In vivo modulation of extracellular hippocampal glutamate and GABA levels and limbic seizures by group I and II metabotropic glutamate receptor ligands.
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 mm (R,S)-3,5-dihydroxyphenylglycine] induced seizures and concomitant augmentations in amino acid dialysate levels. The mGlu1a receptor antagonist LY367385 (1 mm) decreased baseline glutamate but not GABA concentrations, suggesting that mGlu1a 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 mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (50 mg/kg) also clearly abolished pilocarpine-induced seizures. Agonist-mediated actions at mGlu2/3 receptors by LY379268 (100 microm, 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 mGlu2/3 receptor agonist. Group II selective mGluR receptor blockade with LY341495 (1-10 microm) did not alter the rats' behaviour or hippocampal amino acid levels. These data provide a neurochemical basis for the full anticonvulsant effects of mGlu1a and mGlu5 antagonists and the partial effects observed with mGlu2/3 agonists in vivo.
Department of Pharmaceutical Chemistry, Research group Experimental Pharmacology, Pharmaceutical Institute, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Ilse
I
Smolders
Hilde
H
Lindekens
Ralph
R
Clinckers
Alfred
A
Meurs
Michael J
MJ
O'Neill
David
D
Lodge
Guy
G
Ebinger
Yvette
Y
Michotte
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D045604:Extracellular Fluid / Q000737:chemistry / Q000378:metabolism; D018698:Glutamic Acid / Q000032:analysis / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism*; D008024:Ligands; D008032:Limbic System / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D017551:Microdialysis; D010862:Pilocarpine; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D005680:gamma-Aminobutyric Acid / Q000032:analysis / Q000378:metabolism*
D000596:Amino Acids; D000927:Anticonvulsants; D001565:Benzoates; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C118218:LY 379268; D008024:Ligands; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; C474696:methyl-(4-carboxyphenyl)glycine; D010862:Pilocarpine; C079694:alpha-methyl-4-carboxyphenylglycine; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C121465:6-methyl-2-(phenylethynyl)pyridine; D005998:Glycine