Anticonvulsant activity of a mGlu(4alpha) receptor selective agonist, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid.
The metabotropic Group III agonist, (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid (ACPT-1), selective for the mGlu(4alpha) 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)-alpha-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)-alpha-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(4alpha) 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.
Chapman
A G
AG
Department of Neurology, Institute of Psychiatry, King's College London, Denmark Hill, De Crespigny Park, SE5 8AF, London, UK. spgtagc@iop.kcl.ac.uk
Talebi
A
A
Yip
P K
PK
Meldrum
B S
BS
D000161:Acoustic Stimulation; D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010768:Phosphoserine / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors; D012118:Resorcinols / Q000494:pharmacology; D012640:Seizures / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D014233:Tricarboxylic Acids / Q000494:pharmacology*
C409063:1-aminocyclopentane-1,2,4-tricarboxylic acid; C089836:2-amino-2-methyl-4-phosphonobutyrate; C119327:4-phosphonophenylglycine; D000613:Aminobutyrates; D000927:Anticonvulsants; D003517:Cyclopentanes; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; D014233:Tricarboxylic Acids; C101185:alpha-methyl-4-phosphonophenylglycine; C120877:methylserine phosphate; D010768:Phosphoserine; C079215:3,5-dihydroxyphenylglycine; D000409:Alanine; D005998:Glycine; C108823:metabotropic glutamate receptor 4