Oxytocin metabolites as mediators of antidepressant-like effects? Role of insulin-regulated aminopeptidase

Ellen Loyens, Katrien Gremmelprez, Heidi Demaegdt, Siew Yeen Chai, Anthony Albiston, Ken Kersemans, George Olivier, Georges Vauquelin, Patrick Vanderheyden, Yvette Michotte, Paul Gard, Ilse Julia Smolders

Research output: Chapter in Book/Report/Conference proceedingConference paper

Abstract

Introduction: Oxytocin (OT) is a neuromodulator with antidepressant-like activities. Lew et al. showed that OT is rapidly cleaved by insulin-regulated aminopeptidase (IRAP) in vitro. Our goal is to investigate whether OT is also an ex vivo and in vivo substrate of IRAP and whether IRAP modulation would interfere with the antidepressant-like effects of OT.
Methods: To verify that OT is a substrate of IRAP ex vivo, radio-immunoassay (RIA) and electro-spray ionisation mass spectrometry (ESI-MS) were used to study the degradation profile of OT in cortical membranes of IRAP wild-type (WT) and knock-out (KO) mice. In addition, cortical aminopeptidase activity was determined by incubating these membranes with the substrate l-leucine-p-nitroanilide. Rats were implanted with microdialysis probes in the hippocampus and in vivo OT levels were determined in dialysates before and after perfusion of the IRAP inhibitor angiotensin IV (Ang IV). An open field (OF) and forced swim test (FST) was used to study locomotor behavior and to screen OT for antidepressant-like activity, respectively.
Results and discussion: In cortical membranes of WT and KO mice, no OT degradation could be detected by the RIA. However, preliminary microdialysis experiments show that IRAP is responsible for OT degradation, since Ang IV perfusion seems to increase OT levels in rat hippocampal dialysates. In addition, preliminary ESI-MS results point to the presence of OT metabolites in WT mice. Burbach et al. showed that the complete OT structure is required for full endocrine activity, whereas OT metabolites have strong central activities which are different of the parent molecule. We found an antidepressant-like effect of 0.15 mg/kg OT in middle-aged female WT mice, compared to saline treated controls. OF results excluded that these differences are due to locomotor problems. In addition, middle-aged female KO mice treated with saline or OT did not show significant differences in immobility. In line with the findings of Burbach, these data suggest that OT is a substrate of IRAP in vivo and that OT metabolites rather than the intact neuropeptide are responsible for antidepressant-like activity.
Older female WT and KO mice treated with saline, on the contrary, continued to struggle, trying to escape from the cylinder in the FST. Enzymatic studies showed that IRAP levels are declined in these mice, however, we suggest that the marked reduced immobility in old mice is indicative of a problem in understanding the context due to aging rather than the presence of OT metabolites.
Original languageEnglish
Title of host publicationSociety for Neuroscience
Publication statusPublished - 2010
EventFinds and Results from the Swedish Cyprus Expedition: A Gender Perspective at the Medelhavsmuseet - Stockholm, Sweden
Duration: 21 Sep 200925 Sep 2009

Conference

ConferenceFinds and Results from the Swedish Cyprus Expedition: A Gender Perspective at the Medelhavsmuseet
Country/TerritorySweden
CityStockholm
Period21/09/0925/09/09

Keywords

  • oxytocin

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