GABAergic bases of connectivity alterations in the ventral tegmental area of young drinkers: An analysis using the combined technologies of JuSpace toolbox and resting-state functional magnetic resonance imaging

JOURNAL/atin/04.03/02274269-990000000-00025/figure1/v/2026-03-14T142312Z/r/image-tiff Objectives: As a hub of mesolimbic and mesocortical circuits, the ventral tegmental area (VTA) supports saliency processing, reward prediction, and motivated behavior. Dysfunction within these mesolimbic and mesocortical circuits is commonly associated with alcohol misuse. This study aimed to delineate the alterations in VTA resting-state functional connectivity (rsFC) associated with alcohol use severity in young adults and to explore the potential neurochemical mechanisms underpinning these alterations. Methods: This was a cross-sectional study. Data from the Human Connectome Project (HCP), comprising 868 young adults (414 males), were analyzed. To capture a generalized measure of alcohol use severity, we derived a primary component (the first principal component, PC1) via principal component analysis across all available drinking metrics. Whole-brain regression analyses were conducted to model the relationship between VTA rsFC and PC1, both in the entire cohort and within each sex separately. To characterize the neurochemical signatures associated with alcohol-related VTA connectivity patterns, we employed spatial correlation analyses via the JuSpace toolbox. All analyses were evaluated at a corrected threshold. Results: In all the participants, increased alcohol use severity (higher PC1) was positively correlated with reduced functional connectivity ( r = –0.19, P < 0.001) between the VTA and the right inferior frontal gyrus, pars opercularis (IFGpo). Spatial correlation analyses revealed that these VTA connectivity features were associated with GABAa signaling ( r = 0.34, P < 0.001). These results were consistent across both male and female participants. Conclusions: We characterized VTA connectivities and the GABAergic bases of altered VTA connectivities in link with alcohol use severity. This work adds to existing knowledge by highlighting alcohol-related dysfunction in a key reward circuit early in the drinking trajectory, an effect observed in both men and women.