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.