Anticonvulsant actions of LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid)

We have studied the effects in three rodent models of generalised convulsiv e or absence epilepsy of two antagonists of group I metabotropic glutamate receptors that are selective for the mGlu(1) receptor. LY 367385 ((+)-2-met hyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic ac id) have been administered intracerebroventricularly (i.c.v.) to DBA/2 mice and lethargic mice (lh/lh), and focally into the inferior colliculus of ge netically epilepsy prone rats (GEPR). In DBA/2 mice both compounds produce a rapid, transient suppression of sound-induced clonic seizures (LY 367385: ED50 = 12 nmol, i.c.v., 5 min; AIDA: ED50 = 79 nmol, i.c.v., 15 min). In l ethargic mice both compounds significantly reduce the incidence of spontane ous spike and wave discharges on the electroencephalogram, from < 30 to > 1 50 min after the administration of AIDA, 500 nmol, i.c.v., and from 30 to > 150 min after the administration of LY 367385, 250 nmol, i.c.v. LY 367385, 50 nmol, suppresses spontaneous spike and wave discharges from 30 to 60 mi n. In genetically epilepsy prone rats both compounds reduce sound-induced c lonic seizures. LY 367385, 160 nmol bilaterally, fully suppresses clonic se izures after 2-4 h. AIDA is fully effective 30 min after 100 nmol bilateral ly. It is concluded that antagonists of mGlu(1) receptors are potential ant iconvulsant agents and that activation of mGlu(1) receptors probably contri butes to a variety of epileptic syndromes. (C) 1999 Elsevier Science B.V. A ll rights reserved.