Stress affects seizure susceptibility in animals and humans, but the underlying mechanisms are obscure. Here, we provide evidence that
GABA(A) receptor-modulating
neurosteroids derived from
deoxycorticosterone (DOC) play a role in stress-related changes in seizure control. DOC, an adrenal
steroid whose synthesis is enhanced during stress, undergoes sequential metabolic reduction by 5alpha-reductase and 3alpha-hydroxysteroid
oxidoreductase to form 5alpha-dihydrodeoxycorticosterone (DHDOC) and
allotetrahydrodeoxycorticosterone (
THDOC), a
GABA(A) receptor-modulating
neurosteroid with
anticonvulsant properties. Acute swim stress in rats significantly elevated plasma
THDOC concentrations and raised the
pentylenetetrazol (PTZ) seizure threshold. Small systemic doses of DOC produced comparable increases in
THDOC and PTZ seizure threshold. Pretreatment with
finasteride, a 5alpha-reductase inhibitor that blocks the conversion of DOC to DHDOC, reversed the antiseizure effects of stress. DOC also elevated plasma
THDOC levels and protected mice against PTZ, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate,
picrotoxin, and amygdala-kindled
seizures in mice (ED50 values, 84-97 mg/kg).
Finasteride reversed the antiseizure activity of DOC (ED50, 7.2 mg/kg); partial antagonism was also obtained with
indomethacin (100 mg/kg), an inhibitor of 3alpha-hydroxysteroid
oxidoreductase.
Finasteride had no effect on seizure protection by DHDOC and
THDOC, whereas
indomethacin partially reversed DHDOC but not
THDOC. DHDOC, like
THDOC, potentiated
GABA-activated Cl- currents in cultured hippocampal neurons (< or =1 microm) and directly activated
GABA(A) receptor currents (> or =1 microm), compatible with a role for DHDOC in the antiseizure activity of DOC. DOC is a mediator of the physiological effects of acute stress that could contribute to stress-induced changes in seizure susceptibility through its conversion to
neurosteroids with modulatory actions on
GABA(A) receptors including
THDOC and possibly also DHDOC.