Proconvulsant effects of neurosteroids pregnenolone sulfate and dehydroepiandrosterone sulfate in mice.

We have investigated the effects of chronic treatment with the neurosteroids, pregnenolone sulfate and dehydroepiandrosterone sulfate, on the potential neurotoxicity in pentylenetetrazol seizure sensitivity test in mice. Four weeks of subcutaneous treatment with pregnenolone sulfate and dehydroepiandrosterone sulfate, at a dose of 10 mg kg(-1) day(-1), significantly shifted the pentylenetetrazol dose-percent convulsions and latency curves to the left, and markedly decreased the ED50 of pentylenetetrazol for tonic convulsions, indicating the increased sensitivity of mice to seizures. Chronic neurosteroid treatment significantly decreased the body weight of the animals. However, acute treatment of neurosteroids did not modify the seizure reactivity of mice to pentylenetetrazol. Furthermore, the dehydroepiandrosterone sulfate (10 mg kg(-1), s.c.)-induced proconvulsant effect was significantly prevented by chronic pretreatment with progesterone (5 mg kg(-1), s.c.), a precursor for GABA(A) receptor active neurosteroid, allopregnanolone, and dizocilpine (0.1 mg kg(-1), i.p.), a non-competitive NMDA receptor antagonist. These results suggest that long-term administration of neurosteroids pregnenolone sulfate or dehydroepiandrosterone sulfate produces proconvulsant effects.