DIRECT EFFECTS OF METABOTROPIC GLUTAMATE-RECEPTOR COMPOUNDS ON NATIVEAND RECOMBINANT N-METHYL-D-ASPARTATE RECEPTORS

The actions of glutamate in the central nervous system are mediated th rough interaction with fast activating ionotropic receptors and G prot ein-coupled metabotropic glutamate receptors (mGluRs). Studies of thes e receptors have relied on the availability of agonists and antagonist s selective for each receptor class. Compounds that were thought to be selective for mGluRs have been extensively used to study the role of these receptors in the brain. Their use has implicated mGluRs in a wid e range of physiological and pathological processes including the modu lation of N-methyl-D-aspartate (NMDA) receptors and NMDA receptor-depe ndent processes. We report that some of the most commonly used mGluR c ompounds act as antagonists on NMDA receptors at concentrations common ly used to activate or block mGluRs. In addition, several of the drugs also act as agonists at higher concentrations due at least in part to high levels of contaminant amino acids. Our results indicate that cau tion should be used when using these drugs to study the roles of mGluR s in various NMDA-dependent processes. The antagonist effects were dep endent on the concentration of the NR IDA receptor coagonists, prevent ing reappraisal of previously published work.