Activation of glutamate ionotropic receptors represents the primary event in the neurotoxicity process triggered by excitatory amino acids. We demonstrate here that the concentration-dependent stimulation of metabotropic receptor by the selective agonist trans-1-aminocyclopentane-1,3-dicarboxylate (tACPD) counteracts the glutamate-induced neurotoxicity in primary culture of rat cerebellar granule cells. The metabotropic receptor-evoked responses are potentiated by aniracetam, which per se also elicits neuroprotection.