Recent studies have reported that estrogen has antidepressant-like effects in animal models. In this study we used the highly selective ERβ agonist, WAY-200070, to examine the role of ERβ activation on brain neurochemistry and activity in antidepressant and anxiolytic models in male mice. Within 15 min of administration, WAY-200070 (30 mg/kg s.c.) caused the nuclear translocation of striatal ERβ receptors from the cytosol. WAY-200070 also increased c-fos activation 4 h, but not 15 min after administration. Both nuclear translocation and c-fos induction effects of WAY-200070 demonstrate that WAY-200070 has bound to estrogen receptors and triggered downstream events. The absence of these effects in the ERβKO mice confirms that WAY-200070 was targeting ERβ. Administration of WAY-200070 (30 mg/kg s.c.) produced a delayed ∼50% increase in dopamine in the striatum of wild type mice. The effect was significant and maintained from 90 to 240 min. This increase was absent in ERβKO mice. In wild type mice, WAY-200070 (30 mg/kg s.c.) also produced a delayed and transient ∼100% increase in 5-HT. To further investigate the role of ERβ receptors on serotonergic function, 5-HTP accumulation was measured. ERβKO mice were found to have reduced frontal cortex levels of 5-HTP, indicating reduced tryptophan hydroxylase activity. WAY-200070 (3–30 mg/kg s.c.) was also tested in behavioural models. WAY-200070 (30 mg/kg s.c.) reduced immobility time in the mouse tail suspension test indicating an antidepressant-like effect. WAY-200070 (30 mg/kg) showed anxiolytic-like effects in the four-plate test (increased punished crossings) and stress-induced hyperthermia (attenuation of hyperthermic response).
The effects of the selective ERβ agonist, WAY-200070, on dopamine and serotonin, the anxiolytic-like and antidepressant-like effects as well as the genotype specific effects on neurochemistry support that positive modulation of ERβ function may provide a novel treatment for affective disorders.