BENZODIAZEPINE ANTAGONISTS REDUCE EPILEPTIFORM DISCHARGES IN RAT HIPPOCAMPAL SLICES

Purpose: The antiepileptic effects of benzodiazepine-receptor (BZR) ag onists have been well documented. Surprisingly, an antiepileptic effec t for the BZR antagonist, flumazenil, has also been described, the mec hanism of which is unknown. We investigated the effects of nanomolar c oncentrations of flumazenil and a structurally dissimilar BZR antagoni st, propyl-beta-carboline-3-carboxylate (beta-CCP), on normal synaptic responses and epileptiform discharges induced by a variety of methods in the CA1 region of rat hippocampal slices. Methods: Extracellular f ield potentials were recorded from stratum pyramidale of the CA1 regio n. Orthodromic stimulation was delivered by a bipolar electrode placed in the stratum radiatum at the border of the CA2/CA3 regions. Drugs w ere bath applied, and epileptiform discharges were quantified by using the Coastline Bursting Index, which calculates the total length of th e discharge waveform of evoked multiple population spikes. For statist ical comparisons, we calculated the Coastline Bursting Index for the a verage of five traces at the end of the control period (20 min), drug application (20 min), and washout (20-40 min). Results: Flumazenil was without effect on normal synaptic responses; however, flumazenil redu ced epileptiform discharges evoked in the presence of high [K+](o), le u-enkephalin, the BZR inverse agonist, 6,7-dimethoxy-4-ethyl-beta-carb oline-3-carboxylate (DMCM), or after a cold-shock procedure. beta-CCP exhibited an action similar to that observed for flumazenil, suggestin g that the antiepileptic effect is due to properties common to BZR ant agonists. Conclusions: We suggest that the antiepileptic effect we obs erved for flumazenil and beta-CCP is mediated at the BZR and might be due to competition with endogenous BZR inverse agonists released prefe rentially during epileptiform activity.