Epistatic Modifiers and Novel Genetic Contributions to Binge-like Drinking and Motivational Effects of Alcohol

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Project Summary Alcohol use disorders (AUDs) are associated with significant costs to both the individual and society. Genetic and environmental factors contribute to the risk of AUDs and excessive drinking, and a better understanding of the specific risk genes will allow for novel strategies for prevention and treatment. Glyoxalase 1 (GLO1) is a new target in alcohol research identified previously by rodent studies in our lab. Overexpression of Glo1 increases binge-like drinking in mice, suggesting involvement in excessive alcohol intake. The endogenous substrate of GLO1, methylglyoxal (MG), acts as a partial agonist at GABAA receptors. Pharmacological and genetic manipulations that increase MG levels (i.e. GLO1 inhibition, Glo1 gene knockdown) have been shown to reduce binge-like drinking in mice, providing a possible mechanism through which GLO1 modifies alcohol consumption. The goal of this fellowship project is to determine the role of Glo1 and other potential related genetic risk factors for excessive drinking in a mouse model of binge-like intake. Aim 1 will use a novel breeding strategy to generate an F1 panel of inbred mice overexpressing Glo1 on different genetic backgrounds. These mice will be phenotyped for alcohol binge-like drinking. A two-part genome wide association study will be used to 1) map epistatic modifiers of Glo1 that enhance or suppress its effects on alcohol drinking, and 2) identify potential quantitative trait loci associated with binge-like drinking. Aim 2 will investigate why Glo1 modifies alcohol intake, by testing the hypothesis that changes in Glo1 expression alter sensitivity to the reward-enhancing effects of alcohol or alcohol aversion. Together, these experiments will give us a better understanding of how Glo1 overexpression contributes to risk of excessive drinking, and will highlight other genes that modify this risk. This dual approach may identify novel targets and strategies for preventing or treating drinking to intoxication