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OtherNeuropharmacology

Oxysterols Modulate the Acute Effects of Ethanol on Hippocampal NMDA Receptors,LTP and Learning

Yukitoshi Izumi, Steven J. Mennerick, James J Doherty and Charles Zorumski
Journal of Pharmacology and Experimental Therapeutics January 13, 2021, JPET-AR-2020-000376; DOI: https://doi.org/10.1124/jpet.120.000376
Yukitoshi Izumi
1Psychiatry, Washinton University in St. Louis School of Medicine, United States of America
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Steven J. Mennerick
2Dept. of Psychiatry, Washington University School of Medicine, United States of America
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James J Doherty
3Sage Therapeutics, United States of America
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Charles Zorumski
4Washington University, United States of America
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  • For correspondence: zorumskc@wustl.edu
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Abstract

Ethanol is a non-competitive inhibitor of N-methyl-D-aspartate receptors (NMDARs) and acutely disrupts hippocampal synaptic plasticity and learning. In the present study, we examined the effects of oxysterol positive allosteric modulators (PAMs) of NMDARs on ethanol-mediated inhibition of NMDARs, block of long-term potentiation (LTP) and long-term depression (LTD) in rat hippocampal slices, and defects in one-trial learning in vivo. We found that 24S-hydroxycholesterol (24S-HC) and a synthetic oxysterol analogue overcame effects of ethanol on NMDAR-mediated synaptic responses in the CA1 region but did not alter acute effects of ethanol on LTD; the synthetic oxysterol, however, overcame acute inhibition of LTP. In addition, both oxysterols overcame persistent metaplastic effects of ethanol on LTP in vitro, and the synthetic analogue reversed defects in one-trial inhibitory avoidance learning in vivo. These results indicate that effects of ethanol on both LTP and LTD arise by complex mechanisms beyond NMDAR antagonism and that oxysterol NMDAR PAMs may represent a novel approach for preventing and reversing acute ethanol-mediated changes in cognition.

Significance Statement Ethanol acutely inhibits hippocampal NMDARs, LTP and learning. In this study, we found that certain oxysterols that are NMDAR positive allosteric modulators can overcome the acute effects of ethanol on NMDARs, LTP and learning. Oxysterols differ in their effects from agents that inhibit integrated cellular stress responses.

  • alcohol
  • LTD
  • LTP
  • memory
  • neurosteroids
  • synaptic plasticity
  • © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.
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Journal of Pharmacology and Experimental Therapeutics: 376 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 2
1 Feb 2021
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OtherNeuropharmacology

Oxysterols and ethanol

Yukitoshi Izumi, Steven J. Mennerick, James J Doherty and Charles Zorumski
Journal of Pharmacology and Experimental Therapeutics January 13, 2021, JPET-AR-2020-000376; DOI: https://doi.org/10.1124/jpet.120.000376

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OtherNeuropharmacology

Oxysterols and ethanol

Yukitoshi Izumi, Steven J. Mennerick, James J Doherty and Charles Zorumski
Journal of Pharmacology and Experimental Therapeutics January 13, 2021, JPET-AR-2020-000376; DOI: https://doi.org/10.1124/jpet.120.000376
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