This study demonstrates cholecystokinin receptor plasticity in response to salt-loading in the rat and mouse hypothalamus. It identifies, for the first time, the cholecystokinin receptor subtypes involved, firstly by receptor autoradiography and secondly by in situ hybridization. Both species showed increases in hypothalamic [125I]Bolton Hunter-cholecystokinin-8 binding. Co-incubation with the specific cholecystokininA and cholecystokininB antagonists, devazepide and CI-988, indicated that in the rat cholecystokininB receptor binding markedly increased, with a small increase in cholecystokininA receptor binding. In the mouse the response was comprised solely of cholecystokininA receptors. In situ hybridization studies were carried out on a range of peptide messenger ribonucleic acids after salt-loading. In the rat large increases in hypothalamic gene expression were detected for oxytocin, vasopressin, corticotrophin-releasing factor and preprocholecystokinin. In the mouse only vasopressin messenger ribonucleic acid increased, whilst hypothalamic oxytocin, preprocholecystokinin and corticotropin-releasing factor remained unchanged. However, corticotrophin-releasing factor messenger ribonucleic acid increased in the mouse amygdala. In situ hybridization was performed using oligonucleotide probes specific for either the cholecystokininA or cholecystokininB receptor messenger ribonucleic acid, and this showed good agreement with the receptor autoradiography. CholecystokininB receptor expression was upregulated in the rat hypothalamus along with a small but significant increase in cholecystokininA receptors. In the mouse only cholecystokininA receptor expression was increased. In addition to these molecular changes rats lost about 25% of their body weight during six days of salt-challenge, whilst mice continued to grow in line with controls. This work demonstrates differential changes in cholecystokinin receptor subtype binding between the rat and the mouse. It represents the first report of differential changes in cholecystokininA and cholecystokininB receptor messenger ribonucleic acids within the brain, and shows that cholecystokinin receptors within the rodent hypothalamus are capable of plastic responses to chronic osmotic stress.