Status epilepticus (SE) is a neurologic emergency characterized by very prolonged, sometimes refractory seizures associated with a 23 percent mortality. SE is a progressive condition where seizures reduce GABA- medicated inhibition in the hippocampus which in turn leads to more seizures. Past and recent studies of patients and experimental animals having SE suggested the hypothesis that gamma-amino butyric acid type A (GABAA) receptor (GABAR) function is altered during SE. This proposal will directly test this hypothesis by using whole cell patch clamp to study the GABARs present on hippocampal neurons isolated from rats undergoing SE and by study of treatment of SE in rats. Experiments are proposed to accomplish following specific aims: 1) In whole animals the potency and efficacy of anticonvulsants acting at the benzodiazepine site and drugs acting at the barbiturate site of the GABARs will be measured after brief seizures and prolonged seizures of SE. 2) Compare the time course of loss of diazepam sensitivity of dentate granule cell GABARs during SE with the time course of loss of efficacy of diazepam in whole animals undergoing SE. 3) Compare the diazepam and pentobarbital sensitivity of CA1 pyramidal neurons acutely isolated from naive rats and rats undergoing 45 minutes of SE will be. 4) Characterize the detailed pharmacological properties of dentate granule cell GABARs following SE.
