Roles of metabotropic glutamate receptor subtypes in modulation of pentylenetetrazole-induced seizure activity in mice.
The anticonvulsant or proconvulsant properties of ligands at metabotropic glutamate receptors (mGluRs) were examined in a chemoconvulsant model using pentylenetetrazole (PTZ). Mice received mGluR ligands by intracerebroventricular (i.c.v.) infusion prior to a subcutaneous injection of PTZ and the latency to onset of tonic convulsions was recorded. The group I mGluR antagonist 1-aminoindan-1,5-dicarboxylic acid (AIDA) dose-dependently antagonised PTZ-induced seizures with a mean ED50 value of 465 nmol. In contrast, the selective group I mGluR agonist, (S)-3,5-dihydroxyphenylglycine [(S)-DHPG], was proconvulsive and decreased the PTZ-induced seizure latency (ED50=60 nmol i.c.v.). A selective agonist of group II mGluRs, (1S,3S)-1-aminocyclopentane dicarboxylic acid [(1S,3S)-ACPD], was proconvulsive but did not affect PTZ-induced seizure latency. Moreover, the proconvulsant effect of (IS,3S)-ACPD was not blocked by the mGluR2 antagonist, alpha-methylserine-O-phosphate monophenyl ester but was blocked by AIDA suggesting the involvement of group I mGluRs. (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCG-IV), which is a potent mGluR2 antagonist and a group III mGluR agonist at higher doses, increased the PTZ-induced seizure latency (ED50=51 nmol) and this effect was fully reversed by the group III mGluR antagonist, (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4). Similarly, the group III mGluR agonist 1-amino-3-(phosphonomethylene)cyclobutanecarboxylate (cyclobutylene-AP5) increased the PTZ-induced seizure latency (ED50=12 nmol) in a MAP4-sensitive manner. Collectively, these data suggest that mGluR ligands modulate PTZ-induced seizure activity in mice by either antagonizing group I mGluRs or activating group III mGluRs.
Thomsen
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Novo Nordisk A/S, Health Care Discovery, Måløv, Denmark. cht@novo.dk
Dalby
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D000818:Animals; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D003515:Cycloleucine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology; D007263:Infusions, Parenteral; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010433:Pentylenetetrazole / Q000633:toxicity*; D011930:Reaction Time; D012118:Resorcinols / Q000008:administration & dosage / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*
C095756:1-aminoindan-1,5-dicarboxylic acid; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D012118:Resorcinols; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; C079215:3,5-dihydroxyphenylglycine; D005998:Glycine; D010433:Pentylenetetrazole