GAL₃ receptor knockout mice exhibit an alcohol-preferring phenotype

Galanin is a neuropeptide which mediates its effects via three G-protein coupled receptors (GAL_1–3). Administration of a GAL₃ antagonist reduces alcohol self-administration in animal models while allelic variation in the GAL₃ gene has been associated with an increased risk of alcohol use disorders in diverse human populations. Based on the association of GAL₃ with alcoholism, we sought to characterize drug-seeking behavior in GAL₃-deficient mice for the first time. In the two-bottle free choice paradigm, GAL₃-KO mice consistently showed a significantly increased preference for ethanol over water when compared to wildtype littermates. Furthermore, male GAL₃-KO mice displayed significantly increased responding for ethanol under operant conditions. These differences in alcohol seeking behavior in GAL₃-KO mice did not result from altered ethanol metabolism. In contrast to ethanol, GAL₃-KO mice exhibited similar preference for saccharin and sucrose over water, and a similar preference for a high fat diet over a low fat diet as wildtype littermates. No differences in cognitive and locomotor behaviors were observed in GAL₃-KO mice to account for increased alcohol seeking behavior. Overall, these findings suggest genetic ablation of GAL₃ in mice increases alcohol consumption.