title: 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 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.
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, Bethesda, MD, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Daut
authors.forename: Erica F
authors.initials: EF
authors.lastname: Busch
authors.forename: Jessica
authors.initials: J
authors.lastname: Ihne
authors.forename: Daniel
authors.initials: D
authors.lastname: Fisher
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Mishina
authors.forename: Seth G N
authors.initials: SG
authors.lastname: Grant
authors.forename: Marguerite
authors.initials: M
authors.lastname: Camp
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
mesh_terms: D000435:Alcoholic Intoxication / Q000235:genetics*; D000818:Animals; D001007:Anxiety / Q000235:genetics*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D000076122:Disks Large Homolog 4 Protein; D004361:Drug Tolerance / Q000235:genetics*; D000431:Ethanol / Q000494:pharmacology*; D051528:Guanylate Kinases / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D013375:Substance Withdrawal Syndrome / Q000235:genetics*
chemical_list: D002492:Central Nervous System Depressants; D000076122:Disks Large Homolog 4 Protein; D000431:Ethanol; D051528:Guanylate Kinases; D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C501447:Dlg4 protein, mouse
keywords: GluN2A and PSD-95; chronic ethanol; tolerance