The estrus cycle, sensitivity to convulsants and the anticonvulsant effect of a neuroactive steroid.
Recent in vitro work in our laboratory suggests that functional sensitivity of the gamma-aminobutyric acidA receptor complex to the neuroactive progesterone metabolite 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) changes during the estrus cycle. Therefore, the current in vivo studies were conducted to evaluate estrus cycle-related differences in sensitivity to convulsants and the anticonvulsant effect of 3 alpha, 5 alpha-P. The threshold dose for onset to myoclonic twitch, running bouncing clonus and tonic hind-limb extension was measured by constant i.v. infusion of (+)-bicuculline, picrotoxin, pentylenetetrazol, strychnine and methyl-6,7-dimethoxy-4-ethyl-beta- carboline-3-carboxylate. Females in estrus were more sensitive than females in diestrus 1 or males to (+)-bicuculline and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3- carboxylate. Administration of 3 alpha, 5 alpha-P (15 mg/kg i.p. in beta-cyclodextrin) 15 min before infusion of pentylenetetrazol significantly increased the threshold dose for onset to all three convulsions and provided 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 differ between groups injected with 3 alpha, 5 alpha-P, suggesting that the difference in sensitivity to the anticonvulsant effect of 3 alpha, 5 alpha-P was not pharmacokinetic.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, College of Medicine, University of California, Irvine.
D A
DA
Finn
K W
KW
Gee
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004971:Estrus; D005260:Female; D008297:Male; D010433:Pentylenetetrazole; D011280:Pregnanolone / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000209:etiology*; D012737:Sex Factors
D000927:Anticonvulsants; D011280:Pregnanolone; D010433:Pentylenetetrazole