Journal Article

Alterations in Ethanol-Induced Behaviors and Consumption in Knock-In Mice Expressing Ethanol-Resistant NMDA Receptors

Beckley, Jacob T., Smothers, Thetford C., Lench, Daniel H., Holseberg, Zack L., den Hartog, Carolina R., Fedarovich, Hleb, Woodward, John J., Homanics, Gregg E., Gilstrap, Meghin J.

2013

Overview

Ethanol's action on the brain likely reflects altered function of key ion channels such as glutamatergic N-methyl-D-aspartate receptors (NMDARs). In this study, we determined how expression of a mutant GluN1 subunit (F639A) that reduces ethanol inhibition of NMDARs affects ethanol-induced behaviors in mice. Mice homozygous for the F639A allele died prematurely while heterozygous knock-in mice grew and bred normally. Ethanol (44 mM; ∼0.2 g/dl) significantly inhibited NMDA-mediated EPSCs in wild-type mice but had little effect on responses in knock-in mice. Knock-in mice had normal expression of GluN1 and GluN2B protein across different brain regions and a small reduction in levels of GluN2A in medial prefrontal cortex. Ethanol (0.75-2.0 g/kg; i.p.) increased locomotor activity in wild-type mice but had no effect on knock-in mice while MK-801 enhanced activity to the same extent in both groups. Ethanol (2.0 g/kg) reduced rotarod performance equally in both groups but knock-in mice recovered faster following a higher dose (2.5 g/kg). In the elevated zero maze, knock-in mice had a blunted anxiolytic response to ethanol (1.25 g/kg) as compared to wild-type animals. No differences were noted between wild-type and knock-in mice for ethanol-induced loss of righting reflex, sleep time, hypothermia or ethanol metabolism. Knock-in mice consumed less ethanol than wild-type mice during daily limited-access sessions but drank more in an intermittent 24 h access paradigm with no change in taste reactivity or conditioned taste aversion. Overall, these data support the hypothesis that NMDA receptors are important in regulating a specific constellation of effects following exposure to ethanol.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alcoholism / Animals / Behavior / Behavior, Animal - drug effects / Blotting, Western / Brain / Cell Line / Conditioning / Deoxyribonucleic acid / Dizocilpine / DNA / Dopamine / Electrophysiology / Ethanol / Ethanol - pharmacology / Excitatory postsynaptic potentials / Female / Glutamatergic transmission / Glutamic acid receptors (ionotropic) / Humans / Hypothermia / Ion channels / Kinases / Laboratory animals / Locomotor activity / Male / Metabolism / Mice / Mice, Inbred C57BL / Mice, Mutant Strains / MK-801 / Motor Activity - drug effects / Motor Activity - genetics / Mutation / N-methyl-D-aspartate / N-Methyl-D-aspartic acid receptors / Neurobiology / Neurons / Neurosciences / Phosphatase / Physiological aspects / Polyamines / Prefrontal cortex / Proteins / Psychiatry / Receptor mechanisms / Receptors / Receptors, N-Methyl-D-Aspartate - genetics / Receptors, N-Methyl-D-Aspartate - metabolism / Righting reflex / Sleep / Stem cells / Taste / Taste aversion