The effect of systemically-administered cholecystokinin octapeptide (CCK) on hypothalamic oxytocin, vasopressin, and corticotropinreleasing hormone neurons was studied by analysis of c-fos antigen expression in immunocytochemically-characterized neurons in the supraoptic and paraventricular nuclei. CCK (100 pglkg intraperitoneally) caused a marked increase in nuclear c-fos immunocytochemical staining, which peaked at 60 to 90 min after injection. C-fos expression was found in most magnocellular oxytocin neurons in the supraoptic nucleus and in all magnocellular subdivisions of the paraventricular nucleus, but in no vasopressin neurons in either area. C-fos expression was also found in several parvocellular subdivisions of the paraventricular nucleus: in oxytocin neurons within the medial and lateral, but not the dorsal, parvocellular subdivisions, and in corticotropinreleasing hormone neurons in the medial parvocellular subdivision. Injection of lower doses of CCK showed that c-fos expression closely paralleled the pattern of pituitary oxytocin secretion in response to CCK, with a threshold for activation at 1 pglkg, near maximal responses by lopglkg, and maximal responses by 100pglkg. These studies demonstrate that the pattern of c-fos expression in hypothalamic magnocellular neurons following systemic CCK administration mirrors the neurosecretory response of these neurons, both with regard to specificity for the peptides secreted as well as intensity of secretion. They also demonstrate that systemic CCK administration activates c-fos expression in parvocellular oxytocin and corticotropin-releasing hormone neurons, and therefore likely causes secretion of oxytocin and corticotropin-releasing hormone within the brain at the terminal fields of these neurons.Previous studies from this and other laboratories have shown that systemic administration of cholecystokinin (CCK) stimulates pituitary secretion of oxytocin (OT) but not vasopressin (AVP) in rats (1, 2). Electrophysiological recordings from hypothalamic supraoptic nucleus (SON) neurons have confirmed that CCK causes activation of magnocellular neurons rather than simply releasing OT from pituitary axon terminals (3). Additional studies have demonstrated that the well-known effects of CCK to inhibit food intake (4) and gastric emptying and motility (5-7) are correlated with its effects to stimulate pituitary OT secretion (1, 5, 7-10). However, because peripheral infusions of OT do not affect either food intake (10) or gastric motility (11) in rats, we have postulated that centrally-projecting parvocellular OT neurons may be activated in concert with the pituitary-projecting magnocellular neurons to produce or modulate these diverse behavioral and physiological effects (8, 12).Recent studies have demonstrated that the antigen of the protooncogene c-fos is expressed in the nucleus of many activated neurons, including those in the hypothalamus (13). The present studies utilized immunohistochemical staining for c-fos antigen (14) to identify those hypothal...