Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself.

Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnane-20-one), an orally active synthetic analog of the neuroactive steroid allopregnanolone, is a positive allosteric modulator of gamma-aminobutyric acid(A) 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 x ED(50) 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 ED(50) values for ganaxolone after 3- and 7-day treatment with ganaxolone were not significantly different from that in naive rats (ED(50) = 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 (ED(50) = 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 (ED(50) = 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.