The role of serotonin in reward, punishment and behavioural inhibition in humans: Insights from studies with acute tryptophan depletion

• The role of 5-HT (serotonin) in reward, punishment and inhibition is unclear.
• Acute tryptophan depletion (ATD) is a way of decreasing brain 5-HT release in humans.
• We review 36 papers using ATD in studies of winning, losing and inhibition.
• ATD is selective in decreasing punishment but not reward effects.
• Establishing 5-HT's role in aversive processing in humans is a remarkable insight.

Deakin and Graeff proposed that forebrain 5-hydroxytryptamine (5-HT) projections are activated by aversive events and mediate anticipatory coping responses including avoidance learning and suppression of the fight-flight escape/panic response. Other theories proposed 5-HT mediates aspects of behavioural inhibition or reward. Most of the evidence comes from rodent studies. We review 36 experimental studies in humans in which the technique of acute tryptophan depletion (ATD) was used to explicitly address the role of 5-HT in response inhibition, punishment and reward. ATD did not cause disinhibition of responding in the absence of rewards or punishments (9 studies). A major role for 5-HT in reward processing is unlikely but further tests are warranted by some ATD findings. Remarkably, ATD lessened the ability of punishments (losing points or notional money) to restrain behaviour without affecting reward processing in 7 studies. Two of these studies strongly indicate that ATD blocks 5-HT mediated aversively conditioned Pavlovian inhibition and this can explain a number of the behavioural effects of ATD.