The TIS8/egr-1 gene is a member of the class of immediate early genes. Originally discovered as a mitogen induced gene, it can also be induced by synaptic activity. We report here the induction of the TIS8/egr-1 gene by the neurotransmitter 5-hydroxytryptamine (5-HT) in cultured rat phaeochromocytoma PC12 cells. Induction was maximal 40 min after addition of 5-HT to the cells, and declined very rapidly to reach the basal level after 90 min. The electrophoretic mobility-shift assay showed that induction of the TIS8/egr-1 gene by 5-HT was accompanied by increased Egr-1 protein binding to its DNA consensus sequence. We found an overall correlation of 5-HT-induced egr-1 expression with that of c-fos expression. The kinetics of the ability of both gene products to bind to their respective DNA consensus sequence was also similar. The 5-HT-induced activation in Egr-1 binding was inhibited by ketanserin and mesulergine, indicating that 5-HT exerted its action via a 5-HT2 receptor subtype. The tyrosine protein kinase inhibitor genistein abolished induction of the TIS8/egr-1 gene, suggesting that tyrosine kinase activity is required for the induction of early genes by 5-HT. Genistein also inhibited 5-HT-induced Egr-1 binding activity. The increase in phosphotyrosine content of focal adhesion kinase we noticed upon addition of 5-HT to cells suggests that this cytoplasmic tyrosine protein kinase mediates the effect of 5-HT in eliciting early gene induction.