Antiseizure effects of 3α-androstanediol and/or 17β-estradiol may involve actions at estrogen receptor β

Testosterone (T), the principal androgen secreted by the testes, can have antiseizure effects. Some of these effects may be mediated by T’s metabolites. T is metabolized to 3α-androstanediol (3α-diol). T, but not 3α-diol, binds androgen receptor. We investigated effects of 3α-diol (1 mg/kg, SC) and/or an androgen receptor blocker (flutamide 10 mg, SC), 1 hour prior to administration of pentylenetetrazol (85 mg/kg, IP). Juvenile male rats administered 3α-diol had less seizure activity than those administered vehicle. Flutamide had no effects. T is aromatized to 17β-estradiol (E2), which, like 3α-diol, acts at estrogen receptors (ERs). Selective estrogen receptor modulators that favor ERα (propyl pyrazole triol, 17α-E2) or ERβ (diarylpropionitrile, coumestrol, 3α-diol), or both (17β-E2), were administered (0.1 mg/kg, SC) to juvenile male rats 1 hour before pentylenetetrazol. Estrogens with activity at ERβ, but not those selective for ERα, produced antiseizure effects. Actions at ERβ may underlie some antiseizure effects of T’s metabolites.