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bioRxiv · 10.1101/2023.05.05.539592

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

Chapp, A. D.·Nwakama, C. A.·Mermelstein, P. G.·Thomas, M. J.
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Abstract

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 4g/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 neurons in brain slices demonstrated that physiological concentrations of acetic acid (2 mM and 4 mM) increased NAcSh neuronal 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. 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.

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Chapp, A. D., Nwakama, C. A., Mermelstein, P. G., Thomas, M. J.. 2023-05-05. Physiological acetic acid concentrations from ethanol metabolism stimulate accumbens shell neurons via NMDAR activation in a sex-dependent manner. https://doi.org/10.1101/2023.05.05.539592

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