Abstracts

Neurosteroids are endogenous modulators of neuronal excitability with important roles in epilepsy. 3[alpha]-Androstanediol (3[alpha]-Diol) is a neurosteroid synthesized from testosterone in the brain, but the clinical importance of this steroid remains unclear. Recently, 3[alpha]-Diol has been shown to be a powerful anticonvulsant in several animal seizure models. 3[alpha]-Diol has been proposed as an endogenous protective neurosteroid in the brain, and thus could play a role in gender specific forms of epilepsy. The purpose of this study was to determine whether tolerance occurs to the anticonvulsant activity of 3[alpha]-Diol in the pentylenetetrazol (PTZ) seizure test and whether there is cross-tolerance with the benzodiazepine diazepam. In acute studies, 3[alpha]-Diol and diazepam were tested for protective activity against PTZ-induced seizures in a dose-dependent fashion in mice. The median effective dose (ED[sub]50[/sub]) was determined by log-probit analysis. In chronic studies, mice were treated with two daily injections of a 3 x ED[sub]50[/sub] dose of 3[alpha]-Diol (108 mg/kg, s.c.), diazepam (1.5 mg/kg, i.p.), or vehicle for 7 days. On the day after chronic treatment periods, the anticonvulsant potencies of 3[alpha]-Diol and diazepam were determined. 3[alpha]-Diol had an ED[sub]50[/sub] of 36-44 mg/kg against seizures induced by GABA receptor antagonists PTZ, picrotoxin, and DMCM. However, it was inactive against seizures induced by glutamate receptor agonists, kainic acid, NMDA, and 4-aminopyridine. Consistent with allosteric modulation, acute treatment of mice with 3[alpha]-Diol potentiated the anticonvulsant potency of diazepam. The protective potency of 3[alpha]-Diol after 7-day treatment with 3[alpha]-Diol was not significantly different from that in control mice. In contrast, in animals that were treated chronically with 3[alpha]-Diol for 7 days, there was significant reduction in the anticonvulsant potency of diazepam. Chronic treatment with diazepam was not associated with a reduction in the potency of 3[alpha]-Diol, but there was a reduction in the potency of diazepam. These results suggest that tolerance does not develop to the anticonvulsant activity of 3[alpha]-Diol during chronic treatment. However, 3[alpha]-Diol induces cross-tolerance to diazepam. Thus, endogenous androgenic neurosteroids could partly contribute to development of benzodiazepine tolerance during long-term clinical use for their sedative, anticonvulsant, and tranquilizing actions. The lack of tolerance suggests that 3[alpha]-Diol may be an efficacious anticonvulsant over longer time periods than most drugs targeting the benzodiazepine binding site of the GABA-A receptor. (Supported by NC State University)