Linking GABAA receptor subunits to alcohol-induced conditioned taste aversion and recovery from acute alcohol intoxication

GABA type A receptors (GABA(A)-R) are important for ethanol actions and it is of interest to link individual subunits with specific ethanol behaviors. We studied null mutant mice for six different GABA(A)-R subunits (alpha 1, alpha 2, alpha 3, alpha 4, alpha 5 and delta). Only mice lacking the alpha 2 subunit showed reduction of conditioned taste aversion (CTA) to ethanol. These results are in agreement with data from knock-in mice with mutation of the ethanol-sensitive site in the alpha 2-subunit (Blednov et al., 2011). All together, they indicate that aversive property of ethanol is dependent on ethanol action on alpha 2-containing GABA(A)-R. Deletion of the alpha 2-subunit led to faster recovery whereas absence of the alpha 3-subunit slowed recovery from ethanol-induced incoordination (rotarod). Deletion of the other four subunits did not affect this behavior. Similar changes in this behavior for the alpha 2 and alpha 3 null mutants were found for flurazepam motor incoordination. However, no differences in recovery were found in motor-incoordinating effects of an alpha 1-selective modulator (zolpidem) or an alpha 4-selective agonist (gaboxadol). Therefore, recovery of rotarod incoordination is under control of two GABA(A)-R subunits: alpha 2 and alpha 3. For motor activity, alpha 3 null mice demonstrated higher activation by ethanol (1 g/kg) whereas both alpha 2 (-/-) and alpha 3 (-/Y) knockout mice were less sensitive to ethanol-induced reduction of motor activity (1.5 g/kg). These studies demonstrate that the effects of ethanol at GABAergic synapses containing alpha 2 subunit are important for specific behavioral effects of ethanol which may be relevant to the genetic linkage of the alpha 2 subunit with human alcoholism. (c) 2012 Elsevier Ltd. All rights reserved.