An integrative analysis of 5-HTT- mediated mechanism of hyperreactivity to non-threatening voices

The tonic model delineating the serotonin transporter polymorphism’s (5-HTTLPR) 5-HTT-dependent neural modulatory effect on anxietyion points towards a universal underlying mechanism involving a hyper-or-elevated baseline level of arousal even to non-threatening stimuli. However, to our knowledge, this mechanism has never been proven observed in non-clinical cohorts exhibiting high anxiety. Moreover, empirical support regarding said association is mixed, potentially because of publication bias with a relatively small sample size. Hence, how the 5-HTTLPR modulates neural correlates remains controversial. Here we show, we assessed state and trait anxiety in 334 healthy volunteers, and subsequently genotyped the 5-HTTLPR and recorded the mismatch negativity (MMN) elicited by the unexpected presence of emotional prosodies embedded among neutrally-spoken syllables within a passive auditory oddball paradigm (emotional MMN) in 188 of them. Results revealed that 5-HTTLPR short-allele carriers had significantly increased baseline ERPs and reduced fearful MMN, phenomena which can nevertheless be reversed by acute anxiolytic treatment. This provides evidence that the 5-HTT affects the automatic processing of threatening and /non-threatening voices, impacts broadly on social cognition, and conclusively asserts the heightened baseline arousal level as the universal underlying neural mechanism for anxiety-related susceptibilities, functioning as a spectrum-like distribution from high trait anxiety non-patients to anxiety patients.