Dopamine Bidirectionally Biases Incentive and Aversive Salience in Humans

Dopamine is central to reward-driven motivation, but its contribution to aversive salience remains unclear. Dysregulation of this balance may underlie psychiatric disorders characterized by compulsive reward seeking and insensitivity to negative outcomes. We tested whether acute up- or down-regulation of dopaminergic signaling differentially biases the salience of reward- versus loss-predicting cues in humans. In a double-blind, placebo-controlled, within-subject design, 27 healthy adults completed a Monetary Incentive Delay (MID) task under three pharmacological conditions: dopaminergic enhancement (levodopa 100 mg + carbidopa 25 mg), dopamine blockade (risperidone 2 mg), and placebo. Reaction times (RTs) and skin conductance responses (SCRs) indexed behavioral and physiological salience to cues predicting monetary gains or losses of high or low magnitude. Under levodopa, SCRs showed stronger scaling with reward than with loss magnitude (i.e., monetary amount), and participants were slower to avoid small losses, consistent with a shift toward incentive over aversive salience. Conversely, risperidone enhanced SCR sensitivity to losses relative to rewards and slowed responses to small gains, indicating a preferential weighting of aversive over incentive cues. These drug-induced bidirectional shifts indicate that dopaminergic tone operates as a valence-dependent salience regulator, prioritizing gain- versus loss-predicting cues. Dysregulation of this calibration, as in addiction, may simultaneously amplify cue-triggered “wanting” while blunting sensitivity to adverse consequences, thereby promoting compulsive use despite harm.