title: Antidepressant-like effects of oxytocin in mice are dependent on the presence of insulin-regulated aminopeptidase.
abstract: Oxytocin is a neuromodulator with antidepressant-like effects. In vitro, oxytocin is rapidly cleaved by insulin-regulated aminopeptidase (IRAP). Oxytocin metabolites are known to exert strong central activities that are different from the effects of the parent molecule. Our goal is to investigate in vivo whether IRAP deletion modifies the antidepressant-like effects of oxytocin. Male and female C57Bl/6 mice, IRAP wild-type (IRAP(+/+)) and knock-out (IRAP(-/-)) mice were injected subcutaneously with saline, oxytocin or oxytocin combined with angiotensin IV. One hour after injection, immobility was timed during a 5 min forced swim that was preceded by an open field to study locomotor behaviour. Oxytocin induced antidepressant-like effects in male (0.25 mg/kg oxytocin) and female (0.15 mg/kg oxytocin) C57Bl/6 mice subjected to the forced swim test. Oxytocin did not influence locomotor behaviour in mice, as shown with the open field. These findings were reproduced in transgenic male (aged 3-6 months) and female (aged 12-18 months) IRAP(+/+) mice. However, the major findings of our study were that the antidepressant-like effect was reversed in angiotensin IV treated IRAP(+/+) mice and was completely absent in age- and gender-matched IRAP(-/-) mice. The lack of an antidepressant-like effect of oxytocin in young male and middle-aged female IRAP(-/-) mice attributes an important role to IRAP in mediating this effect.
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Loyens
authors.forename: Dimitri
authors.initials: D
authors.lastname: De Bundel
authors.forename: Heidi
authors.initials: H
authors.lastname: Demaegdt
authors.forename: Siew Yeen
authors.initials: SY
authors.lastname: Chai
authors.forename: Patrick
authors.initials: P
authors.lastname: Vanderheyden
authors.forename: Yvette
authors.initials: Y
authors.lastname: Michotte
authors.forename: Paul
authors.initials: P
authors.lastname: Gard
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
mesh_terms: D000367:Age Factors; D000626:Aminopeptidases / Q000378:metabolism*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D010122:Cystinyl Aminopeptidase / Q000172:deficiency / Q000235:genetics; D003863:Depression / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D007099:Imipramine / Q000627:therapeutic use; D046353:Immobility Response, Tonic / Q000187:drug effects; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010121:Oxytocin / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000928:Antidepressive Agents; D007328:Insulin; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D010121:Oxytocin; D000626:Aminopeptidases; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase; D007099:Imipramine