BENZODIAZEPINE ANTAGONIST FLUMAZENIL REDUCES HIPPOCAMPAL EPILEPTIFORMACTIVITY

WE examined the effects of the benzodiazepine antagonist, flumazenil, on epileptiform discharges evoked in the hippocampal CA1 region in vit ro. Application of 100 nM flumazenil did not affect normal synaptic re sponses; however, flumazenil did depress epileptiform discharges induc ed by 8 mM (K+](0). Epileptiform discharges induced by the GABA(A) cha nnel antagonist picrotoxin or by the K+ channel blocker 4-aminopyridin e were unaffected. Application of the high-affinity, low-efficacy benz odiazepine partial inverse agonist, Ro 19-4603, blocked the anticonvul sant effect of flumazenil, indicating that this action of flumazenil i s mediated at a benzodiazepine binding site located on the GABA(A) rec eptor. A likely explanation of the present results is that flumazenil antagonizes the action of an endogenous benzodiazepine inverse agonist , which is released during epileptiform discharges evoked in high K+ A CSF.