In the neostriatum a selective loss of neurons occurs following exposure to N-methyl-D-aspartate receptor agonists. One hypothesis emerging from this observation is that an excitotoxic process via N-methyl-D-aspartate receptors may contribute to the pathogenesis of Huntington's disease, which is characterized by the loss of medium-sized neurons. However, whether there is a selective distribution of N-methyl-D-aspartate receptors in specific populations of neostriatal neurons is unknown. In this study the expression of c-fos mRNA and protein was used to examine the response of neostriatal cells to N-methyl-D-aspartate receptor stimulation in the rat. After intrastriatal injection of the N-methyl-D-aspartate receptor agonist, quinolinic acid, an increase in c-fos mRNA concentrations was detected using in situ hybridization and Northern blot analysis. Western blot analysis showed that not only the c-Fos mRNA protein product but also other Fos-related antigens capable of binding to DNA were increased in response to N-methyl-D-aspartate receptor activation. The selectivity of the neuronal response to N-methyl-D-aspartate receptor activation was examined immunohistochemically at the light and ultrastructural levels. Our results indicate that N-methyl-D-aspartate receptor activation by quinolinic acid stimulates medium spiny neurons to increase c-Fos expression; to a lesser extent, medium aspiny interneurons and glial cells also respond. In contrast, negligible change in c-Fos expression is observed in large neurons. These results are consistent with other evidence that medium-sized spiny neurons are preferentially vulnerable to the toxic effects of excitatory amino acids acting at N-methyl-D-aspartate receptors. An additional implication of these findings is that activation of the N-methyl-D-aspartate receptor in medium spiny neurons leads to increased expression of candidate AP-1 transcription factors, thereby coupling the N-methyl-D-aspartate receptor and regulation of gene expression in signal transduction processes of the neostriatal medium spiny neuron.