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

Abstract

17beta-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) alpha or beta isoforms, selective ER modulators (SERMs) were administered (10 microg; s.c.) to ovariectomized rats 48 h before testing for anxiety behavior. Rats received sesame oil vehicle, 17beta-E2, which has a high affinity for ERalpha and ERbeta, or SERMs that vary in their activity at ERalpha and beta. ERalpha-selective SERMs were propyl pyrazole triol (PPT), which has more selective effects at ERalpha, than does the other ERalpha SERM utilized, 17alpha-E2, which also binds ERbeta. ERbeta-selective SERMs were diarylpropionitrile (DPN) and 7,12-dihydrocoumestan (coumestrol). DPN is more selective at ERbeta than coumestrol, which also binds ERalpha. 17beta-E2 and ERbeta-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 ERalpha-selective SERMs (PPT, 17alpha-E2) was not different from vehicle; however, PPT and 17alpha-E2 enhanced sexual receptivity in a manner similar to 17beta-E2. Coadministration of tamoxifen (10 mg/kg) blocked the antianxiety behavior produced by 17beta-E2, DPN, or coumestrol. Together, these data suggest that actions at ERbeta may underlie some of E2's antianxiety effects.