Probing Inflammation and Reward Sensitivity in Alcohol Use Disorder

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Project Summary / Abstract The proposed predoctoral NRSA aims to examine the role of neuroinflammation in modulating reward response and negative mood in Alcohol Use Disorder (AUD). Chronic alcohol exposure has been shown in animal models to increase both neural and systemic markers of inflammation. Alcohol-induced inflammation has been linked to both chronic alcohol seeking and the behavioral and neurotoxic effects of alcohol. However, the literature on inflammatory signaling and AUD is overwhelmingly preclinical and it is unknown if this relationship can be extrapolated to humans. Therefore, translation to clinical samples is necessary. In humans, addiction is often conceptualized as a reward deficit disorder. Negative emotionality is also implicated in AUD, such that individuals with AUD demonstrate higher levels of negative mood, with a high comorbidity between mood disorders and AUD. Neuroinflammation is associated with negative emotionality, such that cytokines have been shown to play a causal role in the onset of negative mood. Further, brain activation in response to reward stimuli is decreased after inflammation-provoking endotoxin infusion. However, associations between AUD, inflammation, and behavioral outcomes have not yet been established. The proposed study aims to fill this gap in the literature by examining the role of inflammation in negative mood and reward response in a clinical sample of individuals with AUD and light-drinking healthy controls. We will experimentally provoke a systemic inflammatory response, measurable by plasma levels of proinflammatory cytokines. Participants will receive a low dose of endotoxin that has been shown to increase cytokine levels without significant changes in vital signs, therefore safely and acutely mimicking a low-grade inflammatory response. Over the course of 4 hours post-infusion of endotoxin (or placebo) – during which cytokine levels peak at 2 hours and return to near-baseline by hour 4 – participants will be assessed for negative mood at hourly intervals and reward response at peak (hour 2). The first aim of the project is to examine the effects of neuroinflammation on negative mood in AUD versus controls. The second aim is to examine the effects of acute inflammation on reward response in AUD and controls. This proposal’s findings will help to elucidate the role that inflammation plays in modulating mood and reward response in AUD. In addition to these study aims, the proposed F31 will provide me with a breadth of training in psychoneuroimmunology and clinical addictions neuroscience with a focus on the psychobiology of reward, through coursework, collaboration with experts in these fields, and career development including presentations at journal clubs and conferences. This training will take place in Dr. Lara Ray’s Addictions Lab, which utilizes a broad range of laboratory techniques to understand the causes and correlates of substance use disorders. This lab is located at UCLA, a world-class research and training environment.