The CRF/Urocortin systems as therapeutic targets for alcohol use disorders

Development and maintenance of alcohol use disorders have been proposed to recruit critical mechanisms involving Corticotropin Releasing Factor and Urocortins (CRF/Ucns). The CRF/Ucns system is comprised of a family of peptides (CRF, Ucn 1, Ucn 2, Ucn 3) which act upon two receptor subtypes, CRFR1 and CRFR2, each with different affinity profiles to the endogenous peptides and differential brain distribution. Activity of CRF/Ucn system is further modulated by CRF binding protein (CRF-BP), which regulates availability of CRF and Ucns to exert their actions. Extensive evidence in preclinical models support the involvement of CRF/Ucn targets in escalated alcohol drinking, as well as point to changes in CRF/Ucn brain function as a result of chronic alcohol exposure and/or withdrawal. It highlights the role of CRF and CRFR1-mediated signaling in conditions of excessive alcohol taking and seeking, including during various stages of withdrawal and relapse to alcohol. Besides its role in the hypothalamic-pituitary-adrenal (HPA) axis, the importance of extra-hypothalamic CRF pathways, especially in the extended amygdala, in the neurobiology of alcohol abuse and dependence is emphasized. Emerging roles for other targets of the CRF/Ucn system, such as CRF2 receptors, CRF-BP and Ucns in escalated alcohol drinking is also discussed. Finally, the limited translational value of CRF/Ucn interventions in stress-related and alcohol use disorders is discussed. So far, CRFR1 antagonists have shown little or no efficacy in human clinical trials, although a range of unexplored conditions and possibilities remain to be explored.