Vol. 298, Issue 2, 521-530, August 2001

Potassium Channels as Targets for Ethanol: Studies of G-Protein-Coupled Inwardly Rectifying Potassium Channel 2 (GIRK2) Null Mutant Mice

Yuri A. Blednov, M. Stoffel, S. R. Chang and R. Adron Harris

Waggoner Center for Alcohol and Addiction Research and Section of Neurobiology, University of Texas at Austin, Texas (Y.A.B., S.R.C., R.A.H.); and Rockefeller University, New York, New York (M.S.)

G-Protein-coupled inwardly rectifying potassium channels (GIRKs) regulate synaptic transmission and neuronal firing rates. Selective enhancement of GIRK2 function by intoxicating concentrations of ethanol was recently shown for recombinant homomeric and heteromeric channels. We proposed that specific behavioral actions of ethanol are due to activation of GIRK channels and that these behaviors would be reduced or eliminated in GIRK2 null mutant ("knockout") mice. Three behavioral effects of ethanol were absent in mutant mice as compared with wild-type littermates: stimulation of home cage (habituated) motor activity, anxiolytic action in elevated-plus maze test, and handling-induced convulsions (HIC) after an acute injection of ethanol. In contrast to these reductions of ethanol action, mutant mice displayed greater ethanol-stimulated activity in peripheral regions of an open field. There were no differences between mutant and wild-type mice for ethanol-induced sleep time, acute functional tolerance, or HIC following chronic matched consumption of a liquid diet. Ethanol preference and consumption were equal for wild-type and mutant mice using the standard two-bottle choice test with alternation of the bottles. However, this test was complicated by the strong side preference of the mice. When ethanol was presented constantly in their favored location, the consumption of ethanol was substantially higher for mutant than for wild-type mice. In the absence of ethanol, GIRK2 knockout mice showed more motor activity, less anxiety, and higher HIC. These results provide evidence that GIRK2 channels mediate specific behaviors, including anxiety and convulsions, and may influence effects of ethanol on these behaviors.