Activation of type 5 metabotropic glutamate receptors enhances NMDA responses in mice cortical wedges

1 We measured the effects of agonists and antagonists of metabotropic glutamate (mGlu) receptors (types 1 and 5) on NMDA-induced depolarization of mouse cortical wedges in order to characterize the mGlu receptor type responsible for modulating NMDA responses. We also characterized a number of mGlu receptor agents by measuring [H-3]-inositol phosphate (IP) formation in cortical slices and in BHK cells expressing either mGlu 1 or mGlu 5 receptors. 2 (S)-3,5-dihydroxyphenylglycine (DHPG), an agonist of both mGlu 1 and mGlu 5 receptors, at concentrations ranging from 1-10 muM, enhanced up to 105+/-15% the NMDA-induced depolarization. Larger concentrations (100-300 muM) of the compound were inactive in this test. When evaluated on [H-3]-IP synthesis in cortical slices or in cells expressing either mGlu 1 or mGlu 5 receptors, DHPG responses (1-300 muM) increased in a concentration-dependent manner. 3 (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) and (S)-(+)-2-(3'-carboxybicyclo[1.1.1]pentyl)-glycine (CBPG), had partial agonist activity on mGlu 5 receptors, with maximal effects reaching approximately 50% that of the full agonists. These compounds, however, enhanced NMDA-evoked currents with maximal effects not different from those induced by DHPG. Thus the enhancement of [H-3]-IP synthesis and the potentiation of NMDA currents were not directly related. 4 2-methyl-6-(phenylethynyl)-pyridine (MPEP, 1-10 muM), a selective mGlu 5 receptor antagonist, reduced DHPG effects on NM DA currents. 7-(hydroxyimino)cyclopropan[b]-chromen-1a-carboxylic acid ethylester (CPCCOEt, 30 muM), a preferential mGlu 1 receptor antagonist, did not reduce NMDA currents. 5 These results show that mGlu 5 receptor agonists enhance while mGlu 5 receptor antagonists reduce NMDA currents. Thus the use of mGlu 5 receptor agents may be suggested in a number of pathologies related to altered NMDA receptor function.