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

Paul Gard1, Sofiyah Ali2

1University of Brighton, Brighton, UK, 2Brighton & Sussex Medical School, Brighton, UK

The posterior pituitary hormone oxytocin (OT) has dose-dependent actions on learning and memory. In rats, s.c. and i.p. doses in the ng.kg-1 range improve social memory i.e. recognition of conspecific animals. Higher doses in the μg.kg-1 range, however, disrupt social memory, passive and conditioned avoidance, spatial memory, and learned helplessness (reviewed in Gard et al., 2007). The mechanism of this action is unclear, but inhibition of oxytocinase and other peptidases prevents the effects of OT on learned helplessness which suggests that metabolites of OT may be the active moieties; some metabolic products have greater effects on passive avoidance than OT itself (Arletti and Bertolini, 1987).

Oxytocinase is synonymous with insulin-regulated amino peptidase (IRAP); in the presence of insulin, IRAP facilitates the trafficking of GLUT4 to the cell membrane and glucose uptake. IRAP has also been identified as the binding site for angiotensin IV (AIV): the AT4 receptor. AIV and its analogues inhibit IRAP, enhance acquisition of active avoidance and recall of passive avoidance and object recognition and reverse the amnesic effect of scopolamine in the Morris water maze (see Gard et al., 2007). In mice, we have reported that s.c. AIV enhances memory consolidation in the novel object recognition paradigm, but that there were marked strain differences (Gard & Brown, 2007). The aim of this study was to explore strain differences in the effects of OT on memory and the relationship between OT, AIV and IRAP.

Male and female mice (19-30g) of each of three strains (CD, BKW, and C57/BL6,) and female DBA2 were bred and reared in-house under identical conditions. Memory consolidation was assessed using novel object recognition in which mice explored an open field containing two identical objects for 3 min. 1h. later they were again exposed to the same open field and objects for 3 min. After 24h the mice were exposed to the field containing one of the original objects and a novel (different size, shape, colour) 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 object compared with the familiar object. The effects of OT (0.1 ng.kg-1, s.c.) administered immediately after the second training trial, was assessed in comparison to saline controls; n=8 in all cases.

Two-way ANOVA of the results in males indicated that there was a significantly positive effect of OT on novel object recognition (p=0.014), but no significant differences between strains and no significant interaction. In females, OT had no significant effect, but there was a significant difference between strains (p=0.027), with CD mice exhibited poorest recognition and C57/BL6 best. There was no significant interaction. OT had no effect on locomotor activity in either gender.

We have previously reported that AIV significantly improves novel object recognition in male and female C57/BL6 mice and in male BKW and DBA2 mice. The results of the current, small, single-dose study of OT indicate that the strain differences in the effects of AIV and OT are not identical suggesting that the two drugs may not be acting via a common pathway dependent on the activity of IRAP.

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