Regional distribution and pharmacological characteristics of [3H]N-acetyl-aspartyl-glutamate (NAAG) binding sites in rat brain.
Autoradiographical studies revealed that 10 nM [3H]N-acetyl-aspartyl-glutamate (NAAG) labelled grey matter structures, particularly in the hippocamus, cerebral neocortex, striatum, septal nuclei and the cerebellar cortex. The binding was inhibited by (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)-glycine (DCG IV), an agonist at group II metabotropic glutamate receptors (mGluR II). (RS)-alpha-Methyl-4-tetrazolylphenylglycine (MTPG), (RS)-alpha-cyclopropyl-4-phosphonoglycine (CPPG) and (RS)-alpha-methylserine-O-phosphate monophenyl ester (MSOPPE), all antagonists at mGluR II and mGluR III, also inhibited [3H]NAAG binding. Other inhibitors were (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD), a broad-spectrum mGluR agonist with preference for groups I and II and the mGluR I agonists/mGluR II antagonists (S)-3-carboxy-4-hydroxyphenylglycine (3,4-CHPG) and (S)-4-carboxy-3-hydroxyphenylglycine (4,3-CHPG). Neither the mGluR I specific agonist (S)-dihydroxyphenylglycine nor any of the ionotropic glutamate receptor ligands such as kainate, AMPA and MK-801 had strong effects (except for the competitive NMDA antagonist CGS 19755, which produced 20-40% inhibition at 100 microM) suggesting that, at low nM concentrations, [3H]NAAG binds predominantly to metabotropic glutamate receptors, particularly those of the mGluR II type. Several studies have indicated that NAAG can interact with mGluR II and the present study supports this notion by demonstrating that sites capable of binding NAAG at low concentrations and displaying pharmacological characteristics of mGluR II exist in the central nervous tissue. Furthermore, the results show that autoradiography of [3H]NAAG binding can be used to quantify the distribution of such sites in distinct brain regions and study their pharmacology at the same time.
Shave
E
E
Department of Anatomy and Histology, The University of Sydney, NSW, Australia.
Pliss
L
L
Lawrance
M L
ML
FitzGibbon
T
T
Stastny
F
F
Balcar
V J
VJ
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000648:ultrastructure*; D001923:Brain Chemistry; D002268:Carboxypeptidases / Q000378:metabolism; D003080:Cold Temperature; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology; D004151:Dipeptides / Q000378:metabolism* / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D043425:Glutamate Carboxypeptidase II; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism*; D010768:Phosphoserine / Q000031:analogs & derivatives / Q000494:pharmacology; D010875:Pipecolic Acids / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D003521:Cyclopropanes; D004151:Dipeptides; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D010875:Pipecolic Acids; D017470:Receptors, Glutamate; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D013777:Tetrazoles; C101186:alpha-methyl-4-tetrazolylphenylglycine; C108822:metabotropic glutamate receptor 2; C104077:metabotropic glutamate receptor type 1; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; C078245:4-carboxy-3-hydroxyphenylglycine; C073649:(tetrazol-5-yl)glycine; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D010768:Phosphoserine; C027172:isospaglumic acid; C053672:selfotel; D016291:Dizocilpine Maleate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II; D000409:Alanine; D007608:Kainic Acid; D005998:Glycine