The aim of the present study was to analyze biochemical effects of a
neurosteroid,
pregnenolone sulfate (PS), which accompany changes in the threshold of
seizures, and to establish the contribution of local, hippocampal monoaminergic and
amino acid systems, to the control of convulsive activity. Pretreatment of mice with PS (intracerebroventricularly) selectively enhanced the potency of peripherally (intraperitoneally) administered
NMDA at the LD16 (88.0 mg/kg) to induce clonic-tonic convulsions (PS, LD84 = 184.7 nM; 95% CL = 181.4-188.1). The proconvulsive actions of
picrotoxin and
bicuculline, the
GABA-A receptor antagonists, were not modified by pretreatment of mice with PS. Administration of PS alone (up to 240 nM icv) did not show any seizure-like activity. PS given at LD84, together with
NMDA (at the LD16), increased the hippocampal concentration of
alanine, and enhanced local metabolism of
dopamine in a period immediately preceding the onset of
seizures significantly stronger than did
NMDA alone. These and other data indicate that the enhancement by PS of hippocampal levels of
alanine may contribute to the
seizures development as this
amino acid is a precursor of
glutamate, and a co-agonist of the
NMDA receptors. On the other hand, simultaneously occurring stimulation of hippocampal dopaminergic system may be considered a compensatory phenomenon, limiting
seizures propagation through the limbic forebrain. Summarizing, our results show that PS-induced potentiation of
NMDA seizures is accompanied by selective changes in hippocampal
dopamine turnover and
alanine concentration.