Sex chromosome contributions to alcohol drinking behaviors - Project Summary: Men and women have differing vulnerabilities to alcohol. For example, men develop Alcohol Use Disorder at higher rates but research shows that women may escalate their drinking faster and be more motivated to resume use following abstinence. Preclinical research in animals consistently demonstrates higher rates of consumption in females and that gonadal sex, chromosomal sex, and alcohol exposure interact to influence levels of alcohol intake. In regards to chromosomal sex and alcohol drinking behaviors, a subset of genes of interest on the X chromosome are of potential interest because of their ability to escape transcriptional repression in brain tissues. The central hypothesis driving the proposed studies is that X chromosome dosage influences alcohol consumption through overexpression of these genes, but that these effects may depend on gonadal status or alcohol exposure history. Our experiments will test this hypothesis through completion of three primary aims. We will 1) demonstrate that alcohol consumption is reduced in mice with two (i.e., XX) vs. one (i.e., XY or XO) copies of the X chromosome, 2) determine whether a history of alcohol exposure alters expression of genes that escape X chromosome inactivation in the brain and whether these effects depend on gonadal status, and 3) identify the candidate gene Gprasp1 as a regulator of alcohol drinking behaviors via its actions on dopamine receptors. These aims will be achieved through the use of two-bottle choice alcohol drinking tasks, surgical gonadectomy, quantification of gene expression with RTPCR, site-specific gene knockdown, and pharmacological antagonism. Collectively, completion of these aims will demonstrate a role for the X chromosome in alcohol consumption and determine which X chromosome genes that escape inactivation in the brain are regulated by alcohol exposure. Further, we will identify GPCR regulation through Gprasp1 as a mediator of sex differences in alcohol drinking behaviors. These studies will be the first mechanistic demonstration of how sex chromosome complement influences vulnerability to alcohol. Additionally, the proposed work and future related studies have a high likelihood of revealing multiple targets with potential therapeutic efficacy for problematic drinking behaviors in men and women.
