Anticonvulsant activity of a metabotropic glutamate receptor 8 preferential agonist, (R,S)-4-phosphonophenylglycine

Agonists at group III glutamate metabotropic receptors, such as L-serine-O-phosphate, have pro- and anti-convulsant activities in rodent models. We have used intracerebroventricular administration to test a novel group III agonist, (R,S)-4-phosphonophenylglycine (PPG), that is preferential for mglu(8), against sound-induced seizures in DBA/2 mice. Tonic and clonic seizures are abolished at 15 min (ED(50s) 0.14 [0.04-0.4] nmol, and 3.4 [2.1-5.6] nmol, respectively). The protection against tonic and clonic seizures by 20 nmol PPG is complete for 4 h, diminished by 6 h, and absent by 10 h. In contrast, L-Serine-O-phosphate gives only partial protection against sound-induced clonic seizures for 15-30 min (ED(50) 79 [45-139] nmol) in DBA/2 mice. In genetically epilepsy prone rats sound-induced seizures were blocked 5-60 min after the bilateral administration of PPG, 5-10 nmol, into the inferior colliculus. These data suggest that the mglu(8) receptor is a potential target for novel antiepileptic drugs.