Oxytocin (OT) is a neuromodulator with antidepressant (AD)-like effects. In vitro, it is rapidly cleaved by insulin-regulated aminopeptidase (IRAP). OT metabolites are known to exert strong central activities that are different from the parent molecule. Our goal is to investigate in vivo whether IRAP deletion can modify the AD-like effects of OT and whether ageing interferes with AD-like effects of OT. A dose-response curve was performed in male and female C57Bl/6 mice (3 and 14 months) injected subcutaneously with saline (10 ml/kg) or oxytocin (0.05 mg/kg- 0.5 mg/kg). One hour after injection, mice were placed in an open field (OF) for 10 minutes to study locomotor behaviour and they were subjected to a 5 minutes forced swim during which immobility was timed. Young (3–6 months) and middle-aged (12–18 months) male and female IRAP wild-type (WT) and knock-out (KO) mice were also subjected to OF and FST, after injection with the doses OT that showed AD-like effects in C57Bl/6 mice. Treatment of young male C57Bl/6 mice with 0.15 mg/kg and 0.25 mg/kg OT resulted in a decreased immobility time. The effect of 0.25 mg/kg OT was reproduced in young male IRAP WT mice, but not in IRAP KO mice. OT had no effect in either young female C57Bl/6 mice or in young female IRAP WT and KO mice. However, we found an AD-like effect of 0.15 mg/kg OT in middle-aged female C57Bl/6 mice and IRAP WT mice, that was absent in middle-aged female IRAP KO mice. OT did not influence locomotor behaviour in mice, as shown with the OF. The observed AD-like effects of OT in young male and middle-aged female IRAP WT mice were absent in age-matched IRAP KO mice, suggesting that IRAP metabolizes OT in vivo. We suggest that these metabolites rather than the intact neuropeptide mediate the AD-like activity. In addition, AD-like effects of OT are influenced by ageing. This could be explained by a difference in circulating oestrogen and OT levels, however, further work is required to confirm this hypothesis.