ERβ-selective estrogen receptor modulators produce antianxiety behavior when administered systemically to ovariectomized rats

Abstract

17β-Estradiol (E2) may influence anxiety behavior; however, its effects and mechanisms are not well understood. To determine whether E 2'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-E 2, 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. © 2005 Nature Publishing Group. All rights reserved.