Anticonvulsant activity of a mGlu 4α receptor selective agonist, (1 S,3 R,4 S)-1-aminocyclopentane-1,2,4-tricarboxylic acid

Abstract

The metabotropic Group III agonist, (1 S,3 R,4 S)-1-aminocyclopentane-1,2,4-tricarboxylic acid (ACPT-1), selective for the mGlu 4α receptor, suppresses sound-induced seizures in DBA/2 mice following its intracerebroventricular (i.c.v.) administration (ED 50 5.6 [2.9–10.7], nmol i.c.v., 15 min, clonic phase) and in genetically epilepsy-prone (GEP) rats following focal administration into the inferior colliculus (ED 50 0.08 [0.01–0.50], nmol, 60 min, clonic phase). ACPT-1 also protects against clonic seizures induced in DBA/2 mice by the Group I agonist, ( RS)-3,5-dihydroxyphenylglycine (3,5-DHPG) (ED 50 0.60 [0.29–1.2], nmol i.c.v.) and by the Group III antagonist, ( RS)-α-methylserine- O-phosphate (MSOP) (ED 50 49.3 [37.9–64.1], nmol i.c.v.). Another Group III agonist, ( RS)-4-phosphonophenyl-glycine (PPG), preferentially activating the mGlu 8 receptor, previously shown to protect against sound-induced seizures in DBA/2 mice and GEP rats, also protects against seizures induced in DBA/2 by 3,5-DHPG (ED 50 3.7 [2.4–5.7], nmol i.c.v.) and by the Group III antagonist, MSOP (ED 50 40.2 [21.0–77.0], nmol i.c.v.). At very high doses (500 nmol i.c.v. and above), Group III antagonists have pro-convulsant and convulsant activity. The anticonvulsant protection against sound-induced seizures in DBA/2 mice provided by a fully protective dose (20 nmol, i.c.v.) of the mGlu 4 receptor agonist ACPT-1, is partially reversed by the co-administration of the Group III antagonists, MSOP, ( RS)-α-methyl-4-phosphonophenylglycine (MPPG) or ( S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4), in the 20–50 nmol dose range. At doses of 50–200 nmol, MPPG and MAP4 cause further reversal of the ACPT-1 anticonvulsant protection, while the MSOP effect on ACPT-1 protection is abolished at higher doses. In contrast, the anticonvulsant protection against sound-induced seizures in DBA/2 mice provided by a fully protective dose (20 nmol, i.c.v.) of the mGlu 8 receptor agonist PPG, is not significantly affected by the co-administration of the same Group III antagonists, MSOP, MPPG or MAP4. We conclude that activation of either mGlu 4α or mGlu 8 receptors confer anticonvulsant protection in DBA/2 mice. Furthermore, the metabotropic Group III receptor antagonists, MSOP, MPPG, and MAP4 appear to be functionally selective for the mGlu 4 receptor in this system.