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

Jaren A Reeves-Darby; Lais F Berro; Heather L Hembree; James P Shaffery; James K Rowlett; Dishary Sharmin; Prithu Mondal; James M Cook; Donna M Platt

doi:10.1177/02698811251344682

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

J Psychopharmacol. 2025 Jun 20:2698811251344682. doi: 10.1177/02698811251344682. Online ahead of print.

Authors

Jaren A Reeves-Darby^{1

2}, Lais F Berro^{1

2

3}, Heather L Hembree¹, James P Shaffery¹, James K Rowlett^{1

2

3}, Dishary Sharmin⁴, Prithu Mondal⁴, James M Cook⁴, Donna M Platt^{1

2

3}

Affiliations

¹ Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA.
² Graduate Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, USA.
³ Center for Innovation and Discovery in Addictions, University of Mississippi Medical Center, Jackson, MS, USA.
⁴ Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.

PMID: 40539934
DOI: 10.1177/02698811251344682

Abstract

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_AR) compounds with varying subtype selectivity.

Methods: Sprague-Dawley rats received ethanol or subtype-selective GABA_AR 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_AR compounds with varying subtype selectivity suggests that positive modulation of α1, 2, 3, and/or 5 subunit-containing GABA_ARs 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_ARs may be involved in ethanol-induced increases in SWS. The lack of similarity between ethanol and the GABA_AR 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.

Keywords: EEG/EMG recording; Ethanol; GABAA receptors; sleep architecture; spectral power.