Tolerance to ethanol intoxication after chronic ethanol: role of GluN2A and PSD-95

Addict Biol. 2015 Mar;20(2):259-62. doi: 10.1111/adb.12110. Epub 2014 Jan 7.

Abstract

The neural and genetic factors underlying chronic tolerance to alcohol are currently unclear. The GluN2A N-methyl-D-aspartate receptors (NMDAR) subunit and the NMDAR-anchoring protein PSD-95 mediate acute alcohol intoxication and represent putative mechanisms mediating tolerance. We found that chronic intermittent ethanol exposure (CIE) did not produce tolerance [loss of righting reflex (LORR)] or withdrawal-anxiety in C57BL/6J, GluN2A or PSD-95 knockout mice assayed 2-3 days later. However, significant tolerance to LORR was evident 1 day after CIE in C57BL/6J and PSD-95 knockouts, but absent in GluN2A knockouts. These data suggest a role for GluN2A in tolerance, extending evidence that human GluN2A gene variation is involved in alcohol dependence.

Keywords: GluN2A and PSD-95; chronic ethanol; tolerance.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Alcoholic Intoxication / genetics*
  • Animals
  • Anxiety / genetics*
  • Central Nervous System Depressants / pharmacology*
  • Disks Large Homolog 4 Protein
  • Drug Tolerance / genetics*
  • Ethanol / pharmacology*
  • Guanylate Kinases / genetics*
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Knockout
  • Receptors, N-Methyl-D-Aspartate / genetics*
  • Substance Withdrawal Syndrome / genetics*

Substances

  • Central Nervous System Depressants
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Membrane Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Ethanol
  • Guanylate Kinases
  • N-methyl D-aspartate receptor subtype 2A