Sex-specific Mechanisms of Ethanol Withdrawal During Adolescence

PROJECT SUMMARY MAIN 4 Early initiation of alcohol use during adolescence and subsequent binge drinking put young individuals at high risk for developing alcohol use disorder (AUD), with young girls more likely to escalate alcohol consumption over boys. Similar to these human studies, our current work in the DEARC demonstrated enhanced sensitivity of female rats to ethanol withdrawal-related negative affective-like behavioral alterations during early adolescence relative to males. Both sexes were equally affected by withdrawal from chronic exposure when tested in late adolescence. The central amygdala (CeA) is primarily composed of a GABAergic cell population that is sensitive to acute and chronic ethanol and is highly implicated in withdrawal-associated anxiety. The CeA is also responsive to input from sexually dimorphic oxytocin and vasopressin neuropeptide systems. The current proposal will address critical gaps in our understanding of sex differences in sensitivity to ethanol withdrawal during adolescence. Aim 1 will assess withdrawal effects during early or late adolescence, focusing on sex differences in CeA function, connectivity and CeA GABAergic cell activity in adolescent rats. Aim 2 will similarly investigate CeA function, connectivity and CeA GABAergic cell activity in both sexes during withdrawal from chronic ethanol exposure. Finally, Aim 3 will test whether vasopressin and/or oxytocin neuropeptide systems sex-dependently contribute to withdrawal-related negative affect and CeA dysfunction in adolescents.