PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) frequently co-occur and are associated with significant morbidity, mortality, and health care expenditures. Military Veterans are at increased risk for co- occurring AUD and PTSD, with prevalence rates 2-4 times higher than the general population. Our group developed an integrated intervention entitled Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure (COPE). COPE incorporates empirically validated cognitive-behavioral techniques for AUD with Prolonged Exposure (PE) therapy for PTSD. Several randomized controlled trials among Veterans and civilians demonstrate efficacy of COPE in significantly reducing AUD and PTSD symptoms. Despite the positive findings, there remains substantial room for improving treatment outcomes and enhancing retention. Accumulating data suggest that the neuropeptide oxytocin (OT) is a promising candidate to enhance psychosocial interventions for co-occurring AUD and PTSD, as OT targets neurobiological and behavioral dysregulation common to both disorders. Preclinical and clinical studies demonstrate the ability of OT to ameliorate a variety of alcohol-related behaviors (e.g., craving, withdrawal symptoms, tolerance, ethanol self- administration), enhance fear extinction, and promote prosocial behaviors associated with successful psychosocial treatment outcomes (e.g., trust, social cognition). In a randomized controlled pilot study, our group found that OT administration prior to weekly PE therapy sessions was safe, well-tolerated, and resulted in accelerated reduction in PTSD symptoms as compared to placebo. Although the empirical and theoretical support for augmenting psychosocial interventions such as COPE with OT is robust, no studies to date have examined this combined approach. The primary objective of the proposed Stage II study is to examine the efficacy of OT as compared to placebo in reducing (1) alcohol use, and (2) PTSD symptoms among Veterans receiving COPE therapy. To accomplish this, we will employ a manualized, evidence-based, cognitive-behavioral intervention (COPE); a randomized, double-blind, placebo-controlled study design; standardized, repeated dependent measures of clinical outcomes at multiple time points; and we will leverage close collaboration with well-established VA clinics prepared to efficiently translate positive findings into practice. In addition, to evaluate purported neurobiological mechanisms of change, we will employ functional magnetic resonance imaging (fMRI) at pre- and post-treatment and examine AUD biomarkers. The proposed study directly addresses the mission of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) in that it aims to identify pharmacologic treatments to address co-occurring AUD and PTSD simultaneously. The findings from this study will provide new information and mechanistic insights to directly inform clinical practice and accelerat...