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Oxysterols Modulate the Acute Effects of Ethanol on Hippocampal N-Methyl-d-Aspartate Receptors, Long-Term Potentiation, and Learning

Ethanol is a noncompetitive 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, blo...

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Autores principales: Izumi, Yukitoshi, Mennerick, Steven J., Doherty, James J., Zorumski, Charles F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Pharmacology and Experimental Therapeutics 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051516/
https://www.ncbi.nlm.nih.gov/pubmed/33441369
http://dx.doi.org/10.1124/jpet.120.000376
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author Izumi, Yukitoshi
Mennerick, Steven J.
Doherty, James J.
Zorumski, Charles F.
author_facet Izumi, Yukitoshi
Mennerick, Steven J.
Doherty, James J.
Zorumski, Charles F.
author_sort Izumi, Yukitoshi
collection PubMed
description Ethanol is a noncompetitive 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 and a synthetic oxysterol analog, SGE-301, 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 effects of ethanol on LTP in vitro, and the synthetic analog 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. This study 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.
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spelling pubmed-80515162021-04-21 Oxysterols Modulate the Acute Effects of Ethanol on Hippocampal N-Methyl-d-Aspartate Receptors, Long-Term Potentiation, and Learning Izumi, Yukitoshi Mennerick, Steven J. Doherty, James J. Zorumski, Charles F. J Pharmacol Exp Ther Neuropharmacology Ethanol is a noncompetitive 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 and a synthetic oxysterol analog, SGE-301, 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 effects of ethanol on LTP in vitro, and the synthetic analog 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. This study 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. The American Society for Pharmacology and Experimental Therapeutics 2021-04 2021-04 /pmc/articles/PMC8051516/ /pubmed/33441369 http://dx.doi.org/10.1124/jpet.120.000376 Text en Copyright © 2021 by The Author(s) https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed under the CC BY-NC Attribution 4.0 International license (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Neuropharmacology
Izumi, Yukitoshi
Mennerick, Steven J.
Doherty, James J.
Zorumski, Charles F.
Oxysterols Modulate the Acute Effects of Ethanol on Hippocampal N-Methyl-d-Aspartate Receptors, Long-Term Potentiation, and Learning
title Oxysterols Modulate the Acute Effects of Ethanol on Hippocampal N-Methyl-d-Aspartate Receptors, Long-Term Potentiation, and Learning
title_full Oxysterols Modulate the Acute Effects of Ethanol on Hippocampal N-Methyl-d-Aspartate Receptors, Long-Term Potentiation, and Learning
title_fullStr Oxysterols Modulate the Acute Effects of Ethanol on Hippocampal N-Methyl-d-Aspartate Receptors, Long-Term Potentiation, and Learning
title_full_unstemmed Oxysterols Modulate the Acute Effects of Ethanol on Hippocampal N-Methyl-d-Aspartate Receptors, Long-Term Potentiation, and Learning
title_short Oxysterols Modulate the Acute Effects of Ethanol on Hippocampal N-Methyl-d-Aspartate Receptors, Long-Term Potentiation, and Learning
title_sort oxysterols modulate the acute effects of ethanol on hippocampal n-methyl-d-aspartate receptors, long-term potentiation, and learning
topic Neuropharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051516/
https://www.ncbi.nlm.nih.gov/pubmed/33441369
http://dx.doi.org/10.1124/jpet.120.000376
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