Ethanol-induced rapid eye movement sleep suppression in rats: Comparison with subtype-selective GABA A receptor compounds

Background: Alcohol use disorder patients experience reductions in rapid eye movement (REM) sleep and other sleep problems. Little is known about the pharmacological mechanism(s) involved in this effect. Aims: This study compared sleep–wake states and electroencephalography (EEG) spectral power following exposure to ethanol and GABA A receptor (GABA A R) compounds with varying subtype selectivity. Methods: Sprague-Dawley rats received ethanol or subtype-selective GABA A R compounds, followed by EEG/electromyography (EMG) recordings for 12 h. These recordings were analyzed for sleep–wake state and EEG spectral power. Results: Sleep–wake state analysis demonstrated that ethanol, the nonselective compound alprazolam, the α1-selective compound zolpidem, the α2/3-selective compound KRM-II-81, and the α5-selective compound MP-III-022 produced decreases in REM sleep. By contrast, the α4/6-selective compound, gaboxadol, only increased time spent in slow-wave sleep (SWS). KRM-II-81 was the only compound to produce increases in time spent awake. The EEG spectral power analysis revealed that all compounds produced a unique signature, but none produced a signature similar to ethanol. Conclusions: Analysis of sleep–wake states after administration of ethanol or GABA A R compounds with varying subtype selectivity suggests that positive modulation of α1, 2, 3, and/or 5 subunit-containing GABA A Rs is sufficient to suppress REM sleep, and any or all may be involved in ethanol-induced REM sleep suppression. Also, our study suggests that α4/6 subunit-containing GABA A Rs may be involved in ethanol-induced increases in SWS. The lack of similarity between ethanol and the GABA A R compounds in the pharmaco-EEG analysis suggests that neurotransmitter systems besides the GABAergic system are likely involved in the effects of ethanol on EEG spectral power.