Regional distribution and pharmacological characteristics of [H-3]N-acetyl-aspartyl-glutamate (NAAG) binding sites in rat brain

Autoradiographical studies revealed that 10 nM [H-3]N-acetyl-aspartyl-gluta mate (NAAG) labelled grey matter structures, particularly in the hippocamus , cerebral neocortex, striatum, septal nuclei and the cerebellar cortex. Th e binding was inhibited by (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)-glyc ine (DCG IV), an agonist at group II metabotropic glutamate receptors (mGlu R II). (RS)-alpha-Methyl-4-tetrazolylphenylglycine (MTPG), (RS)-alpha-cyclo propyl-4-phosphonoglycine (CPPG) and (RS)-alpha-methylserine-O-phosphate mo nophenyl ester (MSOPPE), all antagonists at mGluR II and mGluR III, also in hibited [H-3]NAAG binding. Other inhibitors were (1S,3R)-1-aminocyclopentan e-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-car boxy-4-hydroxyphenylglycine (3,4-CHPG) and (S)-4-carboxy-3-hydroxyphenylgly cine (4,3-CHPG). Neither the mGluR I specific agonist (S)-dihydroxyphenylgl ycine nor any of the ionotropic glutamate receptor ligands such as kainate, AMPA and MK-801 had strong effects (except for the competitive NMDA antago nist CGS 19755, which produced 20-40% inhibition at 100 mu M) suggesting th at, at low nM concentrations, [3H]NAAG binds predominantly to metabotropic glutamate receptors, particularly those of the mGluR II type. Several studi es have indicated that NAAG can interact with mGluR II and the present stud y supports this notion by demonstrating that sites capable of binding NAAG at low concentrations and displaying pharmacological characteristics of mGl uR II exist in the central nervous tissue. Furthermore, the results show th at autoradiography of [H-3]NAAG binding can be used to quantify the distrib ution of such sites in distinct brain regions and study their pharmacology at the same time. (C) 2000 Elsevier Science Ltd. All rights reserved.