PT  - JOURNAL ARTICLE
AU  - Doodipala S. Reddy
AU  - Michael A. Rogawski
TI  - Chronic Treatment with the Neuroactive Steroid Ganaxolone in the Rat Induces Anticonvulsant Tolerance to Diazepam but Not to Itself
DP  - 2000 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1241--1248
VI  - 295
IP  - 3
4099  - http://jpet.aspetjournals.org/content/295/3/1241.short
4100  - http://jpet.aspetjournals.org/content/295/3/1241.full
SO  - J Pharmacol Exp Ther2000 Dec 01; 295
AB  - 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. U.S. Government