Sex and strain differences in the effects of oxytocin on memory consolidation in mice

R Viana, PR Gard. University of Brighton, Pharmacy & Biomolecular Sciences, BN2 4GJ, UK

Angiotensin IV (ang IV) enhances consolidation of novel object recognition in mice, although there are strain differences in this effect (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 oxytocin (Vanderheyden, 2009). We have recently reported that an oxytocin receptor antagonist (Tyr(Me)2, Orn8-AVT) prevents the effects of both ang IV and oxytocin on memory consolidation in C57/Bl6 mice suggesting the latter mechanism of action (Gard et al., in press). We now wish to report the effects of another oxytocin receptor antagonist (atosiban) on memory consolidation in both C57/Bl6 and DBA2 strain mice.

Memory consolidation was assessed using novel object recognition in which mice explored an open field containing two identical objects for 3 min and again one hour later. After 24h the mice were exposed to the 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, administered subcutaneously immediately after the second training trial, was assessed in comparison to saline controls; n=8 in all cases. The doses of ang IV used were those previously shown to produce the greatest effects: 4.7 µg/kg in C57/Bl6 and 47 µg/kg in DBA2. The antagonistic effects of atosiban (1mg/kg i.p.) were assessed following administration immediately before that of ang IV.

In comparison to saline control, ang IV caused enhanced object discrimination (D score) in both C57/Bl6 and DBA2 strains (P<0.01 and 0.05 respectively). There were no significant effects on locomotor activity in either strain. Atosiban alone had no significant effects on D score in C57/Bl6, but caused an improvement in D score in DBA2 mice (P<0.05). Paradoxically, atosiban increased locomotor activity in C57/Bl6 (P<0.05), but had no significant effect in DBA2. In the presence of atosiban, ang IV failed to produce a significant increase in D score in C57/Bl6, but still caused a increase in DBA2 (P<0.05). The combination of ang IV and atosiban caused a decrease in locomotor activity in C57/Bl6 (P<0.05) and an increase in DBA2 (P<0.05).

The blockade of the precognitive effect of ang IV by atosiban in C57/Bl6 mice supports our previous report for Tyr(Me)2, Orn8-AVT and suggests that ang IV is acting via accumulation of oxytocin in this strain. The lack of such an effect in DBA2 mice suggests a different mechanism of action. We have previously shown that the two strains do not differ in the sequence of IRAP, IRAP expression nor aminopeptidase activity of IRAP (Golding et al., 2010), it would therefore be interesting to explore ang IV-induced glucose uptake in the two strains in order to further elucidate the mechanism of the precognitive action and the basis of the strain difference.

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.