UCLA

Alcohol use disorder (AUD) is a highly prevalent, chronic and relapsing disorder estimated to affect over 100 million people worldwide. Chronic alcohol exposure has been shown in animal models to increase both neural and systemic markers of inflammation. Alcohol- induced inflammation has been linked both to chronic alcohol-seeking and to 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 clinical samples. Therefore, translation to clinical samples is necessary. In humans, addiction is often conceptualized as a reward deficit disorder, and brain activation in response to reward stimuli has been shown to be negatively associated with inflammation. However, associations between AUD, inflammation, and reward sensitivity have not yet been established. The dissertation studies presented herein combine behavioral and biological methods to elucidate this relationship. Chapter 1 consists of an investigation into the clinical and neural correlates of individuals who self-reported their primary motivation for drinking as either reward (i.e. positive reinforcement) or relief (i.e. negative reinforcement), finding differences between the groups on clinical measures of AUD severity and neural activation to visual alcohol cues in reward- associated brain regions. Chapter 2 investigates the effects of ibudilast, a neuroimmune modulatory medication in development for AUD treatment. Ibudilast was found to reduce visual alcohol cue-elicited functional connectivity within reward-related brain circuitry, and this attenuation was correlated with reductions in alcohol consumption. Chapter 3 explores the relationship between alcohol and monocyte production of intracellular cytokines following in vitro stimulation with lipopolysaccharide (LPS), finding that AUD was associated with enhanced sensitivity to the cellular LPS inflammatory challenge. Finally, Chapter 4 presents a brief argument for the use of LPS as a translational tool to experimentally explore the role of inflammation in clinical samples of AUD. Taken together, these findings seek to elucidate biological mechanisms related to reward response and inflammation in AUD. These studies provide clinical and neurobiological data on the relationship between alcohol use and inflammation, and may inform precision medicine and targeted inflammatory medication development for individuals with AUD.