Metabotropic glutamate receptors (mGluRs) can influence neuronal survival and have been shown to be neuroprotective during glutamate toxicity in retinal cells and in cortical neurons. The mechanisms that mediate protection by this group of receptors are not clear. Since nitric oxide (NO) production can lead to neuronal cell death during excessive glutamate release, we examined whether neuronal survival was directly linked to mGluR activity and the NO pathway. Treatment with the mGluR4 receptor subtype agonist, L-(+)-2-amino-4-phosphonobutyric acid, in hippocampal cell cultures protected neurons during NO exposure. Treatment with L-(+)-2-amino-3-phosphonopropionic acid, an antagonist of the mGluR1 receptor subtype and inhibitor of inositol trisphosphate formation, did not significantly alter neuronal survival during NO administration. We conclude that activation of the mGluR4 receptor protects hippocampal neurons from NO toxicity and that the mechanism of NO induced neurodegeneration does not appear to involve inhibition of the mGluR1 receptor subtype activity or the phosphoinositide system.