Protein de novo synthesis is mainly under the control at the level of gene transcription by transcription factors in cell nuclei in eukaryotes. The systemic administration of N-methyl-D-aspartate resulted in selective but transient potentiation of binding of a radiolabeled double-stranded oligonucleotide probe for the nuclear transcription factor activator protein-1 in murine hippocampus, without markedly affecting binding of probes for other transcription factors. By contrast, kainic acid induced more potent and more persistent potentiation of activator protein- binding in the hippocampus than N-methyl-D-aspartate. The protein synthesis inhibitor cycloheximide was effective in significantly preventing the potentiation by N-methyl-D-aspartate, but not that by kainic acid at the doses used. Moreover, kainic acid induced much more and longer expression of immunoreactive c-Fos protein in the hippocampus than N-methyl-D-aspartate. However, neither N-methyl-D-aspartate nor kainate induced expression of cyclic AMP response element binding protein phosphorylated at serine133 in the hippocampus from 10 min to 24 h after the administration. Instead, kainate was more potent than N-methyl-D-aspartate in facilitating both dephosphorylation at serine and phosphorylation at tyrosine of particular nuclear proteins in the hippocampus. These results suggest that N-methyl-D-aspartate and kainate signals may be differentially transduced into cell nuclei to express the activator protein-1 complex through molecular mechanisms which differ from phosphorylation of cyclic AMP response element binding protein at serine133 but involve serine dephosphorylation and/or tyrosine phosphorylation of particular nuclear proteins in the murine hippocampus.