Urocortins: CRF's siblings and their potential role in anxiety, depression and alcohol drinking behavior
Introduction
It is well known that the corticotropin-releasing factor (CRF, also known as the corticotropin-releasing hormone) peptide system is critical for the neuroendocrine and behavioral responses to stressful situations (such as anxiety and depression) in vertebrates (Bale & Vale, 2004; Hauger, Risbrough, Brauns, & Dautzenberg, 2006). Since stress is one of the risk factors of alcoholism, much evidence has been gained confirming the involvement of the CRF system in alcohol abuse and dependence (Heilig & Egli, 2006; Koob & Le Moal, 2001). However, the role of CRF system has been too often simplistically equaled with the role of CRF. This is not surprising, as historically CRF was the first peptide of the CRF system to be discovered (Vale, Spiess, Rivier, & Rivier, 1981).
It is now appreciated that the CRF system is more complex than previously thought and includes several additional players. Specifically, the CRF system includes, in addition to CRF, the three urocortin peptides (Ucn1, Ucn2 and Ucn3), two receptors types, CRFR1 and CRFR2 and the CRF-binding protein (Bale & Vale, 2004; Fekete & Zorrilla, 2006; Joels & Baram, 2009; Kuperman & Chen, 2008; Ryabinin et al., 2002; Steckler & Holsboer, 1999). Table 1 shows that Ucns bind and activate the CRFR2 with high affinity. CRF has a relatively lower affinity for CRFR2 than for CRFR1; Ucn1 has equal affinities for both receptors; and Ucns 2 and 3 appear to be selective for CRFR2 (Hsu & Hsueh, 2001; Lewis et al., 2001; Reyes et al., 2001; Vaughan et al., 1995).
The CRF receptors are distributed differently throughout the brain: while CRFR1 is widely expressed, CRFR2 is expressed in a more discrete but partially overlapping manner. Selective expression of CRFR2 is observed in anxiety and depression-related brain nuclei, including the medial amygdala (MeA), bed nucleus of stria terminalis (BNST), lateral septum (LS) and the dorsal raphe nucleus (DRN) (Chalmers, Lovenberg, & De Souza, 1995; Steckler & Holsboer, 1999; Van Pett et al., 2000). CRF peptide has been found in the paraventricular nucleus of hypothalamus (PVN), neocortex, central nucleus of amygdala (CeA), BNST, hippocampus, raphe nuclei, periaqueductal gray, olfactory bulbs, several thalamic and brain stem nuclei and the cerebellum (Merchenthaler, Hynes, Vigh, Shally, & Petrusz, 1983; Morin, Ling, Liu, Kahl, & Gehlert, 1999; Steckler & Holsboer, 1999; Swanson, Sawchenko, Rivier, & Vale, 1983). Ucn1 in primarily expressed in the centrally-projecting Edinger-Westphal nucleus (EWcp) (Bittencourt et al., 1999; Kozicz, Yanaihara, & Arimura, 1998; Ryabinin, Tsivkovskaia, & Ryabinin, 2005; Vaughan et al., 1995). This brain region (also previously called non-preganglionic Edinger-Westphal nucleus and the perioculomotor urocortin-containing area) should be distinguished from the preganglionic Edinger-Westphal nucleus (EWpg), a cholinergic parasympathetic nucleus known for its oculomotor function, which does not contain Ucn1 (Cavani, Reiner, Cuthbertson, Bittencourt, & Toledo, 2003; Kozicz et al., 2011; May, Reiner, & Ryabinin, 2008; Ryabinin et al., 2005; Vasconcelos et al., 2003; Weitemier, Tsivkovskaia, & Ryabinin, 2005). Earlier literature did not distinguish between EWcp and EWpg, and most often referred to the site of Ucn1 as EW. Besides EWcp, the lateral superior olive and supraoptic nucleus express Ucn1, although at lower levels, and inconsistently between different species (Bittencourt et al., 1999; Spina et al., 2004; Weitemier et al., 2005). Ucn2 is expressed in the PVN, supraoptic nucleus, arcuate nucleus, locus coeruleus, the trigeminal, facial and hypoglossal motor nuclei and the meninges (Reyes et al., 2001; Tanaka et al., 2003). Ucn3 is expressed in medial preoptic area, perifornical area, BNST, MeA, ventral premammillary nucleus, superior olivary nucleus and parabrachial nucleus (Cavalcante, Sita, Mascaro, Bittencourt, & Elias, 2006; Deussing et al., 2010; Lewis et al., 2001; Li, Vaughan, Sawchenko, & Vale, 2002). It also needs to be kept in mind that differences in the distribution of these peptides and receptors between species and even lines of animals have been reported, further complicating the discussion of their function (Weitemier et al., 2005).
The pivotal role of CRF expressed in the PVN, acting on CRFR1 receptors in the pituitary and mediating the hypothalamic-pituitary-adrenal (HPA) axis response to stressors has been well established. Therefore, at first it appeared surprising that while both CRFR1 KOs and CRF KOs showed HPA deficits, deletion of CRFR1, but not CRF, lead to attenuation of anxiety-like behaviors (Weninger et al., 1999). This evidence suggested that other CRF receptor ligands (such as the Ucns) play important roles in the behavioral responses to stressors. Recent studies have focused on elucidating these roles using different methodologies and revealed the importance of Ucns in behaviors related to adaptation and mal-adaptation to stress, such as anxiety, depression and alcohol consumption. Importantly for alcohol research, these studies implicate the Ucns not only in dependence-induced drinking, but also in binge drinking of alcohol. This review focuses on the recent findings in this field.
Section snippets
Role of urocortins in adaptation to stress and anxiety: genetic evidence
While the role of the CRF-CRFR1 system in activating the HPA axis and regulating emotional and cognitive functions following exposure to stressors is well established (Arborelius, Owens, Plotsky, & Nemeroff, 1999; Holsboer, 1999; Nemeroff, 1992; Reul & Holsboer, 2002), the role of the Ucns-CRFR2 system is only beginning to be understood. Interpretation of pharmacological studies testing the roles of specific peptides in stress and anxiety has been difficult because of the partially overlapping
Ucn 1 and the moody brain
Since Ucn1 was the first discovered peptide among the mammalian Ucns (Vaughan et al., 1995), there has been more attention on Ucn1 than on Ucn2 or Ucn3. Soon after the discovery of Ucn1 in EWcp, it became clear that EWcp-Ucn1 neurons show robust activity changes in response to various acute behavioral and pharmacological manipulations (Bachtell, Tsivkovskaia, & Ryabinin, 2002a; Chang, Patel, & Romero, 1995; Gaszner, Csernus, & Kozicz, 2004; Kozicz, 2007, 2009; Kozicz and Arimura, 2001;
The role of corticotropin-releasing factor system in binge-like ethanol intake: pharmacological evidence
Previous preclinical investigations have demonstrated that both the CRFR1 (Chu, Koob, Cole, Zorrilla, & Roberts, 2007; Funk, Zorrilla, Lee, Rice, & Koob, 2007; Gehlert et al., 2007; Hansson et al., 2006; Sommer et al., 2008) and the CRFR2 (Funk & Koob, 2007) in extrahypothalamic brain regions are critically involved in excessive dependence-like ethanol intake in rats stemming from exposure to ethanol vapor (Heilig & Koob, 2007; Lowery & Thiele, 2010). These studies have implicated peptides
Differential roles of Ucns and CRF in regulation of alcohol intake
Since the pharmacological studies described above implicated both CRFR1 and CRFR2 in regulation of alcohol intake in dependent and non-dependent animals, and since CRF has low affinity to CRFR2 receptors (Bale & Vale, 2004), it was hypothesized that not only CRF, but also Ucns could be involved in this behavior (Ryabinin & Weitemier, 2006).
The first line of evidence in agreement with this possibility came from studies mapping immunoreactivity (IR) of the inducible transcription factors (ITFs)
General conclusions and future directions
There has been much progress showing the contribution of Ucns to stress adaptation and regulation of alcohol consumption. The initial focus on CRF as the potentially main player acting on CRF receptors in regulation of these behaviors appears outdated. The importance of Ucns, and in particular Ucn1, in responses to stress and anxiety are more evident in experiments analyzing adaptation to repeated stressors than in experiments testing basal anxiety states or responses to acute stressors. This
Acknowledgments
The authors would like to thank graduate students, postdocs and staff of their laboratories for excellent work leading to this review. This work was supported by NIH grants AA017581, AA013573, AA015148, AA017803, AA013738, AA016647 and AA10760, grants from the Netherlands Scientific Research organization (#819.02.022 and #864.05.008), an FP7 Grant from the European Research Council (#260463) and several research grants from the Israel Science Foundation, Roberto and Renata Ruhman, the Legacy
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