The peptide hormone secretin, as well as its cognate receptor, have been shown to be present within the rodent brain, and.central administration of secretin has been shown to activate neurons within the lamina terminalis and stimulate thirst and vasopressin release from the pituitary (Chu et al., Kidney International 79,280-287, 2011). The aim of this study was to compare the effects of peripherally administered secretin with those of intracerebroventricularly injected secretin on water intake and Fos expression in the hypothalamus in conscious rats. Intracerebroventricular (ICV) secretin (4µg/2 µl) stimulated water drinking and Fos expression in the outer shell of the subfornical organ, dorsal cap of the organum vasculosum of the lamina terminalis (OVLT), median preoptic nucleus, and hypothalamic supraoptic and paraventricular nuclei compared with control vehicle injection. Compared with the effect of control injection of isotonic saline, subcutaneous (s.c.) injection of secretin (100 ug/kg) also stimulated water drinking and increased Fos expression in the subfornical organ, OVLT, and hypothalamic supraoptic and paraventricular nuclei. However the pattern of Fos expression in OVLT and subfornical organ differed from that observed following peripherally injected secretin; the latter being similar to that observed following peripherally infused angiotensin II. We then tested the effect of an angiotensin AT1 antagonist losartan (50mg/kg s.c.) on responses to s.c. secretin (100 ug/kg). Drinking and Fos responses in subfornical organ and OVLT were abolished by peripheral losartan. These data indicate that drinking in response to peripherally injected secretin depends on activation of the renal renin-angiotensin system and circulating angiotensin II’s dipsogenic action on the subfornical organ. By contrast, ICV secretin probably stimulates neurons directly in the lamina terminalis, that drive thirst neural circuitry and vasopressin release. These data support a role for centrally generated secretin in the control of fluid balance in rats.