Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 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.

PubMed Disclaimer

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
See this image and copyright information in PMC

References

    1. Boyce-Rustay JM, Holmes A. Functional roles of NMDA receptor NR2A and NR2B subunits in the acute intoxicating effects of ethanol in mice. Synapse. 2005;56:222–225. - PubMed
    1. Boyce-Rustay JM, Holmes A. Ethanol-related behaviors in mice lacking the NMDA receptor NR2A subunit. Psychopharmacology (Berl) 2006;187:455–466. - PubMed
    1. Camp MC, Feyder M, Ihne J, Palachick B, Hurd B, Karlsson RM, Noronha B, Chen YC, Coba MP, Grant SG, Holmes A. A novel role for PSD-95 in mediating ethanol intoxication, drinking and place preference. Addict Biol. 2011;16:428–439. - PMC - PubMed
    1. Chen YC, Holmes A. Effects of topiramate and other anti-glutamatergic drugs on the acute intoxicating actions of ethanol in mice: modulation by genetic strain and stress. Neuropsychopharmacology. 2009;34:1454–1466. - PMC - PubMed
    1. Debrouse L, Hurd B, Kiselycznyk C, Plitt A, Todaro A, Mishina M, Grant SG, Camp M, Gunduz-Cinar O, Holmes A. Probing the Modulation of Acute Ethanol Intoxication by Pharmacological Manipulation of the NMDAR Glycine Co-Agonist Site. Alcohol Clin Exp Res. 2013;37:223–233. - PMC - PubMed

Publication types

MeSH terms