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

Abstract

Studies in people and animal models suggest that depression is influenced by natural fluctuations in the levels of 17beta-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 ERalpha, rather than ERbeta. 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 ERbeta than for ERalpha (diarylpropionitrile; DPN) to ovariectomised (experiment 3) wildtype and ERbeta knockout (betaERKO) 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 ERbeta SERM would decrease depression-like behaviour in wildtype, but not betaERKO, 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 betaERKO mice. In experiment 3, administration of E(2) or DPN to ovariectomised wildtype, but not betaERKO, mice decreased immobility compared with vehicle administration, these data suggest that ERbeta may be required for some of the anti-depressant-like effects of E(2).

Figure 1

Mean (±SEM) time spent immobile by adult female or male mice. *above bar indicates a significant decrease (P ≤ 0.05).

Figure 2

Mean (±SEM) time spent immobile by cycling WT or βERKO mice in pro-oestrous or dioestrous. ** indicates a significant (P ≤ 0.05) interaction between genotype and oestrous cycle phase condition.

Figure 3

Mean (±SEM) time spent time spent immobile by ovx WT or βERKO mice in administered vehicle, E₂ or DPN. * *indicates a significant (P ≤ 0.05) interaction between genotype and SERM condition.