Diazepam, pentobarbital and D-etomidate produced increases in bicuculline seizure threshold; selective antagonism by RO15-1788, picrotoxin and (+/-)-DMBB

The seizure threshold for different seizure components was measured after slow intravenous infusion of bicuculline in the rat. Clear differences were seen in the seizure threshold for tremor (TRE) and clonic-forepaw (CLOF) as compared to clonic-hindpaw (CLOH) and tonic-forepaw (TONF). Seizure threshold was measured after treatment with different doses of diazepam, pentobarbital, D-etomidate, picrotoxin, RO15-1788 and (+/-)-5-(1,3,-dimethylbutyl)-5-barbituric acid (DMBB). Direct and indirect antagonism between the agonists and antagonists was examined. The interactions between the drugs for TRE and CLOF resemble those described in in vitro receptor-binding assays using the GABA-benzodiazepine-chloride ionophore complex (GBCI). The interactions for CLOH and TONF do not show this resemblance, suggesting less involvement of GABA in these phenomena. Diazepam was selectively antagonized by RO15-1788. D-Etomidate and pentobarbital were directly antagonized by DMBB, suggesting shared activity at the barbiturate site. No evidence was found for an interaction between compounds acting at different sites within the GBCI.