Blockade of pro-cognitive effects of angiotensin IV and physostigmine in mice by oxytocin antagonism

Low doses of oxytocin enhance learning and memory in animal models. Angiotensin IV inhibits cysteine aminopeptidase, also known as insulin-regulated aminopeptidase and oxytocinase, and enhances memory in animals. The mechanism of this effect of angiotensin IV is unknown. This study explored the role of oxytocin in the cognitive effects of angiotensin IV with physostigmine as a control and used isolated smooth muscle to assess the pharmacological selectivity of the observed antagonism. Using novel object recognition in male mice, the effects of angiotensin IV (4.7 μg/kg), oxytocin (0.1 ng/kg) or physostigmine (200 μg/kg) administered subcutaneously immediately after the second training trial, were assessed in the presence and absence of 10 μg/kg β-mercapto-β-β-cyclopenta-methylenepropionyl; O-Me-Tyr2, Orn8-oxytocin, an oxytocin antagonist; n = 8 in all cases. The effects of the antagonist on angiotensin IV, oxytocin and acetylcholine-induced contractions of rat isolated uterus were also determined. Oxytocin, angiotensin IV and physostigmine significantly enhanced consolidation of learning (P = 0.04, 0.004 and 0.008 respectively), and there were no significant effects on locomotor activity. The oxytocin antagonist similarly not only significantly improved novel object recognition (P = 0.03) but also significantly increased locomotor activity (P = 0.04). In the learning paradigm the oxytocin antagonist prevented the effects of oxytocin, angiotensin IV and physostigmine but in the uterus, contractions induced by angiotensin IV and acetylcholine were unaffected whilst effects of oxytocin were significantly reduced. These results suggest that the pro-cognitive effects of angiotensin IV may be mediated by accumulation of endogenous oxytocin although the mechanisms underlying the observed interaction between the oxytocin antagonist and physostigmine are unclear.