Physiological acetic acid concentrations from ethanol metabolism stimulate accumbens shell medium spiny neurons via NMDAR activation in a sex-dependent manner

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 49; no. 5; pp. 885 - 892
• Main Authors: Chapp, Andrew D, Nwakama, Chinonso A, Collins, Andréa R, Mermelstein, Paul G, Thomas, Mark J
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.04.2024
• Subjects: Acetic acid; Acids; Animals; Brain slice preparation; Electrophysiology; Estrus cycle; Ethanol; Ethanol - pharmacology; Excitability; Female; Females; Glutamic acid receptors; Male; Males; Mammals - metabolism; Medium Spiny Neurons; Memantine; Metabolism; Metabolites; N-Methyl-D-aspartic acid receptors; Neurodegeneration; Neurons - metabolism; Nucleus Accumbens; Physiology; Receptors, N-Methyl-D-Aspartate - metabolism; Sex; Spiny neurons
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/s41386-023-01752-8

Recent studies have implicated the ethanol metabolite, acetic acid, as neuroactive, perhaps even more so than ethanol itself. In this study, we investigated sex-specific metabolism of ethanol (1, 2, and 4 g/kg) to acetic acid in vivo to guide electrophysiology experiments in the accumbens shell (NAcSh), a key node in the mammalian reward circuit. There was a sex-dependent difference in serum acetate production, quantified via ion chromatography only at the lowest dose of ethanol (males > females). Ex vivo electrophysiology recordings of NAcSh medium spiny neurons (MSN) in brain slices demonstrated that physiological concentrations of acetic acid (2 mM and 4 mM) increased NAcSh MSN excitability in both sexes. N-methyl-D-aspartate receptor (NMDAR) antagonists, AP5 and memantine, robustly attenuated the acetic acid-induced increase in excitability. Acetic acid-induced NMDAR-dependent inward currents were greater in females compared to males and were not estrous cycle dependent. These findings suggest a novel NMDAR-dependent mechanism by which the ethanol metabolite, acetic acid, may influence neurophysiological effects in a key reward circuit in the brain from ethanol consumption. Furthermore, these findings also highlight a specific sex-dependent sensitivity in females to acetic acid-NMDAR interactions. This may underlie their more rapid advancement to alcohol use disorder and increased risk of alcohol related neurodegeneration compared to males.