ATTENUATION OF ANTICONVULSANT EFFECTS OF DIAZEPAM AFTER CHRONIC TREATMENT WITH BICUCULLINE

Changes in the GABAergic system after chronic treatment with bicuculli ne were examined in two strains of inbred rats, Fischer 344 (F344) and Lewis (LEW). Rats received an IP injection of either bicuculline (2 m g/kg) or vehicle once a day for 12 days. After this chronic treatment, the effects of diazepam (I mg/kg, IP) and pentobarbital (20 mg/kg, IP ) on bicuculline-induced convulsions were measured. Bicuculline was ac utely infused into a tail vein at 0.0415 mg/min, and the infusion was terminated when rats showed seizure. Following the chronic bicuculline treatment, the anticonvulsant effect of diazepam, but not of pentobar bital, was significantly reduced as compared to its effect following c hronic vehicle treatment in both strains. Both diazepam and pentobarbi tal showed a significant difference in anticonvulsant effects between strains (F344 > LEW). The hypnotic effects of muscimol, barbital, pent obarbital, and ethanol following chronic bicuculline treatment were ex amined. There was no significant difference in sleep time induced by t hese drugs between bicuculline- and vehicle-treated rats. These result s suggest that the attenuation of diazepam's anticonvulsant effect aft er chronic bicuculline treatment may result from functional changes in benzodiazepine receptors and that the anticonvulsant effects of diaze pam and pentobarbital may be influenced by genetic factors. Moreover, the hypnotic effects of several drugs tested are apparently not affect ed by chronic bicuculline treatment.