Group III mGlu receptor agonists potentiate the anticonvulsant effect of AMPA and NMDA receptor block.
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.
De Sarro
Giovambattista
G
Cattedra di Farmacologia, Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro, Catanzaro, Italy.
Chimirri
Alba
A
Meldrum
Brian S
BS
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*
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