Antidepressant effects of ERbeta-selective estrogen receptor modulators in the forced swim test

Estradiol (E2) may influence depressive symptomology of women and decrease depressive behavior among rodents. The mechanism(s) for E2's antidepressant effects are not well understood. To determine whether antidepressant effects of E2 may involve actions at intracellular estrogen receptor (ER) alpha or beta isoforms, selective ER modulators (SERMs) were administered (10 microg sc) to ovariectomized rats 48 h before testing in the forced swim test, an animal model of depression, and the horizontal crossing task. Rats received sesame oil vehicle, 17beta-E2, which has a high affinity for ERalpha and ERbeta, SERMs that vary in their activity at ERalpha and beta, or a tricyclic antidepressant (desipramine; 30 mg/kg ip), as a positive control. ERalpha-selective SERMs were propyl pyrazole triol (PPT) and 17alpha-E2. PPT has more selective effects at ERalpha than does 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, ERbeta-selective SERMs (DPN, coumestrol), and desipramine administration produced antidepressive behavior (decreased immobility, increased struggling and swimming). ERalpha-selective SERMs (PPT, 17alpha-E2) were not different from vehicle. There were no differences among groups in the number of beam breaks made in the horizontal crossing task. These data suggest that E2's antidepressive effects may involve actions at ERbeta.