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

Abstract

Studies in people and animal models suggest that depression is influenced by natural fluctuations in the levels of 17β-oestradiol (E₂), as well as administration of E₂-based therapies, such as selective oestrogen receptor modulators (SERMs). Elucidating the effects and mechanisms of E₂ is important to improve future E₂-based therapeutics. An important question is whether effects of E₂ or SERMs for mood regulation act at the α or β isoform of the oestrogen receptor (ER) because some of the unwanted trophic effects of E₂-based therapies may involve actions at ERα, rather than ERβ. 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 E₂ (experiment 2), or administration of E₂ or a SERM that has higher affinity for ERβ than for ERα (diarylpropionitrile; DPN) to ovariectomised (experiment 3) wildtype and ERβ knockout (βERKO) 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, E₂ or administration of an ERβ SERM would decrease depression-like behaviour in wildtype, but not βERKO, 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 E₂ levels), compared with dioestrous (lower circulating E₂ levels), mice had reduced immobility in the forced swim test; this effect was not observed in βERKO mice. In experiment 3, administration of E₂ or DPN to ovariectomised wildtype, but not βERKO, mice decreased immobility compared with vehicle administration, these data suggest that ERβ may be required for some of the anti–depressant-like effects of E₂.