PT  - JOURNAL ARTICLE
AU  - Tushar G. Kokate
AU  - Shun-Ichi Yamaguchi
AU  - Lewis K. Pannell
AU  - Umamaheswari Rajamani
AU  - David M. Carroll
AU  - Andrew B. Grossman
AU  - Michael A. Rogawski
TI  - Lack of Anticonvulsant Tolerance to the Neuroactive Steroid Pregnanolone in Mice
DP  - 1998 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 553--558
VI  - 287
IP  - 2
4099  - http://jpet.aspetjournals.org/content/287/2/553.short
4100  - http://jpet.aspetjournals.org/content/287/2/553.full
SO  - J Pharmacol Exp Ther1998 Nov 01; 287
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics