Dopamine and serotonin neurotransmissions exert complementary control over primate approach and avoidance.

Efficient selection of appropriate responses to emotionally valenced stimuli is crucial for adaptive behavior, and disruptions in such approach-avoidance processes are common in various psychopathological disorders. While the dopamine and serotonin systems are primary targets for psychiatric medications, their precise roles in approach-avoidance behaviors remain unclear. To address this, we compared the effects of acute administration of methylphenidate (MPH) and fluoxetine, which respectively block dopamine and serotonin transporters (DAT and SERT), in four monkeys trained to perform an approach-avoidance task involving responses to valenced stimuli. We conducted PET scans to assess and localize drug binding levels at behaviorally effective doses. The two pharmacological agents improved task performance through distinct yet complementary mechanisms. MPH selectively enhanced the reward-based approach while concurrently binding to striatal DAT, whereas fluoxetine promoted the active avoidance of aversive stimuli through widespread SERT binding within limbic cortico-subcortical circuits. Rather than directly antagonizing each other, MPH and fluoxetine regulated distinct adaptive responses to emotional stimuli in a complementary fashion. Contrary to traditional models that pit dopamine and serotonin functions against each other, these results suggest a more segmented and independent framework for regulating distinct adaptive responses. From a clinical perspective, these findings highlight the potential of combining MPH and fluoxetine to target distinct symptomatic dimensions in psychopathological disorders marked by imbalances in approach-avoidance tendencies.