The effects of water deprivation or i.p. injection of hypertonic salt solution on the expression of the amyloid precursor polypeptide (APP) were studied immunohistochemically in the rat brain, in particular in the supraoptic and paraventricular nuclei, both known to be involved in electrolytic and water homeostasis and to contain mRNAs coding for the various forms of APP. In parallel, the expression of the immediate early gene c-fos was also studied by immunohistochemistry. Both hypertonic saline injection and water deprivation resulted in a rapid and dramatic increase in the levels of amyloid precursor protein-like immunoreactivity in neurones of the supraoptic and paraventricular nuclei. These increases paralleled those seen using c-fos immunohistochemistry. In contrast, no changes were observed in other brain areas, including the subfornical organ, which also contained mRNA and APP-like immunoreactivity. The results indicate that levels of the beta-amyloid precursor protein can be rapidly increased by stressors affecting the activity of well characterized cell populations in the rat hypothalamus. These results suggest the involvement of the beta-amyloid precursor protein in the secretory activities of these cells, or in the initiation of morphological changes which are known to occur after osmotic stress in the supraoptic and paraventricular neurones. Interestingly, the changes were limited to neurones and no modification of beta-amyloid precursor protein levels was observed in glial cells, which are also known to be modified by osmotic stress.