Acute effects of ethanol on hippocampal long-term potentiation and long-term depression are mediated by different mechanisms

Neuroscience. 2005;136(2):509-17. doi: 10.1016/j.neuroscience.2005.08.002. Epub 2005 Oct 10.


To determine potential mechanisms contributing to ethanol-induced cognitive impairment, we examined acute effects of ethanol on hippocampal N-methyl-d-aspartate receptors and forms of synaptic plasticity thought to underlie memory processing. In the CA1 region of rat hippocampal slices, ethanol partially inhibited N-methyl-d-aspartate receptor-mediated synaptic responses at concentrations up to 180 mM. The block of synaptic N-methyl-d-aspartate receptors by 60mM ethanol occluded the effects of 10 microM ifenprodil, an agent that has relative selectivity for N-methyl-D-aspartate receptors expressing NR1 and NR2B subunits. Ethanol did not occlude the effects of a low concentration of 2-amino-5-phosphonovalerate, an antagonist with less N-methyl-d-aspartate receptor subtype selectivity. Recent studies indicate that ifenprodil and other NR2B-selective antagonists inhibit N-methyl-D-aspartate receptor-dependent long-term depression but not long-term potentiation. We found that ethanol reversibly inhibited long-term depression in a manner consistent with its effects on synaptic N-methyl-D-aspartate receptors. Ethanol also inhibited the induction of N-methyl-D-aspartate receptor-dependent long-term potentiation, but the actions on long-term potentiation were complex and largely irreversible over the time course of our experiments. Furthermore, ethanol inhibited a form of long-term potentiation induced by very high frequency stimulation that does not depend on N-methyl-D-aspartate receptor activation. The effects of ethanol on both forms of long-term potentiation, but not on long-term depression, were at least partially reversed by block of GABA type A receptors with picrotoxin. These results indicate that pharmacologically relevant concentrations of ethanol exert preferential effects on a subtype of synaptic N-methyl-D-aspartate receptors in the CA1 hippocampal region. Inhibition of synaptic N-methyl-D-aspartate receptors appears to contribute strongly to ethanol-mediated long-term depression inhibition, but effects on long-term potentiation are complex, involving, at least partially, changes in GABAergic transmission.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Central Nervous System Depressants / antagonists & inhibitors
  • Central Nervous System Depressants / pharmacology*
  • Depression, Chemical
  • Ethanol / antagonists & inhibitors
  • Ethanol / pharmacology*
  • GABA Antagonists / pharmacology
  • Hippocampus / drug effects*
  • In Vitro Techniques
  • Long-Term Potentiation / drug effects*
  • Male
  • Neuronal Plasticity / drug effects*
  • Picrotoxin / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / drug effects


  • Central Nervous System Depressants
  • GABA Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Picrotoxin
  • Ethanol