated with the relapse-like effects of methamphetamine, whereas both OX1 and OX2 receptors are involved in reinstatement- induced sleep impairment. I will conduct reinstatement studies in animals implanted with EEG/EMG/EOG telem- etry. I will investigate the effects of OX1 or OX2 antagonists on methamphetamine- and/or cue-induced rein- statement, as well as on drug- and/or cue-induced sleep impairment, in monkeys self-administering metham- phetamine. For all studies, quantitative pharmacology will be used to assess potential OX1 and OX2 receptor interactions in mediating the effects of methamphetamine. Overall, the lack of treatments for stimulant use dis- order and stimulant-induced sleep impairment represents a significant unmet public health need in the U.S. and worldwide. These results may inform the potential of orexin receptor antagonists as prospective targets for the understanding and treatment of stimulant abuse and stimulant-induced sleep impairment.