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

项目摘要 在寻求酒精使用障碍治疗的个人中，睡眠并发症的发生率很高。 (澳元)。饮酒会导致睡眠障碍，反过来，睡眠障碍会使AUD患者先入为主 持续饮酒，治疗反应差，以及复发。除了影响睡眠的不同阶段 酒精已经被证明可以减少快速眼动(REM)睡眠，其机制是通过 目前尚不清楚这些削减发生在哪些地方。确定酒精的药理机制 抑制REM睡眠可能为治疗AUD患者的睡眠障碍提供潜在的靶点 以及改善整体治疗结果。REM睡眠是由以下几个因素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。一种关键的神经递质是γ- 氨基丁酸(GABA)，它也是酒精行为影响的一个至关重要的中介。我们 假设酒精引起的快速眼动睡眠抑制是由酒精对 α1和/或α5-GABA受体(GABA-AR)亚型以及它们的负性调节 亚型将减弱酒精诱导的快速眼动睡眠抑制。我们将使用脑电图仪 脑电(EEG)和肌电(EMG)记录和亚型选择性GABAAR调节剂确定作用 在酒精诱导的快速眼动睡眠抑制中的特定GABAAR亚型。最重要的假设是 根据三个具体目标进行评估。在Aim1中，我们将评估男性的睡眠-觉醒状态和脑电频谱功率 和雌性SD大鼠灌胃酒精和亚型选择性GABAAR阳性 调制器。我们预测酒精会引起睡眠-觉醒状态和脑电频谱功率的变化 由非选择性正GABAAR调制器产生的变化。我们进一步假设α1-和/或α5- GABAAR正向调制器将导致睡眠-觉醒状态和脑电频谱功率的独特变化，包括 快速眼动睡眠的减少。在目标2中，我们将评估α1-GABAAR亚型在多大程度上介导酒精- 诱导的快速眼动睡眠抑制。我们预测，用负的α1-GABAAR调节剂进行预处理将 防止酒精引起的快速眼动睡眠减少以及阳性的α1-GABAAR调节剂将加剧 酒精导致的快速眼动睡眠减少。最后，在目标3中，我们将评估α5-GABAAR的程度 亚型介导酒精诱导的快速眼动睡眠抑制。我们预测，在α为负的情况下，5- GABAAR调节剂将减弱酒精引起的快速眼动睡眠减少，α阳性的5-GABAAR 调节剂会加重酒精引起的快速眼动睡眠减少。

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.