The effects of intraperitoneally (IP) or intracerebroventricularly (ICV) administered
neurosteroids [
allopregnanolone (AP); 5beta-tetrahydrodeoxycorticosterone (5beta-
THDOC);
dehydroepiandrosterone sulfate (DHEAS);
pregnenolone sulfate (PS)] and their precursors [
progesterone (PROG), pregnanedione (PREG)] on
N-methyl-D-aspartic acid (
NMDA)-,
picrotoxin (PTX)- and
bicuculline (
BIC)-induced
seizures and
ethanol-induced sleep were studied in mice. It was found that IP
injections of (+)
MK-801 most potently antagonized
NMDA-, PTX- and
BIC-induced
seizures, as compared to
diazepam (DZP), PROG and PREG. Both precursors of
neurosteroids appeared only marginally active in the applied models of convulsions. ICV
injections of AP selectively blocked PTX- and
BIC-induced
seizures, whereas 5beta-THDOC and (+)
MK-801 also antagonized
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
ethanol (5.0 g/kg). On the contrary, DHEAS and PS significantly reduced the
hypnotic-like effect of
ethanol. The obtained results suggest that
neurosteroids may modulate in an agonistic (AP, 5beta-THDOC), or antagonistic way (PS, DHEAS), the
GABA(A) receptor complex functions. Some of them (5beta-THDOC) also interact with
NMDA receptors. AP appeared to be the most selectively acting compound, with its profile of action fully comparable to that of
midazolam. AP also enhanced the
hypnotic effect of
ethanol, pointing out to the propensity to interact with centrally depressant agents. These findings, together with the possibility of conversion of some
neurosteroids in the brain to other
steroid hormones (
testosterone,
estradiol and
aldosterone), indicate the limitations of their use for the treatment of neurological and
psychiatric disorders.