Mechanistic studies of alcohol-sleep interactions

酒精与睡眠相互作用的机制研究

• 批准号: 10019443
• 负责人: Yanhua H Huang
• 金额: $ 39.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-17 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019443
• 关键词: Abstinence; Alcohol consumption; Alcohol dependence; Alcohol or Other Drugs use; Alcohol withdrawal syndrome; Alcohols; Anatomy; Chronic; Clinical Research; Cocaine; Data; Development; Electroencephalography; Electrophysiology (science); Ethanol; Female; Habenula; Health; Heavy Drinking; Homeostasis; Hyperactive behavior; Hypothalamic structure; Incubated; Individual; Intervention; Lateral; Light; Measures; Medial; Mediating; Methods; Mission; Modeling; Motivation; National Institute on Alcohol Abuse and Alcoholism; Neurons; Patients; Phase; Predictive Factor; Predisposition; Publishing; REM Sleep; Rattus; Recovery; Relapse; Risk; Rodent; Self Administration; Signal Transduction; Sleep; Sleep Architecture; Sleep Deprivation; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Slice; Structure; Testing; Therapeutic; Time; Withdrawal; Work; alcohol abstinence; alcohol exposure; alcohol measurement; alcohol relapse; alcohol seeking behavior; alcohol use disorder; anxiety-like behavior; base; cholinergic; chronic alcohol ingestion; craving; designer receptors exclusively activated by designer drugs; drinking; drug craving; effective intervention; experimental study; improved; insight; male; melanin-concentrating hormone; negative affect; neuromechanism; neuroregulation; non rapid eye movement; novel; prevent; reduced alcohol use; relating to nervous system; response; restoration; sleep quality; targeted treatment

Abstract Sleep dysregulation is a hallmark of alcohol use disorders (AUDs) and disrupted sleep can contribute to relapse even after months of abstinence. Despite the well-recognized sleep-AUD interactions, few studies have investigated how sleep changes over the development of excessive drinking, and the mechanisms by which sleep disruptions exacerbate drinking and/or relapse liability are largely unknown. Based on several key findings from published studies and preliminary work, one hypothesis is that disrupted REM sleep induces maladaptive changes in the medial (M) and lateral habenula (LHb), which in turn contribute to escalated alcohol intake and promote relapse. The key findings are: 1. Specific REM sleep deficits at 2-3 weeks after alcohol withdrawal are a robust predicting factor for relapse in alcohol dependent patients; 2. Chronic, selective REM sleep fragmentation enhances medial Hb neuron tonic firing and negative affect; 3. Relapse to alcohol seeking is associated with increased activation of MHb and LHb neurons. 4. Sleep fragmentation precipitates drug craving during abstinence from cocaine, while selective consolidation of REM sleep reduces craving. Thus, it is predicted that chronic alcohol drinking and abstinence leads to disrupted REM sleep, which induces Hb hyperactivity, promoting a negative affective state that drives motivation for alcohol and relapse. Likewise, it is predicted that chronic REM sleep disruptions can initiate this cycle, leading to increased risk for developing AUDs. Therefore, aim 1 in this proposal will evaluate the effects of chronic and escalating alcohol drinking and abstinence on sleep architecture and Hb neural activity. The proposed experiments will use the intermittent access two-bottle choice ethanol drinking paradigm combined with chronic EEG/EMG recordings and ex vivo slice electrophysiology. It is expected that the baseline REM sleep features or the REM sleep deficits following alcohol drinking/abstinence may predict the amount of alcohol drinking as well as Hb neural activity. Aim 2 will determine if chronic REM sleep fragmentation promotes the escalation of alcohol intake in the intermittent access model and/or promotes relapse in an operant self-administration model. We will further determine if the REM sleep effects on alcohol intake/relapse are, in part, mediated by REM sleep fragmentation-induced hyperactivity of Hb neurons. Aim 3 will test the treatment potential of interventions that improve REM sleep. Utilizing recently developed REM sleep-selective manipulations, it will be determined if selective REM sleep consolidation can reduce alcohol drinking and relapse, and if this is associated with reduced Hb activity. Overall, the proposed studies will provide a critical assessment of the potential for developing REM sleep- focused therapeutics for preventing relapse, and provide novel mechanistic insight into the interactions between alcohol intake and sleep homeostasis in the context of habenula dysregulation. Thus, this proposal is consistent with the mission of NIAAA RFA-AA-19-006 to perform Mechanistic Studies on Chronic Alcohol Use and Sleep Homeostasis.

抽象的 睡眠失调是酒精使用障碍 (AUD) 的一个标志，睡眠紊乱可能会导致 即使禁欲几个月后也会复发。尽管睡眠与 AUD 之间的相互作用已得到广泛认可，但很少有研究 研究了睡眠如何随着过量饮酒的发展而变化，以及其机制 哪些睡眠中断会加剧酗酒和/或旧病复发的可能性尚不清楚。基于几个关键 根据已发表的研究和初步工作的结果，一个假设是快速眼动睡眠中断会导致 内侧 (M) 和外侧缰核 (LHb) 的适应不良变化，进而导致升级 饮酒并促进复发。主要发现如下： 1. 术后 2-3 周出现特定的 REM 睡眠缺陷 酒精戒断是酒精依赖患者复发的有力预测因素； 2. 慢性、选择性 REM 睡眠碎片化增强内侧 Hb 神经元的紧张性放电和负面情绪； 3. 酗酒复发 寻找与 MHb 和 LHb 神经元的激活增加有关。 4.睡眠碎片化沉淀 戒除可卡因期间会减少对药物的渴望，而选择性巩固快速眼动睡眠会减少对药物的渴望。 因此，据预测，长期饮酒和戒酒会导致快速眼动睡眠中断，从而诱发 血红蛋白过度活跃，促进负面情绪状态，从而驱动酗酒和旧病复发。同样，它 据预测，慢性快速眼动睡眠中断会启动这一循环，从而导致患上这种疾病的风险增加 澳元。因此，本提案中的目标 1 将评估长期和不断增加的饮酒和饮酒的影响 节制对睡眠结构和 Hb 神经活动的影响。建议的实验将使用间歇式 访问两瓶选择乙醇饮用模式结合慢性脑电图/肌电图记录和离体 切片电生理学。预计基线 REM 睡眠特征或 REM 睡眠缺陷如下 饮酒/戒酒可以预测饮酒量以及 Hb 神经活动。目标2将 确定慢性快速眼动睡眠碎片化是否会促进间歇性快速眼动睡眠中酒精摄入量的增加 访问模型和/或促进操作性自我管理模型的复发。我们将进一步确定是否 快速眼动睡眠对酒精摄入/复发的影响部分是由快速眼动睡眠碎片引起的 Hb 神经元过度活跃。目标 3 将测试改善快速眼动睡眠干预措施的治疗潜力。 利用最近开发的快速眼动睡眠选择性操作，将确定选择性快速眼动睡眠是否 巩固治疗可以减少饮酒和复发，并且这与血红蛋白活性降低有关。 总体而言，拟议的研究将为开发快速眼动睡眠的潜力提供严格的评估 专注于预防复发的治疗方法，并为相互作用提供新的机制见解 缰核失调背景下酒精摄入量与睡眠稳态之间的关系。因此，这个提议是 与 NIAAA RFA-AA-19-006 的使命一致，即对慢性酒精使用进行机制研究 和睡眠稳态。