The role of the N-methyl-D-aspartate receptor channel in glutamate neurotoxicity was investigated in cultured hippocampal neurons of the CA1 region. An equation, the survival function, was developed to quantify the effects of putative modulators of neurotoxicity. 2-Amino-5-phosphonovaleric acid (30 microM) reduced the neuronal sensitivity to glutamate by a factor greater than 20, whereas glycine (1 microM) enhanced it by a factor of 7.5 +/- 2.5. Neurons were protected by increasing Mg2+ concentrations in a predictable way based on the ion's ability to block the N-methyl-D-aspartate channel. These findings provide a quantitative basis for the assessment of various neuroprotective agents and add further support to the hypothesis that the N-methyl-D-aspartate channel is central to glutamate neurotoxicity.