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Research ArticleArticle

Lack of Anticonvulsant Tolerance to the Neuroactive Steroid Pregnanolone in Mice

Tushar G. Kokate, Shun-Ichi Yamaguchi, Lewis K. Pannell, Umamaheswari Rajamani, David M. Carroll, Andrew B. Grossman and Michael A. Rogawski
Journal of Pharmacology and Experimental Therapeutics November 1998, 287 (2) 553-558;
Tushar G. Kokate
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Shun-Ichi Yamaguchi
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Lewis K. Pannell
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Umamaheswari Rajamani
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David M. Carroll
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Andrew B. Grossman
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Michael A. Rogawski
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Abstract

GABA-potentiating neuroactive steroids such as pregnanolone have potent protective effects in the pentylenetetrazol seizure test. We sought to determine if tolerance develops to the anticonvulsant activity of pregnanolone with chronic administration. Mice were treated with two daily injections of a 2 × ED50 dose of pregnanolone (25 mg/kg, i.p.) for 7 days. On the day after the chronic treatment protocol, the dose-response relationship for protection in the pentylenetetrazol seizure test was obtained. The ED50value after the chronic treatment protocol was not significantly different from that in naive mice (12 mg/kg), indicating that tolerance does not develop to the anticonvulsant activity of pregnanolone. In subsequent experiments, we extended the chronic treatment protocol to 14 days with three daily injections of pregnanolone (25 mg/kg, i.p.). Again, no tolerance was observed (ED50, 13 mg/kg). The anticonvulsant activity of pregnanolone was well correlated with plasma levels in both the naive and chronically (14 day) treated mice. The estimated plasma concentrations of pregnanolone representing threshold (10%) protection (125–150 ng/ml) and 50% protection (575–700 ng/ml) were similar in naive and chronically treated animals. In both chronically treated and naive animals, plasma levels of pregnanolone declined rapidly (t½, 16–19 min) and there was a corresponding reduction in the anticonvulsant activity. Our results with pregnanolone suggest that tolerance does not develop to the anticonvulsant activity of neuroactive steroids as it does with other GABA potentiating drugs such as benzodiazepines, supporting the potential clinical utility of neuroactive steroids in chronic seizure therapy.

Footnotes

  • Send reprint requests to: Dr. Michael A. Rogawski, NINDS, NIH, Building 10, Room 5N-250, 10 Center Drive MSC 1408, Bethesda, MD 20892-1408.

  • Abbreviations:
    GABA
    γ-aminobutyric acid
    PTZ
    pentylenetetrazol
    BSTFA
    N1O-bis(trimethylsilyl)trifluoroacetamide
    TMCS
    trimethylchlorosilane
    GC-MS
    gas chromatography-mass spectroscopy
    • Received April 14, 1998.
    • Accepted June 23, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 2
1 Nov 1998
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Research ArticleArticle

Lack of Anticonvulsant Tolerance to the Neuroactive Steroid Pregnanolone in Mice

Tushar G. Kokate, Shun-Ichi Yamaguchi, Lewis K. Pannell, Umamaheswari Rajamani, David M. Carroll, Andrew B. Grossman and Michael A. Rogawski
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 553-558;

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Research ArticleArticle

Lack of Anticonvulsant Tolerance to the Neuroactive Steroid Pregnanolone in Mice

Tushar G. Kokate, Shun-Ichi Yamaguchi, Lewis K. Pannell, Umamaheswari Rajamani, David M. Carroll, Andrew B. Grossman and Michael A. Rogawski
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 553-558;
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