The estrus cycle, sensitivity to convulsants and the anticonvulsant effect of a neuroactive steroid

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Abstract

Recent in vitro work in our laboratory suggests that functional sensitivity of the γ-aminobutyric acid(A) receptor complex to the neuroactive progesterone metabolite 3α-hydroxy-5α-pregnan-20-one (3α,5α- 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 3α,5α-P. The threshold dose for onset to myoclonic twitch, running bouncing clonus and tonic hindlimb extension was measured by constant i.v. infusion of (+)-bicuculline, picrotoxin, pentylenetetrazol, strychnine and methyl-6,7-dimethoxy-4-ethyl- β-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-β-carboline-3-carboxylate. Administration of 3α,5α-P (15 mg/kg i.p. in β-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 3α,5α-P did not differ between groups injected with 3α,5α-P, suggesting that the difference in sensitivity to the anticonvulsant effect of 3α,5α-P was not pharmacokinetic. These results are consistent with in vitro data indicating that 3α,5α-P is more potent in diestrus 1 vs. estrus females and suggest that there is a selective interaction between convulsant drugs highly specific for the γ-aminobutyric acid receptor complex and estrus cycle-related changes in neuroactive steroid levels and potency.

Original languageEnglish (US)
Pages (from-to)164-170
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume271
Issue number1
StatePublished - 1994
Externally publishedYes

Fingerprint

Convulsants
Estrus
Anticonvulsants
Steroids
Diestrus
Aminobutyrates
Carbolines
Pentylenetetrazole
Bicuculline
Seizures
Strychnine
Picrotoxin
Civil Rights
Cyclodextrins
Hindlimb
Progesterone
Pharmacokinetics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "The estrus cycle, sensitivity to convulsants and the anticonvulsant effect of a neuroactive steroid",
abstract = "Recent in vitro work in our laboratory suggests that functional sensitivity of the γ-aminobutyric acid(A) receptor complex to the neuroactive progesterone metabolite 3α-hydroxy-5α-pregnan-20-one (3α,5α- 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 3α,5α-P. The threshold dose for onset to myoclonic twitch, running bouncing clonus and tonic hindlimb extension was measured by constant i.v. infusion of (+)-bicuculline, picrotoxin, pentylenetetrazol, strychnine and methyl-6,7-dimethoxy-4-ethyl- β-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-β-carboline-3-carboxylate. Administration of 3α,5α-P (15 mg/kg i.p. in β-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 3α,5α-P did not differ between groups injected with 3α,5α-P, suggesting that the difference in sensitivity to the anticonvulsant effect of 3α,5α-P was not pharmacokinetic. These results are consistent with in vitro data indicating that 3α,5α-P is more potent in diestrus 1 vs. estrus females and suggest that there is a selective interaction between convulsant drugs highly specific for the γ-aminobutyric acid receptor complex and estrus cycle-related changes in neuroactive steroid levels and potency.",
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