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Research ArticleNEUROPHARMACOLOGY

Chronic Treatment with the Neuroactive Steroid Ganaxolone in the Rat Induces Anticonvulsant Tolerance to Diazepam but Not to Itself

Doodipala S. Reddy and Michael A. Rogawski
Journal of Pharmacology and Experimental Therapeutics December 2000, 295 (3) 1241-1248;
Doodipala S. Reddy
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Michael A. Rogawski
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Abstract

Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnane-20-one), an orally active synthetic analog of the neuroactive steroid allopregnanolone, is a positive allosteric modulator of γ-aminobutyric acidA receptors with anticonvulsant properties. We sought to determine whether tolerance occurs to the anticonvulsant activity of ganaxolone in the pentylenetetrazol seizure test and whether there is cross-tolerance with diazepam. Rats were treated with two daily injections of a 2 × ED50 dose of ganaxolone (7 mg/kg s.c.), diazepam (4 mg/kg i.p.), or vehicle for 3 or 7 days. On the day after the chronic treatment periods, the anticonvulsant potencies of ganaxolone and diazepam were determined. The ED50 values for ganaxolone after 3- and 7-day treatment with ganaxolone were not significantly different from that in naive rats (ED50 = 3.5 mg/kg). In contrast, in animals that were treated chronically with ganaxolone for 7 days, there was a significant reduction in the anticonvulsant potency of diazepam (ED50 = 4.0 versus 1.9 mg/kg for naive controls). Chronic treatment with diazepam was not associated with a reduction in the potency of ganaxolone, but there was a reduction in the potency of diazepam (ED50 = 3.7 mg/kg). Plasma ganaxolone determinations indicated that the pharmacokinetic properties of ganaxolone were unchanged after 7-day chronic ganaxolone treatment. The estimated equilibrium plasma concentrations of ganaxolone associated with threshold (750–950 ng/ml) and 50% seizure protection (1215–1295 ng/ml) were similar in naive and chronically treated rats. We conclude that there is no tolerance to the anticonvulsant activity of ganaxolone nor is there cross-tolerance to ganaxolone when tolerance develops to diazepam. However, there is cross-tolerance to diazepam with chronic ganaxolone treatment.

Footnotes

  • Send reprint requests to: Michael A. Rogawski, M.D., Ph.D., Epilepsy Research Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Dr. Room 5N-250 MSC 1408, Bethesda, MD 20892-1408. E-mail:rogawski{at}nih.gov

  • Abbreviations:
    GABA
    γ-aminobutyric acid
    PTZ
    pentylenetetrazol
    AUC
    area under the curve
    • Received June 13, 2000.
    • Accepted August 15, 2000.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 295 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 3
1 Dec 2000
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Research ArticleNEUROPHARMACOLOGY

Chronic Treatment with the Neuroactive Steroid Ganaxolone in the Rat Induces Anticonvulsant Tolerance to Diazepam but Not to Itself

Doodipala S. Reddy and Michael A. Rogawski
Journal of Pharmacology and Experimental Therapeutics December 1, 2000, 295 (3) 1241-1248;

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Research ArticleNEUROPHARMACOLOGY

Chronic Treatment with the Neuroactive Steroid Ganaxolone in the Rat Induces Anticonvulsant Tolerance to Diazepam but Not to Itself

Doodipala S. Reddy and Michael A. Rogawski
Journal of Pharmacology and Experimental Therapeutics December 1, 2000, 295 (3) 1241-1248;
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