The involvement of oxytocin in the pro-cognitive effects of angiotensin IV on one-trial learning.

S Linsdall1, R Payne1, PR Gard2. 1Brighton and Sussex Medical School, Phase 2, BN1 9PX, UK, 2University of Brighton, Pharmacy & Biomolecular Sciences, BN2 4GJ, UK

In a two-trial learning paradigm, subcutaneous administration of angiotensin IV (ang IV) immediately after the second training trial enhances novel object recognition in mice 24 hours later (Golding et al., 2010). The mechanism of this effect of ang IV is unclear but it is believed to act via its angiotensin subtype 4 (AT4) receptor, identified as insulin-regulated aminopeptidase (IRAP). Ang IV enhances the trafficking of IRAP and the co-located insulin-dependent glucose transporter GLUT4 to the cell surface which promotes glucose uptake and it also inhibits the peptidase function of IRAP causing accumulation of endogenous neuropeptides such as oxytocin (Vanderheyden, 2009). We have recently reported that an oxytocin receptor antagonist (d(CH2) 5 [Tyr(Me)2, Orn8-AVT]) prevents this effect of ang IV on memory consolidation suggesting a mechanism of action involving accumulation of endogenous oxytocin (Gard et al., in press). We now report a study of the interplay of ang IV and oxytocin on memory consolidation over a shorter time frame using one-trial learning.

Memory consolidation was assessed using novel object recognition in which mice explored an open field containing two identical objects for 3 min. Three hours later the mice were exposed to the same field containing one of the original objects and a novel object. Time spent exploring each of the objects was recorded over 3 min, as was locomotor activity. Memory was quantified as the proportion of time spent exploring the novel compared with the familiar object. The effects of ang IV (5 µg/kg) and oxytocin (0.1 µg/kg), administered subcutaneously immediately after the training trial, were assessed in comparison to parallel saline controls; n=8 in all cases. The antagonistic effects of d(CH2) 5 [Tyr(Me)2, Orn8-AVT]) (10µg/kg s.c.) were assessed following administration immediately before that of ang IV or oxytocin.

Ang IV and oxytocin significantly improved novel object recognition (p = 0.03 and <0.01 respectively); there was no significant effect of the oxytocin antagonist alone (p=0.12). In the presence of oxytocin antagonist, neither ang IV nor oxytocin had any significant effect on novel object recognition (p=0.33 and 0.21 respectively). There were no significant drug effects on locomotor activity.

These results are the first demonstration of enhanced novel object recognition by ang IV and oxytocin in a one-trial model in mice. They demonstrate that ang IV does not need an extended period of time in order to elicit its memory consolidation effects. This could challenge the suggestion that ang IV acts by inhibition of the aminopeptidase activity of IRAP and the subsequent accumulation of endogenous oxytocin because the time scale may be inadequate for such accumulation; the prevention of the effect of ang IV by co-administration of an oxytocin antagonist however suggests otherwise. The finding that a very low, peripheral, dose of oxytocin, 0.1 µg/kg, is able to enhance memory consolidation in this model reinforces the proposition that the effects of ang IV are mediated by accumulation of endogenous oxytocin.

Gard, P.R. et al., (In press) Eur. J. Pharmacol.

Golding, B.J. et al., (2010) Eur. J. Pharmacol. 641 154-159

Vanderheyden, P.M.L. (2009) Mol. Cell. Endocrinol. 302 159-166.