The endogenous CRFR2 selective ligand Urocortin 3 is expressed in discrete subcortical brain regions with fibers distributed mainly to hypothalamic and limbic structures. Close anatomical association between major Urocortin 3 terminal fields and CRFR2 in hypothalamus, lateral septum and medial amygdala (MEA) suggest it is well placed to modulate behavioral and hormonal responses to stress.

Urocortin 3 was administered intracerebroventricularly to male rats under basal conditions or before a restraint stress, and circulating ACTH, corticosterone, glucose and insulin measured. Urocortin 3 activated the hypothalamic-pituitary-adrenal axis under basal conditions and augmented ACTH responses to restraint stress. Elevated blood glucose with lowered insulin:glucose ratios in both groups suggested increased sympathetic activity. Circulating catecholamines were also increased by Urocortin 3, providing further evidence for sympathoadrenomedullary stimulation. Intracerebroventricular Urocortin 3 increased vasopressin mRNA expression in the parvocellular division of the hypothalamic paraventricular nucleus while CRF expression was unchanged providing a possible mechanism by which Urocortin 3 mediates its actions.

Urocortin 3 mRNA expression was examined following exposure to stress related paradigms. Restraint increased levels in MEA with a trend to increased expression in the rostral perifornical hypothalamic area (PFA) while hemorrhage and food deprivation decreased expression in MEA. Adrenalectomy markedly increased expression in PFA and high level corticosterone replacement restored this to control levels.

The evidence that Urocortin 3 has the potential to influence hormonal components of the stress response and the changes in its expression levels following stressors is consistent with a potential function for the endogenous peptide in modulating stress responses.