Alcohol actions on recombinant glycine receptors (GlyRs) showed that mutations M287L and Q266I of the α1 subunit lead to a reduction in ethanol potentiation of glycine-induced current. Blednov et al. constructed knockin mice with each of these mutations, allowing the use of behavioral testing to determine the influence of these changes on behavioral effects of ethanol and other drugs. Rotarod ataxia was one behavioral effect of ethanol reduced more in the Q266I mutant than the M287L mutant. Mutant mice also differed in ethanol consumption, ethanol-stimulated startle response, signs of acute physical dependence, and duration of loss of righting response produced by ethanol, butanol, ketamine, pentobarbital, and flurazepam. Some of these behavioral changes were mimicked in wild-type mice by acute injections of low, subconvulsive doses of strychnine. Both mutants showed increased acoustic startle response and increased sensitivity to strychnine seizures. In addition to reducing ethanol action on the GlyRs, these mutations reduced glycinergic inhibition, which may also alter sensitivity to GABAergic drugs. These results show the ability of a single amino acid change in the GlyR α1 subunit to decrease specific behavioral actions of ethanol and to alter other nonethanol behaviors, demonstrating the importance of GlyR function in diverse neuronal systems.

See article at J Pharmacol Exp Ther 2012, 340:317–329.

• Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics