RT Journal Article
SR Electronic
T1 Lack of Anticonvulsant Tolerance to the Neuroactive Steroid Pregnanolone in Mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 553
OP 558
VO 287
IS 2
A1 Tushar G. Kokate
A1 Shun-Ichi Yamaguchi
A1 Lewis K. Pannell
A1 Umamaheswari Rajamani
A1 David M. Carroll
A1 Andrew B. Grossman
A1 Michael A. Rogawski
YR 1998
UL http://jpet.aspetjournals.org/content/287/2/553.abstract
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