ERβ-Selective Estrogen Receptor Modulators Produce Antianxiety Behavior when Administered Systemically to Ovariectomized Rats

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Abstract
17β-Estradiol (E2) may influence anxiety behavior; however, its effects and mechanisms are not well understood. To determine whether E2's effects on anxiety behavior may involve actions at intracellular estrogen receptor (ER) α or β isoforms, selective ER modulators (SERMs) were administered (10 μg; s.c.) to ovariectomized rats 48 h before testing for anxiety behavior. Rats received sesame oil vehicle, 17β-E2, which has a high affinity for ERα and ERβ, or SERMs that vary in their activity at ERα and β. ERα-selective SERMs were propyl pyrazole triol (PPT), which has more selective effects at ERα, than does the other ERα SERM utilized, 17α-E2, which also binds ERβ. ERβ-selective SERMs were diarylpropionitrile (DPN) and 7,12-dihydrocoumestan (coumestrol). DPN is more selective at ERβ than coumestrol, which also binds ERα. 17β-E2 and ERβ-selective SERMs (DPN, coumestrol) produced clear antianxiety behavior in the open field, elevated plus maze, emergence, light–dark transition, defensive freezing, and Vogel punished drinking tasks. Anxiety behavior of rats administered ERα-selective SERMs (PPT, 17α-E2) was not different from vehicle; however, PPT and 17α-E2 enhanced sexual receptivity in a manner similar to 17β-E2. Coadministration of tamoxifen (10 mg/kg) blocked the antianxiety behavior produced by 17β-E2, DPN, or coumestrol. Together, these data suggest that actions at ERβ may underlie some of E2's antianxiety effects.

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