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

Ganaxolone (3 alpha -hydroxy-3 beta -methyl-5 alpha -pregnane-20-one), an o rally 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 o ccurs 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 ED50 dose of ganaxolone (7 mg/k g s.c.), diazepam (4 mg/kg i.p.), or vehicle for 3 or 7 days. On the day af ter the chronic treatment periods, the anticonvulsant potencies of ganaxolo ne and diazepam were determined. The ED50 values for ganaxolone after 3- an d 7-day treatment with ganaxolone were not significantly different from tha t in naive rats (ED50 = 3.5 mg/kg). In contrast, in animals that were treat ed chronically with ganaxolone for 7 days, there was a significant reductio n in the anticonvulsant potency of diazepam (ED50 = 4.0 versus 1.9 mg/kg fo r 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 (ED50 = 3.7 mg/kg). Plasma ganaxolone determinations in dicated that the pharmacokinetic properties of ganaxolone were unchanged af ter 7-day chronic ganaxolone treatment. The estimated equilibrium plasma co ncentrations of ganaxolone associated with threshold (750-950 ng/ml) and 50 % seizure protection (1215-1295 ng/ml) were similar in naive and chronicall y treated rats. We conclude that there is no tolerance to the anticonvulsan t activity of ganaxolone nor is there cross-tolerance to ganaxolone when to lerance develops to diazepam. However, there is cross-tolerance to diazepam with chronic ganaxolone treatment.