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.