Urocortins: CRF's siblings and their potential role in anxiety, depression and alcohol drinking behavior

Abstract

It is widely accepted that stress, anxiety, depression and alcohol abuse-related disorders are in large part controlled by corticotropin-releasing factor (CRF) receptors. However, evidence is accumulating that some of the actions on these receptors are mediated not by CRF, but by a family of related Urocortin (Ucn) peptides Ucn1, Ucn2 and Ucn3. The initial narrow focus on CRF as the potential main player acting on CRF receptors appears outdated. Instead it is suggested that CRF and the individual Ucns act in a complementary and brain region-specific fashion to regulate anxiety-related behaviors and alcohol consumption. This review, based on a symposium held in 2011 at the research meeting on “Alcoholism and Stress” in Volterra, Italy, highlights recent evidence for regulation of these behaviors by Ucns. In studies on stress and anxiety, the roles of Ucns, and in particular Ucn1, appear more visible in experiments analyzing adaptation to stressors rather than testing basal anxiety states. Based on these studies, we propose that the contribution of Ucn1 to regulating mood follows a U-like pattern with both high and low activity of Ucn1 contributing to high anxiety states. In studies on alcohol use disorders, the CRF system appears to regulate not only dependence-induced drinking, but also binge drinking and even basal consumption of alcohol. While dependence-induced and binge drinking rely on the actions of CRF on CRFR1 receptors, alcohol consumption in models of these behaviors is inhibited by actions of Ucns on CRFR2. In contrast, alcohol preference is positively influenced by actions of Ucn1, which is capable of acting on both CRFR1 and CRFR2. Because of complex distribution of Ucns in the nervous system, advances in this field will critically depend on development of new tools allowing site-specific analyses of the roles of Ucns and CRF.

Adolescent Intermittent ethanol exposure enhances ethanol activation of the nucleus accumbens while blunting the prefrontal cortex responses in adult rat

“…The EW is well characterized as an ethanol-responsive brain region being uniquely activated by both ethanol administration and ethanol self-administration (Ryabinin et al, 1997). EW contains urocortin neurons that are linked in a complex manner to stress responses and have been hypothesized to contribute the positive reinforcing effects of ethanol (Ryabinin et al, 2012). We found EW, CeA and LA all showed maximal c-Fos responses to the moderate dose ethanol challenge in naïve adult rats with EW correlating with CeA and LaA.…”

A central mesencephalic reticular formation projection to the supraoculomotor area in macaque monkeys

“…Terminals containing urocortin-1 are found in most areas of the brain, however, the cells from which most of these terminals originate can only be found in select areas (Bachtell et al 2002; Kozicz et al 1998; Yamamoto et al 1998). In rodents, urocortin-1 in EW appears to play a role in drinking behavior and appetite (Ryabinin et al 2012; Weitemier and Ryabinin 2006), and it has been associated with stress and reward (Gaszner et al 2004; Kozicz et al 2001). In addition to urocortin-1, other peptides found within EW in cats, rodents and frogs include neuronal populations immunoreactive for CCK, substance P, cocaine-and-amphetamine-regulated transcript (CART) and neuropeptide B [cat: (Maciewicz et al 1983; Phipps et al 1983); rat: (Dun et al 2005; Hokfelt et al 2002; Innis and Aghajanian 1986; Kozicz 2003; Kozicz et al 1998); mouse: (Tanaka et al 2003)].…”

MicroRNA-326 acts as a molecular switch in the regulation of midbrain urocortin 1 expression

“…This postulate was tested in a stress-sensitive model system, the midbrain urocortin 1 (Ucn1) neuronal system. Ucn1 neurons in the rostroventral midbrain, within the centrally projecting Edinger-Westphal nucleus (EWcp) are sensitive to stress: [17][18][19][20][21] mice lacking Ucn1 reveal anxiogenic behaviour, 22 while depressed suicide completers have upregulated midbrain Ucn1 mRNA expression compared with naturally deceased control individuals. 23 Here, we report that the brain-enriched miR-326 acts as an upstream regulator of Ucn1 during a neuronal stress response.…”