Exposure of cultured cerebellar neurons to the putative metabotropic glutamate receptor antagonist L-2-amino-3-phosphonopropionate (L-AP3) for 24 h produced a neurotoxic effect which was prevented by the addition of the NMDA receptor antagonist (+)-10,11-dihydro-5-methyl-5-H-dibenzo-[a,d]-cyclohepten-5,1 0-imine hydrogen maleate (MK-801). MK-801 did also reduce neurotoxicity following 72 h exposure to L-AP3 neurotoxicity in the presence of MK-801 was antagonized by glutamate. Our results suggest that metabotropic glutamate receptors may play an important role in neuronal survival by controlling NMDA receptor-dependent as well as independent pathways.