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 and hence whether oxytocin is an in vivo substrate of IRAP. 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 minutes forced swim, that was preceeded by an open field to study locomotor behavior. 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 behavior in mice, as shown with the open field. These findings were reproduced in transgenic male (3 to 6 months old) and female (12 to 18 months old) 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 and indicates that OT is an in vivo substrate of IRAP.
Bibliographical note© 2012 CINP
- insulin-regulated aminopeptidase