LACK OF ANTICONVULSANT TOLERANCE TO THE NEUROACTIVE STEROID PREGNANOLONE IN MICE

GABA-potentiating neuroactive steroids such as pregnanolone have poten t protective effects in the pentylenetetrazol seizure test. We sought to determine if tolerance develops to the anticonvulsant activity of p regnanolone with chronic administration. Mice were treated with two da ily 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-res ponse relationship for protection in the pentylenetetrazol seizure tes t was obtained. The ED50 value after the chronic treatment protocol wa s not significantly different from that in naive mice (12 mg/kg), indi cating that tolerance does not develop to the anticonvulsant activity of pregnanolone. In subsequent experiments, we extended the chronic tr eatment protocol to 14 days with three daily injections of pregnanolon e (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 thre shold (10%) protection (125-150 ng/ml) and 50% protection (575-700 ng/ ml) were similar in naive and chronically treated animals. In both chr onically treated and naive animals, plasma levels of pregnanolone decl ined rapidly (t(1/2), 16-19 min) and there was a corresponding reducti on in the anticonvulsant activity. Our results with pregnanolone sugge st that tolerance does not develop to the anticonvulsant activity of n euroactive steroids as it does with other GABA potentiating drugs such as benzodiazepines, supporting the potential clinical utility of neur oactive steroids in chronic seizure therapy.