Oxytocinergic Modulation of Threat-Specific Amygdala Sensitization in Humans Is Critically Mediated by Serotonergic Mechanisms

Abstract

Background: 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. Methods: To determine the role of 5-HT in OXT-induced attenuation of amygdala threat reactivity and sensitization/desensitization, we conducted a parallel-group, randomized, placebo-controlled, double-blind experiment during which 121 healthy subjects underwent a transient decrease in 5-HT signaling via acute tryptophan depletion or the corresponding placebo-control protocol before the administration of intranasal OXT or placebo intranasal spray, respectively. Mean and repetition-dependent changes in threat-specific amygdala reactivity toward threatening stimuli (angry faces) as assessed by functional magnetic resonance imaging served as the primary outcome. Results: No main or interaction effects of treatment on amygdala threat reactivity were observed, yet OXT switched bilateral amygdala threat sensitization to desensitization, and this effect was significantly attenuated during decreased central 5-HT signaling via pretreatment with acute tryptophan depletion. Conclusions: 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. OXT may have a therapeutic potential to facilitate amygdala desensitization, and adjunct upregulation of 5-HT neurotransmission may facilitate OXT's anxiolytic potential.