Poor behavioral inhibition is a common feature of neurological and psychiatric disorders. Successful inhibition of a prepotent response in ‘NoGo' paradigms requires the integrity of both the inferior frontal gyrus (IFG) and the serotonergic system. We investigated individual differences in serotonergic regulation of response inhibition. In 24 healthy adults, we used 18F-altanserin positron emission tomography to assess cerebral 5-HT2A receptors, which have been related to impulsivity. We then investigated the impact of two acute manipulations of brain serotonin levels on behavioral and neural correlates of inhibition using intravenous citalopram and acute tryptophan depletion during functional magnetic resonance imaging. We adapted the NoGo paradigm to isolate effects on inhibition per se as opposed to other aspects of the NoGo paradigm. Successful NoGo inhibition was associated with greater activation of the right IFG compared to control trials with alternative responses, indicating that the IFG is activated with inhibition in NoGo trials rather than other aspects of invoked cognitive control. Activation of the left IFG during NoGo trials was greater with citalopram than acute tryptophan depletion. Moreover, with the NoGo-type of response inhibition, the right IFG displayed an interaction between the type of serotonergic challenge and neocortical 5-HT2A receptor binding. Specifically, acute tryptophan depletion (ATD) produced a relatively larger NoGo response in the right IFG in subjects with low 5-HT2A BPP but reduced the NoGo response in those with high 5-HT2A BPP. These links between serotonergic function and response inhibition in healthy subjects may help to interpret serotonergic abnormalities underlying impulsivity in neuropsychiatric disorders.

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Risk avoidance is an important determinant of human behavior. The neurotransmitter serotonin has long been implicated in processing aversive outcomes caused by risky decisions. However, it is unclear whether serotonin provides a neurobiological link between making a risk aversive decision and the response to an aversive outcome. Using pharmacological fMRI, we manipulated the availability of serotonin in healthy volunteers while performing a gambling task. The same group of participants was studied in three fMRI sessions: (i) during intravenous administration of the SSRI citalopram to increase the serotonergic tone, (ii) after acute tryptophan depletion (ATD) to reduce central serotonin levels, or (iii) without interventions. ATD and citalopran had opposite effects on outcome related activity in dorsomedial prefrontal cortex (dmPFC) and amygdala. Relative to the control condition, ATD increased and citalopram decreased the neural response to aversive outcomes in dmPFC. Conversely, ATD decreased and citalopram increased the neural response to aversive outcomes in left amygdala. Critically, these pharmacological effects were restricted to aversive outcomes that were caused by low-risk decision and led to a high missed reward. ATD and citalopram did not alter the neural response to positive outcomes in dmPFC, but relative to ATD, citalopram produced a bilateral increase in the amygdala response to large wins caused by high-risk choices. The results show a selective involvement of the serotonergic system in neocortical processing of aversive outcomes resulting from risk-averse decisions, thereby linking risk aversion and processing of aversive outcomes in goal-directed behaviors.