Serotonergic modulation of response inhibition and re-engagement? Results of a study in healthy human volunteers.

OBJECTIVE: Cognitive functions dependent on the prefrontal cortex, such as the ability to suppress behavior (response inhibition) and initiate a new one (response re-engagement) is important in the activities of daily life. Central serotonin (5-HT) function is thought to be a critical component of these cognitive functions. In recent studies, 5-HT failed to affect stop-signal reaction time (SSRT), a fundamental process in behavioral inhibition. We were interested if response inhibition and re-engagement are influenced through central 5-HT activity as mediated via the 5-HT transporter. METHODS: Here, using a stop-change task, we investigated the effects of acute and repeated treatment with 10 mg escitalopram, a selective 5-HT reuptake inhibitor, in 36 healthy human volunteers on response inhibition and re-engagement in a randomized, double-blind, placebo-controlled study with cross-over design. RESULTS: Results do not show an influence of escitalopram on response inhibition or response re-engagement as we did not find differences in SSRT or change reaction time (CRT). CONCLUSIONS: These findings support the results of previous studies suggesting that 5-HT is not critical in inhibition of already initiated responses and response re-engagement. We hypothesize that results are due to different forms of behavioral inhibition and 5-HT may critical to other forms.

The role of 5-HT in response inhibition and re-engagement.

In animal and human research, the neurotransmitter serotonin (5-HT) has been implicated in inhibitory control. Using functional magnetic resonance imaging (fMRI), the present study investigated the acute effects of pharmacological modulation of the serotonergic system on brain activation during response inhibition and re-engagement in healthy human volunteers. In a randomized double-blind placebo-controlled cross-over design 14 men received either a single oral dose of the selective serotonin reuptake inhibitor (SSRI) escitalopram (10mg) or a placebo. At the time of the expected plasma peak concentration, participants performed a stop-change task during fMRI. Escitalopram did not affect behavioural performance, since the main effect did not reveal significant differences between reaction times of go-, stop- or change-trials. During successful response inhibition, escitalopram, however, was associated with enhanced brain activation in right prefrontal cortex, right supplementary/pre-motor and bilateral cingulate cortex, and subcortical regions. During inhibition failures, escitalopram also modulated a broad network of brain regions, including anterior cingulate, right parietal cortex, right orbitofrontal cortex, and areas in right temporal cortex and subcortical regions. During response re-engagement escitalopram increased brain activation in right inferior frontal gyrus and precuneus as well as in left middle temporal gyrus. The results implicate the involvement of 5-HT in neural regulation of response inhibition and re-engagement. This study also provides evidence that 5-HT affects both action restraint and action cancellation through modulation of activation of brain areas. The results support the view for a fronto-striatal circuitry for response inhibition in conjunction with serotonin.