Oxytocinergic Modulation of Stress-Associated Amygdala-Hippocampus Pathways in Humans Is Mediated by Serotonergic Mechanisms

Abstract

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 with four treatment groups in n = 112 healthy male participants. Participants underwent a transient decrease in 5-HT signaling via acute tryptophan depletion (ATD) or a corresponding placebo-control protocol (ATDc) before the administration of intranasal OXT (24 International Units) or placebo intranasal spray. 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 showed a trend for an association with self-reported stress perception in everyday life. No interactive effects were observed for the right amygdala. 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.

Altered brain activity and functional connectivity after MDMA-assisted therapy for post-traumatic stress disorder

“…Carhart-Harris et al ( 54 ) demonstrated that amygdala-hippocampal RSFC is increased acutely in MDMA administration compared to placebo and this increase occurred in a manner that correlated with the drug’s subjective effects at a near-significant level, leading these researchers to propose that this functional connection was a primary target of MDMA-AT. Increased amygdala-hippocampal RSFC has also been linked to intranasal oxytocin administration after stress exposure ( 53 ) and this effect was mediated by serotonin signaling ( 55 )—two neuromodulators that play a significant role in the pro-social and fear extinction effects of MDMA ( 20 , 56 – 61 ). Prior to our analysis (although after the study was designed and the data collected), we hypothesized that the RSFC between the amygdala and hippocampus would be higher after MDMA-AT compared to pre-therapy levels.…”

“…We found a trend suggesting that RSFC between the amygdala and hippocampus was strengthened post-therapy, particularly in the left hemisphere (Figure 3). Prior work suggests that modulation of amygdalae-hippocampal RSFC may be an important component of MDMA-AT for PTSD (43,(51)(52)(53)(54)(55), thus investigating this connection in future studies is warranted. We also found participants had increased activation in areas involved with self-referential processing and autobiographical memory while listening to traumatic versus neutral memory narrations pre-therapy (Figures 4A-D), and that no significant contrast existed after MDMA-AT (Figure 4E).…”

“…Finally, the pre-specified aim of this study was to estimate longitudinal (baseline to 2-months after final MDMA session) changes in ROI response to traumatic audio scripts. Between the start of data collection and analysis, new literature emerged ( 54 , 55 ) implicating amygdala-hippocampus RSFC as a potential target of MDMA-AT, compelling us to expand our analysis beyond the pre-specified aims. Functional connectivity estimates from shorter scans (e.g., five minutes in the case of our resting-state data) can have lower reliability ( 113 ) and therefore the trends in increased RSFC between amygdala and hippocampal regions reported here should be considered preliminary.…”

“…In healthy volunteers, the acute administration of MDMA increases amygdala-hippocampal RSFC ( 54 ). Intranasal oxytocin also increases amygdala-hippocampal RSFC ( 53 ), and this effect appears to be mediated by serotonin system signaling ( 55 )—two neuromodulators that MDMA significantly increases in the extracellular/plasma concentration of, and that play a crucial role in its effects on pro-social behavior and fear extinction ( 20 , 56 – 61 ). Despite evidence that RSFC between the amygdala and hippocampus is implicated in PTSD and that this connection may be modulated by MDMA, no study to date has shown relationships between changes in these regions’ functional connectivity and the therapeutic effects of MDMA-AT.…”

“…Prior to analysis, we hypothesized that MDMA-AT would increase RSFC between the amygdala and hippocampus (43,(52)(53)(54)(55)64). We further hypothesized that, at baseline, brain activity would be higher during the trauma-related listening task compared with the neutral listening task in regions associated with autobiographical memory, fear, and emotion, and that this effect would be reduced post-treatment (30).…”