Abstracts

RATIONALE: The classic metabotropic Group III agonists, L-AP4 (L(+)-2-amino-4-phosphonobutyric acid) and L-SOP (L-serine-0-phosphate) are thought to act presynaptically on mGlu4, mGlu7 and mGlu8. In rodent models of epilepsy they have early transient proconvulsant actions and prolonged anticonvulsant actions. (R,S)-4-phosphonophenylglycine is a cyclic analogue of L-AP4 and L-SOP, with a preferential agonist action at mGlu8. ACPT-1, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid, is a prefential agonist for mGlu4. We have compared their acute anticonvulsant activity in mouse models. METHODS: Clonic seizures were induced in 3-4 week old DBA/2 mice by a sound stimulus, by the intracerebroventricular (icv) administration of the Group I metabotropic agonist, 3,5-DHPG, 3,5-dihydroxyphenylglycine, (1.5 mol icv)or by the icv administration of the Group III metabotropic antagonist, MSOP, (R,S)methylserine-O-phosphate (3 mol icv). PPG or ACPT-1 were dissolved in saline containing 10% cremophor and were given icv to DBA/2 mice prior to sound stimulation, or co-administered icv with the convulsant compounds. RESULTS: PPG and ACPT-1 (icv, -15 min) are approximately equipotent in suppressing sound-induced clonic seizures (ED50 values of 3.4 and 5.6 nmol respectively). Full protection against sound-induced seizures by 20 nmol ACPT-1 is partially reversed by 20 to 50 nmole of the Group III metabotropic antagonists, MSOP, MAP4 and MPPG. The anticonvulsant action of PPG, in contrast, is not affected by the same antagonists.However, both PPG and ACPT-1, when co-administered with MSOP, protect against MSOP-induced clonic seizures with ED50 values around 50 nmol. PPG and ACPT-1 potently suppress seizures induced by the Group I agonist, 3,5-DHPG, (ED50 values (nmol icv)of 3.68 [2.36-5.73] and 0.60 [0.29-1.23] respectively). CONCLUSIONS: PPG and ACPT-1 show acute anticonvulsant activity without proconvulsant effects. Differences in their potencies in different models presumably relate to their different selectivity for mGluRs.