Alcohol-induced decreases in REM sleep: GABA-A receptor subtypes

酒精引起的快速眼动睡眠减少：GABA-A 受体亚型

• 批准号: 10627938
• 负责人: Jaren Asher Reeves-Darby
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10627938
• 关键词: Acute; Affect; Alcohol consumption; Alcohols; Animals; Attenuated; Behavioral; Brain Stem; Characteristics; Data; Electroencephalography; Exhibits; Female; GABA-A Receptor; Goals; High Prevalence; Hippocampus; Histologic; Human; Hypothalamic structure; Individual; Investigation; Ligands; Mediating; Mediator; Neurotransmitters; Patients; Pharmacology; Pharmacology Study; Prevalence; Property; Prosencephalon; Protein Isoforms; Protein Subunits; REM Sleep; Rattus; Relapse; Research; Reticular Formation; Role; Series; Sleep; Sleep Architecture; Sleep Stages; Sleep disturbances; Specificity; Sprague-Dawley Rats; System; Time; Transgenic Mice; Treatment outcome; alcohol abuse therapy; alcohol effect; alcohol prevention; alcohol use disorder; antagonist; design; experimental study; gamma-Aminobutyric Acid; immunocytochemistry; improved; male; new therapeutic target; pharmacologic; power analysis; receptor; sedative; sleep regulation; treatment response

Project Summary There is a high prevalence of sleep complications among individuals seeking treatment for alcohol use disorder (AUD). Alcohol consumption induces sleep disturbances, and in turn, disrupted sleep predisposes AUD patients to continued alcohol use, poor treatment response, and relapse. In addition to affecting different stages of sleep architecture, alcohol has been shown to decrease rapid eye movement (REM) sleep, and the mechanisms by which these reductions occur remain unclear. Identifying the pharmacological mechanism by which alcohol suppresses REM sleep may provide a potential target for treating sleep disturbances observed in AUD patients and improving overall treatment outcomes. REM sleep is generated and maintained by the interplay of several neurotransmitter systems in the brainstem, forebrain, and hypothalamus. One key neurotransmitter is γ- aminobutyric acid (GABA), which also is a critically important mediator of alcohol's behavioral effects. We hypothesize that alcohol-induced REM sleep suppression is driven by alcohol's positive modulation of α1- and/or α5-GABAA receptor (GABAAR) subtypes and, further, that negative modulation of these subtypes will attenuate alcohol-induced REM sleep suppression. We will use electroencephalographic (EEG) and electromyogram (EMG) recordings and subtype-selective GABAAR modulators to determine the role of specific GABAAR subtypes in alcohol-induced suppression of REM sleep. The overarching hypothesis will be evaluated in three Specific Aims. In Aim1, we will evaluate sleep-wake states and EEG spectral power in male and female Sprague Dawley rats following administration of alcohol and subtype-selective GABAAR positive modulators. We predict alcohol will induce changes in sleep-wake states and EEG spectral power that mimic changes produced by non-selective positive GABAAR modulators. We further hypothesize that α1- and/or α5- GABAAR positive modulators will elicit unique changes in sleep-wake states and EEG spectral power that include a reduction in REM sleep. In Aim 2, we will evaluate the extent to which α1-GABAAR subtypes mediate alcohol- induced REM sleep suppression. We predict that pretreatment with a negative α1-GABAAR modulator will prevent alcohol-induced reductions in REM sleep and that a positive α1-GABAAR modulator will exacerbate alcohol-induced reductions in REM sleep. Finally, in Aim 3, we will evaluate the extent to which α5-GABAAR subtypes mediate alcohol-induced REM sleep suppression. We predict that pretreatment with a negative α5- GABAAR modulator will attenuate alcohol-induced reductions in REM sleep and that a positive α5-GABAAR modulator will aggravate alcohol-induced reductions in REM sleep.

项目概要 在寻求酒精使用障碍治疗的个体中，睡眠并发症的发生率很高 (AUD)。酒精会引起睡眠障碍，反过来，睡眠紊乱又容易导致 AUD 患者。 除了影响不同阶段的睡眠外，持续饮酒、治疗反应不佳和复发也是如此。 建筑学方面，酒精已被证明会降低快速眼动 (REM) 睡眠，其机制是 这些减少是如何发生的仍不清楚。 抑制快速眼动睡眠可能为治疗 AUD 患者的睡眠障碍提供潜在目标 改善整体治疗效果 快速眼动睡眠是通过多种相互作用产生和维持的。 脑干、前脑和下丘脑的神经递质系统之一关键神经递质是 γ-。 氨基丁酸（GABA），它也是酒精行为影响的一个极其重要的调节剂。 其次，酒精引起的快速眼动睡眠抑制是由酒精的正调节驱动的 α1-和/或α5-GABAA 受体 (GABAAR) 亚型，以及这些亚型的负调节 亚型会减轻酒精引起的快速眼动睡眠抑制。我们将使用脑电图。 (EEG) 和肌电图 (EMG) 记录和亚型选择性 GABAAR 调节剂以确定作用 特定 GABAAR 亚型在酒精引起的快速眼动睡眠抑制中的作用。 在三个具体目标中进行评估 在目标 1 中，我们将评估男性的睡眠-觉醒状态和脑电图频谱功率。 和雌性 Sprague Dawley 大鼠饮酒后且亚型选择性 GABAAR 呈阳性 我们预测酒精会引起模仿睡眠-觉醒状态和脑电图频谱功率的变化。 我们进一步研究了α1-和/或α5-非选择性正GABAAR调节剂产生的变化。 GABAAR 正调制器将引起睡眠-觉醒状态和脑电图频谱功率的独特变化，包括 在目标 2 中，我们将评估 α1-GABAAR 亚型介导酒精的程度。 我们预测用负 α1-GABAAR 调节剂进行预处理会抑制 REM 睡眠。 防止酒精引起的快速眼动睡眠减少，并且积极的 α1-GABAAR 调节剂会恶化 最后，在目标 3 中，我们将评估 α5-GABAAR 的程度。 我们预测负α5-预处理会介导酒精引起的快速眼动睡眠抑制。 GABAAR 调节剂将减轻酒精引起的快速眼动睡眠的减少，并且积极的 α5-GABAAR 调节剂会加剧酒精引起的快速眼动睡眠减少。