Oxytocinergic modulation of threat-specific amygdala sensitization in humans is critically mediated by serotonergic mechanisms

Abstract

Overarching conceptualizations propose that the complex social-emotional effects of oxytocin (OXT) in humans are partly mediated by interactions with other neurotransmitter systems.Recent animal models suggest that the anxiolytic effects of OXT are critically mediated by the serotonin (5-HT) system, yet direct evidence in humans is lacking. To determine the role of 5-HT in OXT-induced attenuation of amygdala threat reactivity and sensitization/ desensitization, 121 healthy subjects underwent a transient decrease in 5-HT signaling via acute tryptophan depletion (ATD) before the administration of intranasal OXT or the corresponding placebo-control protocols, respectively. Mean and repetition-dependent changes in threat-specific amygdala reactivity towards threatening stimuli (angry faces) as assessed by fMRI served as the primary outcome. No treatment main or interaction effects on amygdala threat reactivity were observed, yet OXT switched bilateral superficial amygdala sensitization to desensitization and this effect was significantly attenuated during decreased central 5HT signaling via pretreatment with ATD. The present findings provide the first evidence for a role of OXT in threat-specific amygdala desensitization in humans and suggest that these effects are critically mediated by the 5-HT system.