title: Group III mGlu receptor agonists potentiate the anticonvulsant effect of AMPA and NMDA receptor block.
abstract: We report the anticonvulsant action in DBA/2 mice of two mGlu Group III receptor agonists: (R,S)-4-phosphonophenylglycine, (R,S)-PPG, a compound with moderate mGlu8 selectivity, and of (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid, ACPT-1, a selective agonist for mGlu4alpha receptors. Both compounds, given intracerebroventricularly at doses which did not show marked anticonvulsant activity, produced a consistent shift to the left of the dose-response curves (i.e. enhanced the anticonvulsant properties) of 1-(4'-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one hydrochloride, CFM-2, a noncompetitive AMPA receptor antagonist, and 3-((+/-)-2-carboxypiperazin-4-yl)-1-phosphonic acid, CPPene, a competitive NMDA receptor antagonist, in DBA/2 mice. In addition, (R,S)-PPG and ACPT-1 administered intracerebroventricularly prolonged the time course of the anticonvulsant properties of CFM-2 (33 micromol/kg, i.p.) and CPPene (3.3 micromol/kg, i.p.) administered intraperitoneally. We conclude that modest reduction of synaptic glutamate release by activation of Group III metabotropic receptors potentiates the anticonvulsant effect of AMPA and NMDA receptor blockade.
authors.affiliation: Cattedra di Farmacologia, Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro, Catanzaro, Italy.
authors.forename: Giovambattista
authors.initials: G
authors.lastname: De Sarro
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
authors.forename: Brian S
authors.initials: BS
authors.lastname: Meldrum
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001570:Benzodiazepinones / Q000627:therapeutic use*; D003517:Cyclopentanes / Q000627:therapeutic use*; D004357:Drug Synergism; D005260:Female; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012640:Seizures / Q000517:prevention & control*; D014233:Tricarboxylic Acids / Q000627:therapeutic use*
chemical_list: C409063:1-aminocyclopentane-1,2,4-tricarboxylic acid; D000927:Anticonvulsants; D001570:Benzodiazepinones; C119033:CFM 2; D003517:Cyclopentanes; D018094:Receptors, Metabotropic Glutamate; D014233:Tricarboxylic Acids; C108823:metabotropic glutamate receptor 4