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, Michael A Rogawski

Research output: Contribution to journalArticle

60 Scopus citations

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 x 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 ED50 value 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 (t( 1/2 ), 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 n chronic seizure therapy.

Original languageEnglish (US)
Pages (from-to)553-558
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume287
Issue number2
StatePublished - 1998
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology

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    Kokate, T. G., Yamaguchi, S. I., Pannell, L. K., Rajamani, U., Carroll, D. M., Grossman, A. B., & Rogawski, M. A. (1998). Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice. Journal of Pharmacology and Experimental Therapeutics, 287(2), 553-558.