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

Estradiol (E-2) may influence depressive symptomology of women and decrease depressive behavior among rodents. The mechanism(s) for E-2's antidepressant effects are not well understood. To determine whether antidepressant effects of E-2 may involve actions at intracellular estrogen receptor (ER) alpha or beta isoforms, selective ER modulators (SERMs) were administered (10 mug 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-E-2, 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-E-2. PPT has more selective effects at ERalpha than does 17alpha-E-2, 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-E-2, ERbeta-selective SERMs (DPN, coumestrol), and desipramine administration produced antidepressive behavior (decreased immobility, increased struggling and swimming). ERalpha-selective SERMs (PPT, 17alpha-E-2) 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 E-2's antidepressive effects may involve actions at ERbeta. (C) 2004 Elsevier Inc. All rights reserved.