The first member of the CRF/Ucn family to be isolated, CRF, was originally discovered for its crucial role in activation of the Hypothalamic-Pituitary-Adrenal (HPA) axis (Vale et al., 1981), but it also mediates a broad range of coordinated physiologic and behavioral stress responses, as well as neuroadaptations that develop as a result of addiction (Heilig and Koob, 2007; Koob and Zorrilla, 2010; Shalev et al., 2010). With the discovery of the urocortins (Ucn1, Ucn2, Ucn3), it has become clear that the complexity of the CRF/Ucn system is greater than initially appreciated (Lewis et al., 2001; Lovenberg et al., 1995; Potter et al., 1991; Reyes et al., 2001; Vaughan et al., 1995). While the urocortins share 20 – 45% sequence homology with CRF, physiological functions of CRF/Ucn family peptides are not highly conserved. For example, Ucn2 and Ucn3 do not seem to directly influence stress reactivity but instead alter social behaviors in mice, suggesting that mammals have adapted these peptides for regulation of social interactions (Breu et al., 2012; Deussing et al., 2010). Figure 1 presents a schematic of the contribution of the Ucn/CRF systems to stress- and addiction related behaviors.
