Acute depletion of dopamine precursors in the human brain: effects on functional connectivity and alcohol attentional bias

Individuals who abuse alcohol often show exaggerated attentional bias (AB) towards alcohol-related cues, which is thought to reflect reward conditioning processes. Rodent studies indicate that dopaminergic pathways play a key role in conditioned responses to reward- and alcohol-associated cues. However, investigation of the dopaminergic circuitry mediating this process in humans remains limited. We hypothesized that depletion of central dopamine levels in adult alcohol drinkers would attenuate AB and that these effects would be mediated by altered function in frontolimbic circuitry. Thirty-four male participants (22–38 years, including both social and heavy drinkers) underwent a two-session, placebo-controlled, double-blind dopamine precursor depletion procedure. At each visit, participants consumed either a balanced amino acid (control) beverage or an amino acid beverage lacking dopamine precursors (order counterbalanced), underwent resting-state fMRI, and completed behavioral testing on three AB tasks: an alcohol dot-probe task, an alcohol attentional blink task, and a task measuring AB to a reward-conditioned cue. Dopamine depletion significantly diminished AB in each behavioral task, with larger effects among subjects reporting higher levels of binge drinking. The depletion procedure significantly decreased resting-state functional connectivity among ventral tegmental area, striatum, amygdala, and prefrontal regions. Beverage-related AB decreases were mediated by decreases in functional connectivity between the fronto-insular cortex and striatum and, for alcohol AB only, between anterior cingulate cortex and amygdala. The results support a substantial role for dopamine in AB, and suggest specific dopamine-modulated functional connections between frontal, limbic, striatal, and brainstem regions mediate general reward AB versus alcohol AB.