Alcohol use disorder (AUD) is a chronic relapsing disease that constitutes a major health problem for Veterans and society in general. Likewise, stress-related disorders, such as post-traumatic stress disorder (PTSD) are highly debilitating and present with especially high prevalence in Veterans as well. Stress is known to play a significant role in triggering relapse and promoting excessive, harmful levels of alcohol use. This is of particular concern because the frequent co-occurrence of stress and alcohol related disorders is associated with more severe clinical symptoms and medical complications compared to either disorder alone. The prevalence of PTSD and AUD comorbidity is especially high in Veterans, with prevalence rates reported in the 55-75% range. Given the high prevalence of PTSD-AUD comorbidity in Veterans, it is not surprising that the Department of Veterans Affairs has highlighted this as a special and high priority research area. Thus, the need to better understand underlying mechanisms of stress-alcohol interactions is paramount to developing more effective treatment strategies to address this significant medical problem. The overall focus of Dr. Becker’s Alcohol Research Program at the Charleston RHJ VA Medical Center is aimed at elucidating neural mechanisms and brain circuits underlying the ability of stress and chronic alcohol (ethanol) exposure to promote/mediate excessive levels of drinking. The Becker research lab has played a leading role in developing novel, clinically relevant animal models that enable multidisciplinary analyses of the complex and dynamic nature of stress-alcohol interactions. The research program employs a comprehensive and integrative approach, utilizing innovative neurobehavioral, neurochemical, and molecular biology techniques to address research questions of particular relevance to the overall VA health care mission. One line of research focuses on the role of brain-derived neurotrophic factor (BDNF) in stress-enhanced alcohol drinking. We showed that chronic alcohol-induced excessive drinking is associated with a deficit in cortical BDNF expression, an effect exacerbated by stress. Increasing cortical BDNF activity reversed these effects and since exercise is known to elevate BDNF levels in brain, we are currently employing molecular and pharmacological approaches to examine mechanisms by which exercise increases BDNF signaling in the brain and thereby reversing the ability of stress to enhance alcohol drinking. Another set of studies utilizes molecular, chemogenetic, and pharmacological approaches to examine mechanisms and circuitry underlying adaptations in pro-stress (dynorphin) and anti-stress (oxytocin) neuropeptides that contribute to stress-enhanced drinking and relapse. Using a novel model of PTSD-AUD comorbidity that demonstrates long-lasting sensitization of stress-induced alcohol relapse/drinking in mice with a history of chronic stress exposure, selective targeting of subpopulations of...