title: Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice.
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 (t1/2, 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 in chronic seizure therapy.
authors.affiliation: Neuronal Excitability Section, Epilepsy Research Branch, National Institute of Neurological Disorders and Stroke, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: T G
authors.initials: TG
authors.lastname: Kokate
authors.forename: S
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: L K
authors.initials: LK
authors.lastname: Pannell
authors.forename: U
authors.initials: U
authors.lastname: Rajamani
authors.forename: D M
authors.initials: DM
authors.lastname: Carroll
authors.forename: A B
authors.initials: AB
authors.lastname: Grossman
authors.forename: M A
authors.initials: MA
authors.lastname: Rogawski
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004361:Drug Tolerance; D018757:GABA Modulators / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011280:Pregnanolone / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D018757:GABA Modulators; D011280:Pregnanolone