The effects of neurosteroids on picrotoxin-, bicuculline- and NMDA-inducedseizures, and a hypnotic effect of ethanol

The effects of intraperitoneally (IP) or intracerebroventricularly (ICV) ad ministered neurosteroids [allopregnanolone (AP); 5 beta -tetrahydrojeoxycor ticosterone (5 beta -THDOC); dehydroepiandrosterone sulfate (DHEAS); pregne nolone sulfate (PS)] and their precursors [progesterone (PROG), pregnanedio ne (PREG)] on N-methyl-D-aspartic acid NMDA)-, picrotoxin (PTX)- and bicucu lline (BIC)-induced seizures and ethanol-induced sleep were studied in mice . It was found that IP injections of (+)MK-801 most potently antagonized NM DA-, PTX- and BIG-induced seizures, as compared to diazepam (DZP), FROG and PREG. Both precursors of neurosteroids appeared only marginally active in the applied models of convulsions. ICV injections of AP selectively blocked PTX- and BIG-induced seizures, whereas 5 beta -THDOC and (+)MK-801 also an tagonized NMDA-induced convulsions. ICV administered DHEAS induced seizures in a dose-dependent way. ICV injections of AP and midazolam shortened the latency and prolonged the duration of sleep induced by IP injections of eth anol (5.0 g/kg). On the contrary, DHEAS and PS significantly reduced the hy pnotic-like effect of ethanol. The obtained results suggest that neurostero ids may modulate in an agonistic (AP, 5 beta -THDOC), or antagonistic way ( PS, DHEAS), the GABA(A) receptor complex functions. Some of them (5 beta -T HDOC) also interact with NMDA receptors. AP appeared to be the most selecti vely acting compound, with its profile of action fully comparable to that o f midazolam. AP also enhanced the hypnotic effect of ethanol, pointing out to the propensity to interact with centrally depressant agents. These findi ngs, together with the possibility of conversion of some neurosteroids in t he brain to other steroid hormones (testosterone, estradiol and aldosterone ), indicate the limitations of their use for the treatment of neurological and psychiatric disorders. (C) 2000 Elsevier Science Inc. All rights reserv ed.