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

项目摘要 患有兴奋剂使用障碍的人表现出睡眠问题的高患病率，睡眠中断可能 影响药物成瘾的过程。鉴于这种双向互动，理解神经生物学机制- 睡眠障碍和兴奋剂滥用之间的联系可能为开发广泛有效的药物提供关键信息。 积极治疗。我以前的研究表明，甲基苯丙胺损害了rhe- 催眠猴和甲基苯丙胺相关线索在猴复发模型中呈现 复发导致睡眠障碍。最近的研究表明，食欲素（下丘脑分泌素）系统是一个关键的 增强过程以及睡眠-觉醒状态的调节剂，以及食欲素-1（OX 1）和 食欲素-2（OX 2）受体可能调节睡眠与兴奋剂滥用之间的关系。工作中的hy- 本申请的假设是食欲素介导的机制在相互作用中起主要作用， 服用甲基苯丙胺，甲基苯丙胺相关的复发触发因素，以及睡眠障碍- 我是说。我的研究策略是围绕三个具体目标组织的，在雌性和雄性恒河猴中进行 猴子目的1（K99阶段）将评估实验者白天施用美沙酮的假设。 非他明会通过减少慢波（N3）睡眠和快速眼动的时间来扰乱夜间睡眠， 睡眠，而OX 2受体调节甲基苯丙胺诱导的睡眠障碍。我要投资- 应用多导睡眠描记术评估亚型选择性食欲素受体拮抗剂对睡眠-觉醒周期的影响 基于脑电图/肌电图/眼电图的遥测记录 (EEG/EMG/EOG）和定量行为观察。目标2（R 00阶段）将评价以下假设： OX 1受体调节甲基苯丙胺的强化作用，而OX 2受体介导睡眠 在甲基苯丙胺自我给药的背景下的损害。我将研究亚型-se- 将评价选择性食欲素受体拮抗剂对静脉内甲基苯丙胺自我给药和睡眠的影响 使用活动记录仪。目标3（R 00阶段）将评价OX 1受体与以下假设相关： 甲基苯丙胺的复发样作用，而OX 1和OX 2受体都参与恢复- 导致睡眠障碍。我将在植入EEG/EMG/EOG Telem的动物中进行恢复研究- - 是的我将研究OX 1或OX 2拮抗剂对甲基苯丙胺和/或线索诱导的再狭窄的影响。 声明，以及药物和/或线索诱导的睡眠障碍，在猴子自我管理的metham- 非他明对于所有研究，将使用定量药理学评估潜在的OX 1和OX 2受体 在介导甲基苯丙胺的影响的相互作用。总的来说，缺乏兴奋剂使用的治疗方法， 秩序和兴奋剂引起的睡眠障碍代表了美国一个重大的未满足的公共卫生需求， 国际吧这些结果可能会告知食欲素受体拮抗剂作为潜在靶点的潜力， 了解和治疗兴奋剂滥用和兴奋剂引起的睡眠障碍。

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.