ACTIVATION OF THE METABOTROPIC GLUTAMATE-RECEPTOR MGLUR5 PREVENTS GLUTAMATE TOXICITY IN PRIMARY CULTURES OF CEREBELLAR NEURONS

1-Aminocyclopentane-trans-1,3-dicarboxylic acid, an agonist of the met abotropic glutamate receptors 1, 2, 3 and 5, prevents neurotoxicity of glutamate and of N-methyl-D-aspartate in primary cultures of cerebell ar neurons. The aim of this work was to assess which of the metabotrop ic glutamate receptors (mGluRs) is responsible for the protective effe ct. We tested the protective effects of selective agonists for each ty pe of receptor. It is shown that glutamate and N-methyl-D-aspartate ne urotoxicity are prevented by the following compounds: 1-aminocyclo-pen tane-trans-1,3-dicarboxylic acid, agonist of mGluR1, 2, 3 and 5; 3,5-d ihydroxyphenylglycine, agonist of mGluR1 and 5; S-4-carboxy-3-hydroxyp henylglycine, agonist of mGluR5 and antagonist of mGluR1; trans-azetid ine-2,4-dicarboxylic acid, agonist of mGluR5, Glutamate neurotoxicity is not prevented by (2S,1'S,2'S)-2-(2'-carboxycyclopropyl)glycine, an agonist of mGluR2 and mGluR3. Moreover, the protective effect of 1-ami nocyclo-pentane-trans-1,3-dicarboxylic acid is prevented by alpha-meth yl-4-carboxyphenylglycine, an antagonist of mGluR1 and 5, but not by a lpha-methyl-4-tetrazoylphenylglycine, an antagonist of mGluR2 and 3. A protective effect of activation of mGluR1 can not be ruled out becaus e of the limitations imposed by the lack of specificity of the agonist s and antagonists currently available. The results shown clearly indic ate that activation of mGluR5 prevents glutamate and N-methyl-D-aspart ate neurotoxicity in primary cultures of cerebellar neurons.