It has been observed that diabetes results in increased neuropeptide Y (NPY) in various brain regions, especially the paraventricular nucleus, which projects to the nucleus of the solitary tract (NTS). Because previous studies indicated a pathophysiological relationship between diabetes and NPY, we investigated the effect of diabetes on the sensitivity of NTS-mediated responses to NPY administration. Rats were made diabetic using streptozocin (55 mg/kg iv) and maintained for 48 to 50 days. Normal and streptozocin-diabetic rats were anesthetized with urethan and alpha-chloralose, instrumented for cardiovascular and respiratory monitoring, and positioned in a stereotaxic apparatus. The brain stem was exposed surgically. NPY (0.15 nmol/kg) was microinjected into the NTS and the cardiovascular and respiratory parameters were monitored for 60 min. Diabetes increased systolic (SAP), diastolic (DAP), and mean (Pa) blood pressure but not pulse pressure (PP) and heart rate (HR). Respiratory parameters were not altered. NPY significantly decreased SAP, DAP, Pa, PP, HR, respiratory rate, and minute volume in normal animals. In diabetic animals, NPY also decreased SAP, DAP, and Pa but pronouncedly increased PP. Although NPY decreased the SAP and Pa in diabetic animals, the response was attenuated compared with normal animals. The respiratory parameters and HR of diabetic animals, unlike normal animals, did not respond to NPY administration. We conclude that chronic diabetes results in a decreased sensitivity to NTS-mediated responses and that the hyporesponsiveness of the NTS to NPY modulation may be important in the tendency toward elevated blood pressure and hypertension in diabetes.