Convulsant actions of the neurosteroid pregnenolone sulfate in mice

Pregnenolone sulfate (PS) is an endogenous neurosteroid known to antagonize GABA(A) receptor-mediated inhibitory responses and potentiate NMDA recepto r-mediated excitatory responses in vitro. To assess the actions of the ster oid as a modulator of seizure susceptibility in vivo, PS (30-300 nmol) was administered intracerebroventricularly in mice. At doses of 50 to 150 nmol, PS elicited seizures characterized by head jerks, rearing and falling, sev ere forelimb and hindlimb clonus, opisthotonos and explosive running. The s eizures increased in severity and frequency with time and eventually progre ssed to status epilepticus, tonic hindlimb extension and death. The doses p roducing convulsions in 50% (CD50) and 97% (CD97) of animals were 92 and 20 5 nmol, respectively. A subconvulsant dose of PS (50 nmol) significantly in creased the convulsant potencies of systemically administered pentylenetetr azol (30-50 mg/kg) and NMDA (50-100 mg/kg). Systemically administered PS at doses as high as 100 mg/kg failed to induce seizures or alter the convulsa nt potencies of pentylenetetrazol and NMDA. Protection against PS (205 nmol )-induced seizures and lethality was conferred by the GABA(A) receptor posi tive allosteric modulators clonazepam and allopregnanolone, and by the NMDA receptor antagonists dizocilpine and (R)-CPP. The overall pharmacological profile suggests that the convulsant actions of PS are mediated predominant ly via its effects on GABA(A) receptors, and also possibly by effects on NM DA receptors. (C) 1999 Elsevier Science B.V. All rights reserved.