Roles of group II metabotropic glutamate receptors in modulation of seizure activity

Evidence suggests that metabotropic glutamate receptors (mGluR) are involve d in mediating seizures and epileptogenesis. In the present experiments, th e selective, group II mGluR agonist (+)-2-aminobicyclo-[3.1.0]hexane-2,6-di carboxylic acid (LY354740, 0.1-1.0 mu M) inhibited spontaneous epileptiform discharges which developed in rat cortical slices in Mg2+-free medium. LY3 54740 (4-16 mg/kg) administered prior to an injection of pentylenetetrazol (80 mg/kg) or picrotoxin (3.2 mg/ kg) produced a dose-dependent decrease in the number of mice exhibiting clonic convulsions, but had no effect on N-m ethyl-D-aspartate (NMDA, 150 mg/kg)-induced convulsions. LY354740 (4-16 mg/ kg) did not affect lethality induced in mice by pentylenetetrazol, picrotox in or NMDA. LY354740 potentiated the anticonvulsant activity of the convent ional antiepileptic drug diazepam, significantly decreasing the ED50 for th at drug's effect on pentylenetetrazol-induced convulsions by 30%, but had n o influence on anticonvulsant activity of ethosuximide and valproic acid. A pharmacokinetic interaction between LY354740 and diazepam. leading to the lowering of the plasma level of free diazepam, was also demonstrated. Our d ata suggest that the group II mGluR agonist LY354740 possesses anti-seizure activity and may modify the effects of some conventional antiepileptic dru gs.