ACTIVATION OF MULTIPLE METABOTROPIC GLUTAMATE-RECEPTOR SUBTYPES PREVENTS NMDA-INDUCED EXCITOTOXICITY IN RAT HIPPOCAMPAL SLICES

Metabotropic glutamate receptors (mGluRs) belong to a relative large r eceptor family consisting of multiple members with important roles in a number of brain functions. We report here that activation of mGluRs prevents the neurotoxic effect induced by N-methyl-D-aspartate (NMDA) in slices from the rat hippocampus, Neuroprotection was elicited when slices were simultaneously exposed to both the selective mGluR agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (tACPD) and NMD A. Persisting stimulation of mGluRs after the toxic exposure did not i mprove the survival of pyramidal or granular cells, The neuroprotectio n elicited by tACPD was also evoked by its active isomer, (1S,3R)-ACPD , and was prevented by the selective mGluR antagonist (+)-alpha-methyl -4-carboxyphenyl-glycine (500 mu M), confirming that mGluR activation is involved in the mechanism of action of tACPD. The effect of 100 mu M tACPD was reproduced by 100 mu M quisqualate, an agonist for mGluR1 and mGluR5, and by 1 mu M of (2S,1's,2's)-2-carboxycyclopropyl-glycin a preferential agonist of mGluR2 and mGluR3 subtypes. No neuroprotecti on was induced by L-2-amino-4-phosphonobutyrate, a selective agonist f or mGluR4, mGluR6, mGluR7 and mGluR8, at 500 mu M. Since the NMDA-medi ated cell death in hippocampal slices is considered relevant to ischae mia-induced brain injury, these results indicate that mGluRs may be im portant safety devices used by neurons to decrease their sensitivity t o excitotoxic stimuli and increase their chance of survival.