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

Neuropsychopharmacology volume 49, pages 885–892 (2024)Cite this article

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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 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.

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Fig. 1: Serum acetate after ethanol exposure.
Fig. 2: Acetic acid increases NAcSh MSN excitability.
Fig. 3: Impact of NMDAR antagonist on acetic acid induced increase in NAcSh MSN excitability.
Fig. 4: Acetic acid induces NMDAR-mediated inward currents and produces a more robust response in females.

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Acknowledgements

We would like to thank Chau-Mi H. Phan and Pramit J. Jagtap for their assistance. We would also like to thank Dr. Manuel Esguerra, Dr. Timothy W. Chapp, Dr. Scott M. Chapp, Casey L. Mallo and Dr. Qing-Hui Chen for their proofreading and suggestions.

Funding

This study was supported by NIH R01DA041808 (MJT and PGM), T32DA007234 (ADC) and an MnDRIVE fellowship (ADC).

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Author notes

  1. These authors contributed equally: Andrew D. Chapp, Chinonso A. Nwakama.

Authors and Affiliations

  1. Department of Neuroscience, University of Minnesota, Minneapolis, MN, 55455, USA

    Andrew D. Chapp, Chinonso A. Nwakama, Paul G. Mermelstein & Mark J. Thomas

  2. Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, MN, 55445, USA

    Andrew D. Chapp, Chinonso A. Nwakama, Paul G. Mermelstein & Mark J. Thomas

  3. Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Chinonso A. Nwakama

  4. Department of Psychiatry, University of California San Francisco Fresno, Fresno, CA, 93701, USA

    Andréa R. Collins

  5. Center for Neural Circuits in Addiction, University of Minnesota, Minneapolis, MN, 55455, USA

    Paul G. Mermelstein & Mark J. Thomas

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Contributions

ADC and CAN performed experiments; ADC and CAN, analyzed data; ADC, CAN, PGM and MJT, prepared figures; ADC, CAN, ARC, PGM and MJT drafted manuscript; ADC, CAN, ARC, PGM and MJT interpreted results of experiment; ADC, CAN, ARC, PGM and MJT edited and revised manuscript.

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Correspondence to Paul G. Mermelstein or Mark J. Thomas.

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Chapp, A.D., Nwakama, C.A., Collins, A.R. et al. Physiological acetic acid concentrations from ethanol metabolism stimulate accumbens shell medium spiny neurons via NMDAR activation in a sex-dependent manner. Neuropsychopharmacol. 49, 885–892 (2024). https://doi.org/10.1038/s41386-023-01752-8

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