Previous studies in our laboratory suggest that neurotensin (NT) acts centrally to modulate adrenocorticotropin hormone (ACTH) and corticosterone release. In the present studies, we examined hypothalamic-pituitary-adrenal (HPA) function under basal conditions and during restraint stress following central administration of the highly specific NT receptor antagonist, SR48692. Chronic delivery of SR48692 to the paraventricular nucleus (PVN) of the hypothalamus via indwelling central cannulae attenuated both the diurnal- and stress-induced elevations in HPA activity. Thus, SR48692 decreased the diurnal increase in plasma ACTH and corticosterone during the evening phase of the cycle, but did not affect morning levels. Restraint-induced increases in plasma ACTH and corticosterone levels were also significantly reduced in the SR48692-implanted animals. This suggests that the inhibitory effects of SR48692 were restricted to periods of stimulated HPA activity. A decrease in corticotropin-releasing hormone (CRH)-like immunoreactivity was observed within the PVN following chronic SR48692, and parallel decreases in CRH-like immunoreactivity were observed within the external zone of the median eminence. These findings suggest that endogenous NT serves to increase HPA activity during periods of enhanced stimulation.