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In vivo modulation of extracellular hippocampal glutamate and GABA levels and limbic seizures by group I and II metabotropic glutamate receptor ligands
Author(s) -
Smolders Ilse,
Lindekens Hilde,
Clinckers Ralph,
Meurs Alfred,
O'Neill Michael J.,
Lodge David,
Ebinger Guy,
Michotte Yvette
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.02251.x
Subject(s) - metabotropic glutamate receptor , glutamate receptor , metabotropic receptor , metabotropic glutamate receptor 5 , agonist , metabotropic glutamate receptor 1 , pharmacology , chemistry , metabotropic glutamate receptor 2 , medicine , neuroscience , endocrinology , biology , receptor , biochemistry
The effects of several metabotropic receptor (mGluR) ligands on baseline hippocampal glutamate and GABA overflow in conscious rats and the modulation of limbic seizure activity by these ligands were investigated. Intrahippocampal mGluR group I agonist perfusion via a microdialysis probe [1 m m (R,S)‐3,5‐dihydroxyphenylglycine] induced seizures and concomitant augmentations in amino acid dialysate levels. The mGlu 1a receptor antagonist LY367385 (1 m m ) decreased baseline glutamate but not GABA concentrations, suggesting that mGlu 1a receptors, which regulate hippocampal glutamate levels, are tonically activated by endogenous glutamate. This decrease in glutamate may contribute to the reported LY367385‐mediated anticonvulsant effect. The mGlu 5 receptor antagonist 2‐methyl‐6‐(phenylethynyl)‐pyridine (50 mg/kg) also clearly abolished pilocarpine‐induced seizures. Agonist‐mediated actions at mGlu 2/3 receptors by LY379268 (100 µ m , 10 mg/kg intraperitoneally) decreased basal hippocampal GABA but not glutamate levels. This may partly explain the increased excitation following systemic LY379268 administration and the lack of complete anticonvulsant protection within our epilepsy model with the mGlu 2/3 receptor agonist. Group II selective mGluR receptor blockade with LY341495 (1–10 µ m ) did not alter the rats' behaviour or hippocampal amino acid levels. These data provide a neurochemical basis for the full anticonvulsant effects of mGlu 1a and mGlu 5 antagonists and the partial effects observed with mGlu 2/3 agonists in vivo.