Oxytocinergic modulation of stress-associated amygdala-hippocampus pathways in humans is specially mediated by serotonergic mechanisms

Background: The hypothalamic neuropeptide oxytocin (OXT) may exert anxiolytic and stress-reducing actions via modulatory effects on amygdala circuits. Animal models and initial findings in humans suggest that some of these effects are mediated by interactions with other neurotransmitter systems, in particular the serotonin (5-HT) system. Against this background, the present pharmacological resting state fMRI study aimed at determining whether effects of OXT on stress-associated amygdala intrinsic networks are mediated by 5-HT. Methods: We employed a randomized placebo-controlled double-blind parallel-group pharmacological fMRI resting state experiment during which n = 112 healthy male participants underwent a transient decrease in 5-HT signaling via acute tryptophan depletion (ATD+) or the corresponding placebo-control protocols (ATD-) before the administration of intranasal OXT or placebo intranasal spray, respectively. Results: OXT and 5-HT modulation exerted interactive effects on the coupling of the left amygdala with the ipsilateral hippocampus and adjacent midbrain. OXT increased intrinsic coupling in this pathway, while this effect of OXT was significantly attenuated during transiently decreased central serotonergic signaling induced via ATD+. In the absence of OXT or 5-HT modulation this pathway was associated with self-reported stress perception in everyday life, while an OXT-induced modulation of this pathway was following ATD- pre-treatment. Conclusions: Together, the findings provide first evidence that effects of OXT on stress-associated amygdala-hippocampal-midbrain pathways are critically mediated by the 5-HT system in men.