Adult female wildtype, but not oestrogen receptor beta knockout, mice have decreased depression-like behaviour during pro-oestrus and following administration of oestradiol or diarylpropionitrile

Studies in people and animal models suggest that depression is influenced by natural fluctuations in the levels of 17 beta-oestradiol (E-2), as well as administration of E-2-based therapies, such as selective oestrogen receptor modulators (SERMs). Elucidating the effects and mechanisms of E-2 is important to improve future E-2-based therapeutics. An important question is whether effects of E-2 or SERMs for mood regulation act at the alpha or beta isoform of the oestrogen receptor (ER) because some of the unwanted trophic effects of E-2-based therapies may involve actions at ER alpha, rather than ER beta. In the present study, whether there are sex differences in depression-like behaviour of adult mice (experiment 1), and the effects of natural fluctuations in E-2 (experiment 2), or administration of E-2 or a SERM that has higher affinity for ER beta than for ERa (diarylpropionitrile; DPN) to ovariectomised (experiment 3) wildtype and ER beta knockout (beta ERK0) mice were investigated. Results of this study supported our hypotheses that: there would be sex differences favouring males for depression-like behaviour and endogenous increases in, or exogenous administration of, E-2 or administration of an ER beta SERM would decrease depression-like behaviour in wildtype, but not beta ERK0, mice. In experiment 1, adult male mice spent less time immobile in the forced swim test (i.e., showed less depression-like behaviour) compared with female mice. In experiment 2, pro-oestrous (higher circulating E-2 levels), compared with dioestrous (lower circulating E-2 levels), mice had reduced immobility in the forced swim test; this effect was not observed in beta ERK0 mice. In experiment 3, administration of E-2 or DPN to ovariectomised wildtype, but not beta ERK0, mice decreased immobility compared with vehicle administration, these data suggest that ER beta may be required for some of the anti-depressant-like effects of E-2.