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.

项目摘要 在寻求饮酒障碍治疗的个体中，睡眠并发症患病率很高 （aud）。饮酒会诱发睡眠障碍，进而诱发睡眠易感性患者 继续饮酒，治疗反应不佳和缓解。除了影响不同的睡眠阶段 建筑，酒精已显示可降低眼睛快速运动（REM）睡眠，而机制则通过 这些减少的发生尚不清楚。识别酒精的药物机制 抑制REM睡眠可能为治疗AUD患者观察到的睡眠障碍提供了潜在的目标 并改善整体治疗结果。 REM睡眠是由几个相互作用产生和维护的 脑干，前脑和下丘脑中的神经递质系统。一个关键的神经递质是γ- 氨基丁酸（GABA），这也是酒精行为影响的至关重要的介体。我们 假设酒精引起的REM睡眠抑制是由酒精的正面调制驱动的 α1-和/或α5-GABAA受体（GABAAR）亚型，此外，这些负面调节 亚型会减弱酒精引起的REM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 酒精诱导的REM睡眠抑制中的特定Gabaar亚型。总体假设将是 以三个特定目标进行评估。在AIM1中，我们将评估男性的睡眠效果状态和脑电图频谱功率 雌性Sprague Dawley大鼠酒精和亚型选择性Gabaar阳性 调节器。我们预测酒精会引起睡眠效果状态的变化和脑电图光谱能力 非选择性阳性GABAAR调节剂产生的变化。我们进一步假设α1和/或α5- GABAAR正调制器将引起睡眠效果状态和EEG光谱功能的独特变化，其中包括 REM睡眠的减少。在AIM 2中，我们将评估α1-gabaar子类型媒体专辑的程度 诱导REM睡眠抑制。我们预测用负α1-GABAAR调节器进行预处理将 防止酒精诱导的REM睡眠减少，并且阳性α1-Gabaar调节剂会加剧 酒精引起的REM睡眠减少。最后，在AIM 3中，我们将评估α5-GABAAR的程度 亚型介导酒精诱导的REM睡眠抑制。我们预测，α5-负的预处理 GABAAR调节器将减轻酒精诱导的REM睡眠减少，并且α5-Gabaar阳性 调节器将加剧酒精引起的REM睡眠减少。