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

Abstract

1 We measured the e ects 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 [ 3 H]-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 mM, enhanced up to 105+15% the NMDA-induced depolarization. Larger concentrations (100 ± 300 mM) of the compound were inactive in this test. When evaluated on [ 3 H]-IP synthesis in cortical slices or in cells expressing either mGlu 1 or mGlu 5 receptors, DHPG responses (1 ± 300 mM) 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 e ects reaching approximately 50% that of the full agonists. These compounds, however, enhanced NMDA-evoked currents with maximal e ects not di erent from those induced by DHPG. Thus the enhancement of [ 3 H]-IP synthesis and the potentiation of NMDA currents were not directly related. 4 2-methyl-6-(phenylethynyl)-pyridine (MPEP, 1 ± 10 mM), a selective mGlu 5 receptor antagonist, reduced DHPG e ects on NMDA currents. 7-(hydroxyimino)cyclopropan[b]-chromen-1a-carboxylic acid ethylester (CPCCOEt, 30 mM), 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.

Inhibitory effects of MPEP, an mGluR5 antagonist, and memantine, an N-methyl-D-aspartate receptor antagonist, on morphine antinociceptive tolerance in mice

“…MGluR5 antagonists reduced NMDA receptor activity in several brain areas (Doherty et al 1997;Anwyl 1999;Awad et al 2000;Attucci et al 2001;Pisani et al 2001). These data suggest functional interaction between these receptors, most likely mediated by PKC activation.…”

Modulation by group 1 metabotropic glutamate receptors of depotentiation in the dentate gyrus of freely moving rats

“…Sole activation of mGluR1 results in an increase in intracellular calcium concentrations, depolarization of CA1 pyramidal neurons, and an increased frequency of spontaneous inhibitory postsynaptic potentials . Sole activation of mGluR5 results in suppression of the calcium-activated potassium current (I AHP ) and a potentiation of NMDA receptor currents (Jia et al, 1998;Attucci Mannaioni et al, 2001). Thus, aside from their overlapping mechanisms, mGluR1 and mGluR5 make quite distinct functional contributions that appear to have distinct consequences for synaptic plasticity and memory processes.…”

“…The elevation of postsynaptic intracellular calcium levels resulting from activation of Group 1 mGluRs thus seems a likely mechanism underlying the involvement of these receptors in both LTP and depotentiation. This occurs on the one hand through mobilization of calcium from intracellular stores mediated by mGluR1 ) and a potentiation of NMDA receptor currents mediated by mGluR5 (Jia et al, 1998;Attucci et al, 2001;Mannaioni et al, 2001). AIDA, in a concentration of 200 lM reduces NMDA receptor currents in vitro (Contractor et al, 1998).…”

Brevetoxin-induced phosphorylation of Pyk2 and Src in murine neocortical neurons involves distinct signaling pathways

“…In hippocampal neurons, it has been shown that mGluR 5 regulates NMDA receptor currents via Src activity (Lu et al, 1997;Mannaioni et al, 2001). Similarly, in mouse cortical wedges activation of mGluR 5 enhances NMDA responses (Attucci et al, 2001). It is noteworthy that the MTEP inhibition of PbTx-2-induced Src activation was not complete, whereas Src activation was completely abolished by a PLC inhibitor.…”