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

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

Rachel A Daut  1 , Erica F Busch, Jessica Ihne, Daniel Fisher, Masayoshi Mishina, Seth G N Grant, Marguerite Camp, Andrew Holmes
Affiliations

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

Rachel A Daut et al. Addict Biol. 2015 Mar.

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.

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Figures

Figure 1
Figure 1. Effects of CIE on withdrawal-anxiety and tolerance in GluN2A KO and PSD-95 KO
(A) Effect of CIE and GluN2A genotype on light/dark exploration time in light. (B) Effect of CIE and GluN2A genotype on EtOH-induced rotarod ataxia. (C) Effect of CIE and GluN2A genotype on EtOH-induced LORR. (D) Effect of CIE and PSD-95 genotype on light/dark exploration time in light. (E) Effect of CIE and PSD-95 genotype on EtOH-induced rotarod ataxia. (F) Effect of CIE and PSD-95 genotype on EtOH-induced LORR. Data are Means ±SEM. *P<.05
Figure 2
Figure 2. Effects of CIE on tolerance in C57BL/6J mice, GluN2A KO and PSD-95 KO
(A) Effect of prolonged CIE on EtOH-induced LORR in C57BL/6J. (B) Effect of CIE on EtOH-induced LORR 1 day post-CIE in C57BL/6J. (C) Effect of CIE on EtOH-induced LORR 1 day post-CIE in a replicate C57BL/6J sample. (D) Effect of CIE and GluN2A genotype on EtOH-induced LORR 1 day post-CIE. (E) Effect of CIE and PSD-95 genotype on EtOH-induced LORR 1 day post-CIE. Data are Means ±SEM. *P<.05
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