PROJECT SUMMARY MAIN 1 It is increasingly appreciated that multiple biological, psychological and sociocultural factors contribute to sex differences in alcohol consumption and associated health consequences in humans. The three main sex biasing biological factors, including sex chromosome complement and organizational and activational effects of gonadal hormones, can independently and interactively influence behavior, including ethanol consumption and preference. In work using the four core genotypes mice, in which sex chromosome complement and gonadal type segregate independently, we found that these two factors interact on ethanol intake during a limited access period when assessed in early adolescence. In this renewal period, we seek to test the hypothesis that sex chromosome complement affects the escalation of ethanol consumption that occurs across a chronic adolescent intermittent access period in a manner that depends upon the gonadal milieu. Additionally, we will assess the contributions of sex differences in ethanol pharmacokinetics and pharmacodynamics in these effects. Based upon recent work from our group demonstrating sexually dimorphic consequences of adolescent intermittent ethanol exposure on nucleus accumbens dopamine release, we will additionally examine how adolescent ethanol drinking affects this neurotransmitter system, and whether dysregulation of extrahypothalamic oxytocin release contributes to these observed effects. Finally, we will measure the impact of adolescent ethanol drinking on expression of X-chromosome genes that escape inactivation and that may causally contribute to sex chromosome complement effects on ethanol responsiveness. By conducting this integrated set of behavioral, neurochemical and genetic studies, we will develop a more comprehensive understanding of the mechanisms by which the major sex biasing biological factors regulate escalated ethanol drinking during adolescence and its consequences for brain and behavior.