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

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. This study compared sleep-wake states and electroencephalography (EEG) spectral power following exposure to ethanol and GABAA receptor (GABAAR) compounds with varying subtype selectivity. Sprague-Dawley rats received ethanol or subtype-selective GABAAR compounds, followed by EEG/electromyography (EMG) recordings for 12 h. These recordings were analyzed for sleep-wake state and EEG spectral power. 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. Analysis of sleep-wake states after administration of ethanol or GABAAR compounds with varying subtype selectivity suggests that positive modulation of α1, 2, 3, and/or 5 subunit-containing GABAARs 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 GABAARs may be involved in ethanol-induced increases in SWS. The lack of similarity between ethanol and the GABAAR 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.