Component 3 - Frontolimbic circuits, dopamine and attentional bias to alcohol c

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Attentional bias toward drug-related stimuli is commonly reported in substance use disorders and is positively correlated with craving. By capturing attention and facilitating drug-seeking behavior, alcohol-associated stimuli can promote continued drinking and relapse. The goals of this project are to (1) determine the neuromodulatory role of dopamine in attentional bias to alcohol cues in heavydrinking humans, (2) model early aspects of attentional bias to alcohol cues in rats, and (3) use that animal model to mechanistically probe brain circuits mediating attentional bias, by using pharmacology, electrochemistry, and optogenetics. These goals synergize with the overall aim of the Center to understand alcohol induced pathology in brain circuits that regulate alcohol use. Moreover, this project potentially identifies novel therapeutic targets for alcohol use disorders. The proposed studies test the overall hypothesis that projections from the prefrontal cortex to the mesolimbic system regulate Pavlovianconditioned attentional bias towards alcohol cues in heavy-drinking humans and binge-alcohol-exposed rats. To address this hypothesis, two aims manipulate dopamine function in humans and rats to determine the effects of dopamine on attentional bias to alcohol cues, and a third aim translates human measurements of frontolimbic connectivity to rat studies that activate and inactivate particular neural pathways in order to identify brain circuits mediating attentional bias. Together, these highly innovative studies reveal how chronic alcohol exposure alters appetitive responses to alcohol cues. These translational studies examine pathology in frontolimbic circuits associated with chronic alcohol exposure that manifest In altered attention and response to alcohol-associated stimuli. The combination of human behavior and imaging with rodent measures of behavior, dopamine release and selective manipulation of prefrontal cortical projections provides a mechanistic approach to identify how alcohol cues usurp attention and behavior to perpetuate compulsive alcohol use.