The precise mechanisms by which beneficial responses to acute stress are transformed into long-term pathological effects of chronic stress are largely unknown. Western blot analyses revealed that members of the AP1 transcription factor family are differentially regulated by single and repeated stress in the rat adrenal medulla, suggesting distinct roles in establishing stress-induced patterns of gene expression in this tissue. The induction of c-fos was transient, whereas marked elevation of long-lasting Fos-related antigens, including Fra2, was observed after repeated immobilization. We investigated DNA protein interactions at the AP1-like promoter elements of two stress-responsive genes, tyrosine hydroxylase and dopamine β-hydroxylase. Increased DNA-binding activity was displayed in adrenomedullary extract from repeatedly stressed rats, which was predominantly composed of c-Jun- and Fra2-containing dimers. The induction of Fra2 and increased AP1-like binding activity was reflected in sustained transcriptional activation of tyrosine hydroxylase and dopamine β-hydroxylase genes after repeated episodes of stress. The functional link between Fra2 and regulation of tyrosine hydroxylase and dopamine β-hydroxylase transcription was confirmed in PC12 cells coexpressing this factor and the corresponding promoter–reporter gene constructs. These studies emphasize the potential importance of stress-evoked increases in the expression of the Fra2 gene forin vivo adaptations of the adrenal catecholamine producing system.