Activation of the G-protein-coupled receptor GPR30 induces anxiogenic effects in mice, similar to oestradiol

RATIONALE: The influence of ovarian hormones on behaviour is well accepted, and oestrogen replacement therapy has proven to be beneficial in several cases of menopausal mood disorders. However, there are also some adverse effects of such a therapy, like anxiety and dysphoria. In fact, some women feel better at low levels of oestrogen and worse when levels fluctuate. Still, it is unclear which receptors might mediate negative emotional effects. OBJECTIVES: The aim of this study was to identify which oestrogen receptor(s) are capable of mediating negative emotional effects and, therefore, may represent candidates responsible for the adverse side effects observed in oestrogen replacement therapy. RESULTS: We provide evidence from mouse behavioural tests that oestrogen-induced anxiogenic-like effects might be mediated, at least in part, by the G protein-coupled receptor GPR30. The short-term application of specific agonists against the alpha and beta oestrogen receptors did not result in marked behavioural changes. In contrast, the specific stimulation of GPR30 in male and ovariectomized female mice induced anxiogenic effects. The anxiogenic effects induced by the specific GPR30 agonist G-1 were comparable (and non-accumulative) to those observed after low doses of the general oestrogen receptor agonist 17b-oestradiol in male mice, thereby reflecting the behavioural changes observed in intact female mice during early pro-oestrus. CONCLUSIONS: Our data suggest that GPR30 induces acute anxiogenic effects of oestrogen in rodents. It is tempting to speculate that a potential imbalance in the expression of the anxiolytic beta oestrogen receptor and the anxiogenic GPR30 may also be involved in the negative symptoms of oestrogen replacement therapy in humans.