Sunday, May 11, 2025
5/11/2025
Alcohol-induced decreases in REM sleep: GABA-A receptor subtypes - 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.
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