Effect of extracellular long-time microperfusion of high concentrations of glutamate and glycine on picrotoxin seizure thresholds in the hippocampus of freely moving rats

The effect of high concentrations of glutamate and glycine on picrotoxin seizure thresholds was investigated by perfusion through microdialysis probes in the hippocampus of freely moving rats. Microperfusion of glutamate at concentrations up to 1 mM, produced no changes in behavior or basal EEG recordings, but microperfusion of 200 microM glutamate was sufficient to lower the picrotoxin seizure threshold down to 50% in 60% of the animals studied and produced an increase of 180+/-23% in seizure duration. Microperfusion of 1 mM glutamate reduced seizure threshold in all animals, and markedly prolonged seizure duration (230+/-30%). Microperfusion of 200 microM or 1 mM glycine lowered picrotoxin seizure thresholds down to 50% in 70% of the animals and lengthened seizure duration up to 176+/-43%. Continuous microperfusion of the antagonist for the glycine binding site in NMDA receptors 5,7-dichlorokynurenic acid (100 microM) reversed the effect of both glutamate (1 mM) and glycine (1 mM) and suppressed seizures completely in 90% of the animals. These results indicate that although neurotoxicity is not achieved by perfusing glutamate and glycine at concentrations as high as 1 mM, neuronal excitability is modified by altering extracellular glutamate and glycine concentrations, and they suggest that glutamate-induced neuronal hyperexcitability is induced through mechanisms different from excitotoxicity.