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

The neural and genetic factors underlying chronic tolerance to alcohol are currently unclear. The GluN2A NMDAR subunit and the NMDAR-anchoring protein PSD-95 mediate acute alcohol intoxication and represent putative mechanisms mediating tolerance. We found 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.