The magnocellular hypothalamo-neurohypophysial system is, via a release of vasopressin from nerve terminals in the neurohypophysis to the peripheral blood, centrally involved in the regulation of body salt and water homeostasis. Furthermore, it has been shown that expression of neuropeptides co-existing with vasopressin or oxytocin in magnocellular neurons is influenced by salt loading. We here report, that neuropeptide Y (NPY)-immunoreactivity, which is normally not observed in the magnocellular neurons of the hypothalamic supraoptic and paraventricular nuclei of rats becomes immunohistochemically detectable after salt loading. Using a double-immunohistochemical procedure on the same brain sections, it is shown that NPY is co-existing with either vasopressin or oxytocin in these neurons. Within the neurohypophysis of normal rats, a moderate number of predominantly fine calibered NPY-immunoreactive nerve fibers most often coursing along vessels is observed in addition to a low number of large peptidergic terminals. In salt-loaded rats, however, the number of NPY-immunoreactive neurohypophysial large nerve terminals in apposition to vascular lumina is drastically increased. By using quantitative receptor autoradiography, it is demonstrated that in salt-loaded animals, the number of neurohypophysial NPY binding sites is decreased to nearly undetectable levels (0.054 +/- 0.02 fmol/mg) compared to a very high density of binding sites in normal animals (1.151 +/- 0.15 fmol/mg). This raises evidence that NPY containing hypothalamo-neurohypophysial neurons as well as peripherally released NPY may be involved in the regulation of water homeostasis via NPY receptors in the neurohypophysis.