The present studies were carried out to investigate the mechanisms through which systemic angiotensin II (AII) acts within the central nervous system to influence the release of anterior pituitary hormones in the Sprague-Dawley rat. In particular, these studies have examined the role of the subfornical organ (SFO) as an essential structure mediating these responses. Extracellular single-unit recordings were obtained from 199 paraventricular nucleus (PVN) neurons anti-dromically identified as projecting to the median eminence. Different groups of these neurons were tested for the effects of either electrical stimulation in the SFO (n = 87) or systemic AII administration in intact (n = 49) and SFO-lesioned (n = 25) animals. Of cells tested with SFO stimulation 45% were excited, 16% inhibited, and the remainder unaffected. Neurons which were excited were primarily located just medial to the magnocellular neurons in the region where the majority of corticotropin-releasing hormone immunoreactive cells are found. In contrast, inhibitory responses were observed in cells located in the dorsal medial PVN, a region containing thyrotropin-releasing hormone, somatostatin, and dopamine PVN-median eminence neurons. Following systemic AII 42% of cells tested showed increased activity specific to the effects of this peptide, and 20% showed alterations in activity associated with the cardiovascular changes induced by AII. In contrast, following SFO lesion only 8% of neurons tested showed specific excitatory responses to AII. In order to test the hypothesis that systemic AII may activate this excitatory SFO to PVN pathway, a further group of 35 neurons were tested with both SFO stimulation and AII. Excitatory responses to AII were observed in 13 of these cells, each of which was also excited by SFO stimulation. These studies describe mechanisms through which the central nervous system may sense peripheral concentrations of peptide hormones and modulate the activity of neural pathways which in turn influence the activity of PVN neurons which control the secretion of anterior pituitary hormones.