Because ethanol directly binds and activates GIRK channels46-48,156, they may mediate some ethanol-related behaviors. In fact, ethanol has been shown to enhance GABAB-activated GIRK currents in neurons of the VTA156, which would decrease the firing frequency of DA VTA neurons in rodents. As discussed above, GIRK channels likely have a role in the analgesic effects of ethanol138,157, but whether they also contribute to the reinforcing effects of ethanol is less clear. GIRK2 knockout mice exhibit reduced conditioned taste aversion, compared to wild-type mice suggesting that GIRK activation could be involved in the motivational response of ethanol158,. However, these differences were observed with moderate but not high doses of ethanoll158. Using a different approach, involving identification of a quantitative trait locus (QTL) with large effects on predisposition to physical dependence and associated withdrawal from sedative hypnotics such as ethanol, a 0.44 Mb region of mouse chromosome 1 was mapped for this QTL that contains Girk3 (Kcnj9)34. In a behavioral assay designed to measure withdrawal, GIRK3 −/− mice show less severe withdrawal symptoms from ethanol and barbituarates use34.
