THE ESTRUS CYCLE, SENSITIVITY TO CONVULSANTS AND THE ANTICONVULSANT EFFECT OF A NEUROACTIVE STEROID

Recent in vitro work in our laboratory suggests that functional sensit ivity of the gamma-aminobutyric acid(A) receptor complex to the neuroa ctive progesterone metabolite 3 alpha-hydroxy-5 alpha-pregnan-20-one ( 3 alpha,5 alpha-P) changes during the estrus cycle. Therefore, the cur rent in vivo studies were conducted to evaluate estrus cycle-related d ifferences in sensitivity to convulsants and the anticonvulsant effect of 3 alpha,5 alpha-P. The threshold dose for onset to myoclonic twitc h, running bouncing clonus and tonic hindlimb extension was measured b y constant i.v. infusion of (+)-bicuculline, picrotoxin, pentylenetetr azol, strychnine and ,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate . Females in estrus were more sensitive than females in diestrus 1 or males to (+)-bicuculline and ,7-dimethoxy-4-ethyl-beta-carboline-3-car boxylate. Administration of 3 alpha,5 alpha-P (15 mg/kg i.p. in beta-c yclodextrin) 15 min before infusion of pentylenetetrazol significantly increased the threshold dose for onset to all three convulsions and p rovided equal protection against tonic convulsions. The dose for onset to myoclonic twitch was significantly higher in females in diestrus 1 than females in estrus or males. Plasma 3 alpha,5 alpha-P did not dif fer between groups injected with 3 alpha,5 alpha-P, suggesting that th e difference in sensitivity to the anticonvulsant effect of 3 alpha,5 alpha-P was not pharmacokinetic. These results are consistent with in vitro data indicating that 3 alpha,5 alpha-P is more potent in diestru s 1 vs. estrus females and suggest that there is a selective interacti on between convulsant drugs highly specific for the gamma-aminobutyric acid receptor complex and estrus cycle-related changes in neuroactive steroid levels and potency.