Beyond negative valence: 2-week administration of a serotonergic antidepressant enhances both reward and effort learning signals

To make good decisions, humans need to learn about and integrate different sources of appetitive and aversive information. While serotonin has been linked to value-based decision-making, its role in learning is less clear, with acute manipulations often producing inconsistent results. Here, we show that when the effects of a selective serotonin reuptake inhibitor (SSRI, citalopram) are studied over longer timescales, learning is robustly improved. We measured brain activity with functional magnetic resonance imaging (fMRI) in volunteers as they performed a concurrent appetitive (money) and aversive (effort) learning task. We found that 2 weeks of citalopram enhanced reward and effort learning signals in a widespread network of brain regions, including ventromedial prefrontal and anterior cingulate cortex. At a behavioral level, this was accompanied by more robust reward learning. This suggests that serotonin can modulate the ability to learn via a mechanism that is independent of stimulus valence. Such effects may partly underlie SSRIs’ impact in treating psychological illnesses. Our results highlight both a specific function in learning for serotonin and the importance of studying its role across longer timescales.Author summary: Drugs acting on the neurotransmitter serotonin in the brain are commonly prescribed to treat depression, but we still lack a complete understanding of their effects on the brain and behavior. We do, however, know that patients who suffer from depression learn about the links between their choices and pleasant and unpleasant outcomes in a different manner than healthy controls. Neural markers of learning are also weakened in depressed people. Here, we looked at the effects of a short-term course (2 weeks) of a serotonergic antidepressant on brain and behavior in healthy volunteers while they learnt to predict what consequences their choices had in a simple computer task. We found that the antidepressant increased how strongly brain areas concerned with predictions of pleasant and unpleasant consequences became active during learning of the task. At the same time, participants who had taken the antidepressant also performed better on the task. Our results suggest that serotonergic drugs might exert their beneficial clinical effects by changing how the brain learns.