Stress triggers responses important to maintain internal homeostasis, and yet when prolonged can cause medical consequences that are most likely mediated by changes in gene expression. In this study we examine the alterations in gene expression of neuropeptide Y (NPY), a potent vasoconstrictor, with stress. Stressors, such as immobilization and cold, were found to increase adrenal NPY gene expression in rats. Adrenal prepro-NPY mRNA levels were elevated by a relatively short period of stress. A single immobilization was sufficient for an increase in prepro-NPY mRNA, that remained elevated for as long as one day later. This rise in adrenal NPY mRNA was abolished by the transcriptional inhibitor actinomycin D. Repeated (2 and 7) daily immobilizations led to a further rise and sustained elevations of prepro-NPY mRNA levels. This increase persisted 2-3 days after the cessation of repeated stress. The stress-elicited increase in NPY gene expression is transsynaptic requiring splanchnic innervation and mediated by nicotinic receptors. Hypophysectomy did not prevent the stress elicited rise in adrenal prepro-NPY mRNA levels. These results suggest that long lasting changes in NPY gene expression might be an important component in the homeostatic mechanisms triggered by chronic stress.