Alcohol use disorders (AUDs) are disabling and prevalent conditions that affect almost one-third of Americans. In addition to the devastating effects of AUDs, secondary effects include increased risk for suicide, depression, and substance use disorders. While initial treatments exist, unfortunately, relapse is common, making long- term recovery difficult. Given the high rates of relapse, interventions that seek to prevent relapse have high potential impact. Animal models of addiction have substantially informed our understanding of the stages of addiction? binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation?and their underlying pathophysiology. Chronic alcohol exposure causes neuroadaptive brain changes in an attempt to maintain homeostasis. During early abstinence, hyperactive stress systems result in negative affect, anxiety, and depression which are thought to lead to relapse through negative reinforcement. An emerging theme from animal models is the involvement of the extended amygdala, including the bed nucleus of the stria terminalis (BNST), in withdrawal and reinstatement. While animal models of addiction are heavily studied under the assumption of their utility in translation to humans, the role of the BNST in human alcohol abstinence remains unknown. A major barrier to this work has been technological limitations in neuroimaging of the BNST because of its small size. We have recently overcome this challenge and have characterized the BNST neural circuitry in humans and have developed novel methods to examine BNST function. Our published findings show vast consistencies in BNST circuitry across species, providing a necessary foundation for translational studies. Our pilot studies show that the BNST is specifically engaged in mildly stressful situations where an upcoming threat is unpredictable. To investigate the role of the BNST in human addiction, we will study adults with moderate- severe AUDs who have been abstinent for one month, a critical time for relapse. The study will focus on three specific aims: (1) Determine whether there are intrinsic differences in BNST function and BNST circuit connectivity during early abstinence; (2) Determine whether there are task-based differences in BNST function and BNST circuit connectivity during early abstinence; (3) Determine the relationship between BNST function/connectivity, stress response (cortisol and skin conductance), and anxiety/depression symptoms in early abstinence. Based on findings from animal models, we predict that during early abstinence, the BNST will show hyperactivity and altered connectivity both ?at-rest? (intrinsic) and in response to a mildly stressful task. Furthermore, we predict that variation in stress response will mediate the relationship between BNST function/connectivity and anxiety and mood symptoms. The successful completion of this study will fill a critical knowledge gap, assessing the predictive validity of animal models championed by much of the neurobiology community that have heavily implicated the extended amygdala and BNST in alcohol use disorders. Elucidating these neural mechanisms is a crucial step in identifying novel targets for the prevention and treatment of alcohol use disorders.

Public Health Relevance

Alcohol use disorders are a substantial public health problem and relapse following treatment remains a substantial barrier to long-term recovery. This study will determine whether function of the bed nucleus of the stria terminalis?a region critically involved in withdrawal in rodent models?is altered in early abstinence from alcohol in humans. Such knowledge is critical for identifying novel brain targets and guiding the development of new interventions to prevent and treat alcohol use disorders.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZAA1-JJ (01)M)
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Xu, Benjamin
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Vanderbilt University Medical Center
Independent Hospitals
United States
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