Several behavioral traits relevant for alcoholism are controlled by ɣ2 subunit containing GABAA receptors on dopamine neurons in mice

Andrea Stojakovic, Magdalena Walczak, Przemysław E Cieślak, Aleksandra Trenk, Johan Sköld, Joanna Zajdel, Elahe Mirrasekhian, Camilla Karlsson, Annika Thorsell, Markus Heilig, Jan Rodriguez Parkitna, Tomasz Błasiak, David Engblom

The risk factors for developing alcohol addiction include impulsivity, high sensitivity to the rewarding action of ethanol, and low sensitivity to its sedative and intoxicating effects. Genetic variation in GABAAreceptor subunits, including the ɣ2 subunit (Gabrg2), affects the risk for developing alcoholism. Alcohol directly potentiates GABAAreceptors and activates the mesolimbic dopamine system. Here, we deleted Gabrg2 selectively in dopamine cells of adult mice. The deletion resulted in elevated firing of dopamine neurons and made them less sensitive to drugs acting at GABAAreceptors. At the behavioral level, the deletion increased exploratory behavior and augmented both correct and incorrect responding in the go/no-go task, a test often used to assay the response inhibition component of impulsivity. In addition, conditioned place preference to alcohol, but not to cocaine or morphine, was increased. Ethanol-induced locomotor activation was enhanced in the mice lacking Gabrg2 on dopaminergic cells, whereas the sedative effect of alcohol was reduced. Finally, the alcohol drinking, but not the alcohol preference, at a high concentration was increased in the mutant mice. In summary, deletion of Gabrg2 on dopamine cells induced several behavioral traits associated with high risk of developing alcoholism. The findings suggest that mice lacking Gabrg2 on dopaminergic cells could be used as models for individuals at high risk for developing alcoholism and that GABAAreceptors on dopamine cells are protective against the development of excessive alcohol drinking.