Effective treatments for alcohol-use disorder (AUD), especially for women veterans are critically needed, as rates of AUD in women veterans have been steadily increasing. Sex differences in psychosocial and biological risk factors, however, have not been systematically studied in clinical trials for AUD. Women veterans have a higher prevalence of trauma and abuse than men, and 70% of women veterans experience military sexual trauma and 36% report being victims of military sexual assault or rape. Abuse and trauma are significant predictors for AUD in women veterans but not in men. Exposure to trauma and consequent impairments in emotion regulation are significant risk factors for women with AUD and likely interact with immunological and neurobiological pathways to promote greater addiction severity. Despite clear evidence that psychosocial vulnerabilities, such as trauma and emotion regulation difficulties contribute to greater risk for relapse in women , there has been a paucity of studies that evaluate how these risk factors interact with sex-specific differences in immunological and neurobiological systems to influence treatment outcome. The primary objective of this study is to identify the mechanistic link between sex-dependent risk factors and treatment efficacy in a 12-week randomized placebo-controlled trial of naltrexone (NTX). This proposal will extend and leverage previous studies of NTX to determine whether the neuromodulatory and anti-inflammatory properties of NTX improve brain function, reduce inflammation and enhance emotion regulation in a sex- dependent manner. Validated rating scales will comprehensively assess trauma history, including military sexual trauma, combat exposure, physical or sexual assault, intimate partner violence and other traumatic life events. Functional magnetic resonance imaging (fMRI) at rest and during an emotion regulation task will assess limbic system connectivity and reactivity, respectively. Inflammation and neuronal integrity will be assessed with magnetic resonance spectroscopy and a multiplex panel assay of peripheral inflammatory markers. This project will first identify sex differences in the relationships between trauma and emotion regulation, inflammation and limbic function deficits. The mechanism of NTX on biobehavioral interactions to improve drinking behavior will then be assessed by testing whether reductions in alcohol use is moderated by changes in or interactions between emotion regulation, inflammation or limbic function. Sex-dependent mechanisms underlying NTX response will also be tested to examine if moderating effects on treatment outcome differ between men and women veterans. Findings from this project will identify psychosocial factors that influence immunological and neurobiological systems and clarify how these risk factors manifest in emotion regulation deficits and alcohol use in a sex- dependent manner. This systematic study of sex differences will provide a mechanistic unde...