Oxytocin is a neuromodulator with antidepressant-like effects. In vitro, oxytocin is rapidly cleaved by insulinregulatedaminopeptidase (IRAP). Oxytocin metabolites are known to exert strong central activities that aredifferent from the effects of the parent molecule. Our goal is to investigate in vivo whether IRAP deletionmodifies the antidepressant-like effects of oxytocin. Male and female C57Bl/6 mice, IRAP wild-type (IRAP+/+)and knock-out (IRAPx/x) mice were injected subcutaneously with saline, oxytocin or oxytocin combined withangiotensin IV. One hour after injection, immobility was timed during a 5 min forced swim that was preceded byan open field to study locomotor behaviour. Oxytocin induced antidepressant-like effects in male (0.25 mg/kgoxytocin) and female (0.15 mg/kg oxytocin) C57Bl/6 mice subjected to the forced swim test. Oxytocin did notinfluence locomotor behaviour in mice, as shown with the open field. These findings were reproduced intransgenic male (aged 3–6 months) and female (aged 12–18 months) IRAP+/+ mice. However, the major findingsof our study were that the antidepressant-like effect was reversed in angiotensin IV treated IRAP+/+ miceand was completely absent in age- and gender-matched IRAPx/x mice. The lack of an antidepressant-like effectof oxytocin in young male and middle-aged female IRAPx/x mice attributes an important role to IRAP inmediating this effect.Received 14 October 2011; Reviewed 31 January 2012; Revised 24 August 2012; Accepted 28 August 2012;First published online 26 November 2012Key words: Antidepressant, insulin-regulated aminopeptidase, oxytocin.