Elsevier

Alcohol

Volume 46, Issue 4, June 2012, Pages 349-357
Alcohol

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

https://doi.org/10.1016/j.alcohol.2011.10.007Get rights and content

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 The initial narrow focus on CRF as the potential main player acting on CRF receptors appears outdated.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.

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

References (136)

  • M. Heilig et al.

    Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms

    Pharmacology & Therapeutics

    (2006)
  • M. Heilig et al.

    A key role for corticotropin-releasing factor in alcohol dependence

    Trends in Neurosciences

    (2007)
  • S.C. Heinrichs et al.

    Corticotropin-releasing factor CRF1, but not CRF2, receptors mediate anxiogenic-like behavior

    Regulatory Peptides

    (1997)
  • F. Holsboer

    The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety

    Journal of Psychiatric Research

    (1999)
  • F. Holsboer et al.

    Corticotropin-releasing-factor induced pituitary-adrenal response in depression

    Lancet

    (1984)
  • G.F. Koob

    The role of CRF and CRF-related peptides in the dark side of addiction

    Brain Research

    (2010)
  • G.F. Koob et al.

    Drug addiction, dysregulation of reward, and allostasis

    Neuropsychopharmacology

    (2001)
  • T. Kozicz

    On the role of urocortin 1 in the non-preganglionic Edinger-Westphal nucleus in stress adaptation

    General and Comparative Endocrinology

    (2007)
  • T. Kozicz et al.

    Gender-related urocortin 1 and brain-derived neurotrophic factor expression in the adult human midbrain of suicide victims with major depression

    Neuroscience

    (2008)
  • Y. Kuperman et al.

    Urocortins: emerging metabolic and energy homeostasis perspectives

    Trends in Endocrinology & Metabolism

    (2008)
  • M. Lanteri-Minet et al.

    Spinal and hindbrain structures involved in visceroception and visceronociception as revealed by the expression of Fos, Jun and Krox-24 proteins

    Neuroscience

    (1993)
  • G. Liebsch et al.

    Differential behavioural effects of chronic infusion of CRH 1 and CRH 2 receptor antisense oligonucleotides into the rat brain

    Journal of Psychiatric Research

    (1999)
  • A.M. Linden et al.

    Effects of mGlu2 or mGlu3 receptor deletions on mGlu2/3 receptor agonist (LY354740)-induced brain c-Fos expression: specific roles for mGlu2 in the amygdala and subcortical nuclei, and mGlu3 in the hippocampus

    Neuropharmacology

    (2006)
  • I. Merchenthaler et al.

    Immunocytochemical localization of corticotropin releasing factor (CRF) in the rat spinal cord

    Brain Research

    (1983)
  • S.M. Morin et al.

    Differential distribution of urocortin- and corticotropin-releasing factor-like immunoreactivities in the rat brain

    Neuroscience

    (1999)
  • M. Palkovits et al.

    Neuronal activation in the CNS during different forms of acute renal failure in rats

    Neuroscience

    (2009)
  • J.M. Reul et al.

    Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression

    Current Opinion in Pharmacology

    (2002)
  • J.S. Rhodes et al.

    Evaluation of a simple model of ethanol drinking to intoxication in C57BL/6J mice

    Physiology & Behavior

    (2005)
  • T. Rouwette et al.

    Differential responses of corticotropin-releasing factor and urocortin 1 to acute pain stress in the rat brain

    Neuroscience

    (2011)
  • A.E. Ryabinin et al.

    ITF expression in mouse brain during acquisition of alcohol self-administration

    Brain Research

    (2001)
  • A.E. Ryabinin et al.

    Urocortin 1-containing neurons in the human Edinger-Westphal nucleus

    Neuroscience

    (2005)
  • A.E. Ryabinin et al.

    The urocortin 1 neurocircuit: ethanol-sensitivity and potential involvement in alcohol consumption

    Brain Research Reviews

    (2006)
  • A.E. Ryabinin et al.

    Urocortin 1 microinjection into the mouse lateral septum regulates the acquisition and expression of alcohol consumption

    Neuroscience

    (2008)
  • A.M. Anacker et al.

    Prairie voles as a novel model of socially facilitated excessive drinking

    Addiction Biology

    (2011)
  • L. Arborelius et al.

    The role of corticotropin-releasing factor in depression and anxiety disorders

    Journal of Endocrinology

    (1999)
  • R.K. Bachtell et al.

    Alcohol-induced c-Fos expression in the Edinger-Westphal nucleus: pharmacological and signal transduction mechanisms

    Journal of Pharmacology and Experimental Therapeutics

    (2002)
  • R.K. Bachtell et al.

    The Edinger-Westphal-lateral septum urocortin pathway and its relationship to alcohol consumption

    Journal of Neuroscience

    (2003)
  • R.K. Bachtell et al.

    Lesions of the Edinger-Westphal nucleus in C57BL/6J mice disrupt ethanol-induced hypothermia and ethanol consumption

    European Journal of Neuroscience

    (2004)
  • T.L. Bale et al.

    Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress

    Nature Genetics

    (2000)
  • T.L. Bale et al.

    Increased depression-like behaviors in corticotropin-releasing factor receptor-2-deficient mice: sexually dichotomous responses

    Journal of Neuroscience

    (2003)
  • T.L. Bale et al.

    CRF and CRF receptors: role in stress responsivity and other behaviors

    Annual Review of Pharmacology and Toxicology

    (2004)
  • J.C. Bittencourt et al.

    Urocortin expression in rat brain: evidence against a pervasive relationship of urocortin-containing projections with targets bearing type 2 CRF receptors

    Journal of Comparative Neurology

    (1999)
  • D.G. Blazer et al.

    The epidemiology of at-risk and binge drinking among middle-aged and elderly community adults: National Survey on Drug Use and Health

    American Journal of Psychiatry

    (2009)
  • J.A. Cavani et al.

    Evidence that urocortin is absent from neurons of the Edinger-Westphal nucleus in pigeons

    Brazilian Journal of Medical and Biological Research

    (2003)
  • D.T. Chalmers et al.

    Localization of novel corticotropin-releasing factor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor expression

    Journal of Neuroscience

    (1995)
  • A. Chen et al.

    Urocortin 2-deficient mice exhibit gender-specific alterations in circadian hypothalamus-pituitary-adrenal axis and depressive-like behavior

    Journal of Neuroscience

    (2006)
  • S.C. Coste et al.

    Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2

    Nature Genetics

    (2000)
  • Council, N.I.A.A.A

    NIAAA council approves definition of binge drinking

    (2004)
  • K.E. Courtney et al.

    Binge drinking in young adults: data, definitions, and determinants

    Psychological Bulletin

    (2009)
  • M.S. Cowen et al.

    Alcoholism and neuropeptides: an update

    CNS & Neurological Disorders–Drug Targets

    (2006)
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