PROCONVULSANT EFFECTS OF NEUROSTEROIDS PREGNENOLONE SULFATE AND DEHYDROEPIANDROSTERONE-SULFATE IN MICE

We have investigated the effects of chronic treatment with the neurost eroids, pregnenolone sulfate and dehydroepiandrosterone sulfate, on th e potential neurotoxicity in pentylenetetrazol seizure sensitivity tes t in mice. Four weeks of subcutaneous treatment with pregnenolone sulf ate and dehydroepiandrosterone sulfate, at a dose of 10 mg kg(-1) day( -1), significantly shifted the pentylenetetrazol dose-percent convulsi ons and latency curves to the left, and markedly decreased the ED50 of pentylenetetrazol for tonic convulsions, indicating the increased sen sitivity of mice to seizures. Chronic neurosteroid treatment significa ntly decreased the body weight of the animals. However, acute treatmen t of neurosteroids did not modify the seizure reactivity of mice to pe ntylenetetrazol. Furthermore, the dehydroepiandrosterone sulfate (10 m g kg(-1), s.c.)-induced proconvulsant effect was significantly prevent ed by chronic pretreatment with progesterone (5 mg kg(-1), s.c.), a pr ecursor for GABA(A) receptor active neurosteroid, allopregnanolone, an d dizocilpine (0.1 mg kg(-1) i.p.), a non-competitive NMDA receptor an tagonist. These results suggest that long-term administration of neuro steroids pregnenolone sulfate or dehydroepiandrosterone sulfate produc es proconvulsant effects. (C) 1998 Elsevier Science B.V.