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

Abstract

The neural and genetic factors underlying chronic tolerance to alcohol are currently unclear. The GluN2AN-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. The mechanisms underlying chronic tolerance to alcohol remain 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 or withdrawal-anxiety in C57BL/6J, GluN2A or PSD-95 knockout mice. However, significant tolerance to LORR was evident 1 day after CIE in C57BL/6J and PSD-95 knockouts, but not GluN2A knockouts. These data suggest a role for GluN2A in tolerance.