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

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 [3H]‐inositol phosphate (IP) formation in cortical slices and in BHK cells expressing either mGlu 1 or mGlu 5 receptors. (S)‐3,5‐dihydroxyphenylglycine (DHPG), an agonist of both mGlu 1 and mGlu 5 receptors, at concentrations ranging from 1 – 10 μM, enhanced up to 105±15% the NMDA‐induced depolarization. Larger concentrations (100 – 300 μM) of the compound were inactive in this test. When evaluated on [3H]‐IP synthesis in cortical slices or in cells expressing either mGlu 1 or mGlu 5 receptors, DHPG responses (1 – 300 μM) increased in a concentration‐dependent manner. (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 [3H]‐IP synthesis and the potentiation of NMDA currents were not directly related. 2‐methyl‐6‐(phenylethynyl)‐pyridine (MPEP, 1 – 10 μM), a selective mGlu 5 receptor antagonist, reduced DHPG effects on NMDA currents. 7‐(hydroxyimino)cyclopropan[b]‐chromen‐1a‐carboxylic acid ethylester (CPCCOEt, 30 μM), a preferential mGlu 1 receptor antagonist, did not reduce NMDA currents. 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. British Journal of Pharmacology (2001) 132, 799–806; doi:10.1038/sj.bjp.0703904