Behavioral studies and genetic alterations in Corticotropin-Releasing Hormone (CRH) Neurocircuitry: Insights into human psychiatric disorders

Behavioral Sciences

Volumn 2, Issue 2, 2012, Pages 135-171

  Laryea, Gloria ^a,b   Arnett, Melinda G ^b   Muglia, Louis J ^b  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER   (United States)

Author keywords

Anxiety; Corticotropin releasing hormone; CRH binding protein; CRH receptors; Depression; Human polymorphisms; Psychiatric disorders

Indexed keywords

EID: 84876071215     PISSN: None     EISSN: 2076328X     Source Type: Journal    
DOI: 10.3390/bs2020135     Document Type: Review

References (146)

1. Vale, W.; Spiess, J.; Rivier, C.; Rivier, J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 1981, 213, 1394–1397.
2. Lewis, K.; Li, C.; Perrin, M.H.; Blount, A; Kunitake, K.; Donaldson, C.; Vaughan, J.; Reyes, T.M.; Gulyas, J.; Fischer, W.; et al. Identification of urocortin III, an additional member of the corticotropin-releasing factor CRF family with high affinity for the CRF2 receptor. Proc. Natl. Acad. Sci. USA 2001, 98, 7570–7575.
3. Brar, B.; Sanderson, T.; Wang, N.; Lowry, P.J. Post-translational processing of human procorticotrophin-releasing factor in transfected mouse neuroblastoma and Chinese hamster ovary cell lines. J. Endocrinol. 1997, 154, 431–440.
4. Grigoriadis, D.E.; Lovenberg, T.W.; Chalmers, D.T.; Liaw, C.; Souza, E.B.D.E. Characterization of Corticotropin- releasing factor receptor subtypes. Ann. NY Acad. Sci. 1996, 780, 60–80.
5. Muglia, L.J.; Jacobson, L.; Luedke, C.; Vogt, S.K.; Schaefer, M.L.; Dikkes, P.; Fukuda, S.; Sakai, Y.; Suda, T.; Majzoub, J.A. Corticotropin-releasing hormone links pituitary adrenocorticotropin gene expression and release during adrenal insufficiency. J. Clin. Invest. 2000, 105, 1269–1277.
6. Muller, M.B. Selective activation of the hypothalamic vasopressinergic system in mice deficient for the Corticotropin-Releasing Hormone Receptor 1 is dependent on glucocorticoids. Endocrinology 2000, 141, 4262–4269.
7. Preil, J.; Müller, M.B.; Gesing, A.; Reul, J.M.; Sillaber, I.; van Gaalen, M.M.; Landgrebe, J.; Holsboer, F.; Stenzel-Poore, M.; Wurst, W. Regulation of the hypothalamic-pituitary-adrenocortical system in mice deficient for CRH receptors 1 and 2. Endocrinology 2001, 142, 4946–4955.
8. Surget, A.; Belzung, C. Involvement of vasopressin in affective disorders. Eur. J. Pharmacol. 2008, 583, 340–349.
9. Bao, A.M.; Swaab, D.F. Corticotropin-releasing hormone and arginine vasopressin in depression focus on the human postmortem hypothalamus. Vitam. Horm. 2010, 82, 339–365.
10. Chalmers, D.T.; Lovenberg, T.W.; De Souza, E.B. Localization of novel corticotropin-releasing factor receptor CRF2 mRNA expression to specific subcortical nuclei in rat brain: Comparison with CRF1 receptor mRNA expression. J. Neurosci. 1995, 15, 6340–6350.
11. Reul, J. Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. Curr. Opin. Pharmacol. 2002, 2, 23–33.
12. Reyes, T.M.; Lewis, K.; Perrin, M.H.; Kunitake, K.S.; Vaughan, J.; Arias, C.A.; Hogenesch, J.B.; Gulyas, J.; Rivier, J.; Vale, W.W.; et al. Urocortin II: A member of the corticotropin-releasing factor CRF neuropeptide family that is selectively bound by type 2 CRF receptors. Proc. Natl. Acad. Sci. USA 2001, 98, 2843–2848.
13. Vaughan, J.; Donaldson, C.; Bittencourt, J.; Perrin, M.H.; Lewis, K.; Sutton, S.; Chan, R.; Turnbull, A.V.; Lovejoy, D.; Rivier, C. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 1995, 378, 287–292.
14. Kostich, W.A.; Grzanna, R.; Lu, N.Z.; Largent, B.L. Immunohistochemical visualization of corticotropin-releasing factor type 1 (CRF1) receptors in monkey brain. J. Comp. Neurol. 2004, 478, 111–125.
15. Sánchez, M.M.; Young, L.J.; Plotsky, P.M.; Insel, T.R. Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain. J. Comp. Neurol. 1999, 408, 365–377.
16. Hsu, D.T.; Mickey, B.J.; Langenecker, S.A.; Heitzeg, M.M.; Love, T.M.; Wang, H.; Kennedy, S.E.; Peciña, M.; Shafir, T.; Hodgkinson, C.A.; et al. Variation in the Corticotropin-Releasing Hormone Receptor 1 (CRHR1) Gene Influences fMRI Signal Responses during Emotional Stimulus Processing. J. Neurosci. 2012, 32, 3253–3260.
17. Hiroi, N.; Wong, M.L.; Licinio, J.; Park, C.; Young, M.; Gold, P.W.; Chrousos, G.P.; Bornstein, S.R. Expression of corticotropin releasing hormone receptors type I and type II mRNA in suicide victims and controls. Mol. Psychiatr. 2001, 6, 540–546.
18. Chen, R.; Lewis, K.A.; Perrin, M.H.; Vale, W.W. Expression cloning of a human corticotropin-releasing-factor receptor. Proc. Natl. Acad. Sci. USA 1993, 90, 8967–8971.
19. Pisarchik, A.; Slominski, A.T. Alternative splicing of CRH-R1 receptors in human and mouse skin: Identification of new variants and their differential expression. FASEB J. 2001, 15, 2754–2756.
20. Perrin, M.; Donaldson, C.; Chen, R.; Blount, A.; Berggren, T.; Bilezikjian, L.; Sawchenko, P.; Vale, W. Identification of a second corticotropin-releasing factor receptor gene and characterization of a cDNA expressed in heart. Proc. Natl. Acad. Sci. USA 1995, 92, 2969–2973.
21. Lovenberg, T.W.; Liaw, C.W.; Grigoriadis, D.E.; Clevenger, W.; Chalmers, D.T.; De Souza, E.B.; Oltersdorf, T. Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Proc. Natl. Acad. Sci. USA 1995, 92, 836–840.
22. Refojo, D.; Schweizer, M.; Kuehne, C.; Ehrenberg, S.; Thoeringer, C.; Vogl, A.M.; Dedic, N.; Schumacher, M.; von Wolff, G.; Avrabos, C.; et al. Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR. Science 2011, 333, 1903–1907.
23. McLean, M.; Bisits, A.; Davies, J.; Woods, R.; Lowry, P.; Smith, R. A placental clock controlling the length of human pregnancy. Nature Med. 1995, 1, 460–463.
24. Behan, D.P.; De Souza, E.B.; Lowry, P.J.; Potter, E.; Sawchenko, P.; Vale, W.W. Corticotropin releasing factor CRF binding protein: A novel regulator of CRF and related peptides. Front Neuroendocrin. 1995, 16, 362–382.
25. Orth, D.N.; Mount, C.D. Specific high-affinity binding protein for human corticotropin-releasing hormone in normal human plasma. Biochem. Biophys. Res. Commun. 1987, 143, 411–417.
26. Potter, E.; Behan, D.P.; Fischer, W.H.; Linton, E.A.; Lowry, P.J.; Vale, W.W. Cloning and characterization of the cDNAs for human and rat corticotropin releasing factor-binding proteins. Nature 1991, 349, 423–426.
27. Seasholtz, A.F.; Burrows, H.L.; Karolyi, I.J.; Camper, S.A. Mouse models of altered CRH-binding protein expression. Peptides 2001, 22, 743–751.
28. Potter, E.; Behan, D.P.; Linton, E.A.; Lowry, P.J.; Sawchenko, P.E.; Vale, W.W. The central distribution of a corticotropin-releasing factor CRF-binding protein predicts multiple sites and modes of interaction with CRF. Proc. Natl. Acad. Sci. USA 1992, 89, 4192–4196.
29. Behan, D.P.; Khongsaly, O.; Ling, N.; De Souza, E.B. Urocortin interaction with corticotropin-releasing factor CRF binding protein CRF-BP: A novel mechanism for elevating “free” CRF levels in human brain. Brain Res. 1996, 725, 263–267.
30. Gallagher, J.P.; Orozco-Cabal, L.F.; Liu, J.; Shinnick-Gallagher, P. Synaptic physiology of central CRH system. Eur. J. Pharmacol. 2008, 583, 215–225.
31. Liu, J.; Yu, B.; Neugebauer, V.; Grigoriadis, D.E.; Rivier, J.; Vale, W.W.; Shinnick-Gallagher, P.; Gallagher, J.P. Corticotropin-releasing factor and Urocortin I modulate excitatory glutamatergic synaptic transmission. J. Neurosci. 2004, 24, 4020–4029.
32. Blank, T.; Nijholt, I.; Eckart, K.; Spiess, J. Priming of long-term potentiation in mouse hippocampus by corticotropin-releasing factor and acute stress: Implications for hippocampus-dependent learning. J. Neurosci. 2002, 22, 3788–3794.
33. Nemeroff, C.B.; Widerlov, E.; Bissette, G.; Walleus, H.; Karlsson, I.; Eklund, K.; Kilts, C.D.; Loosen, P.T.; Vale, W. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984, 226, 1342–1344.
34. Bremner, J.D.; Licinio, J.; Darnell, A.; Krystal, J.H.; Owens, M.J.; Southwick, S.M.; Nemeroff, C.B.; Charney, D.S. Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am. J. Psychiatr. 1997, 154, 624–629.
35. Binder, E.B.; Owens, M.J.; Liu, W.; Deveau, T.C.; Rush, a J.; Trivedi, M.H.; Fava, M.; Bradley, B.; Ressler, K.J.; Nemeroff, C.B. Association of polymorphisms in genes regulating the corticotropin-releasing factor system with antidepressant treatment response. Arch. Gen. Psychiatr. 2010, 67, 369–379.
36. Mitchell, A. The role of corticotropin releasing factor in depressive illness: A critical review. Neurosci. Biobehav. Rev. 1998, 22, 635–651.
37. Bonne, O.; Gill, J.M.; Luckenbaugh, D.A.; Collins, C.; Owens, M.J.; Alesci, S.; Neumeister, A.; Yuan, P.; Kinkead, B.; Manji, H.K.; et al. Corticotropin-releasing factor, interleukin-6, brain-derived neurotrophic factor, insulin-like growth factor-1, and substance P in the cerebrospinal fluid of civilians with posttraumatic stress disorder before and after treatment with paroxetine. J. Clin. Psychiatr. 2011, 72, 1124–1128.
38. Imaki, T.; Shibasaki, T.; Hotta, M.; Demura, H. Intracerebroventricular administration of corticotropin-releasing factor induces c-fos mRNA expression in brain regions related to stress responses: Comparison with pattern of c-fos mRNA induction after stress. Brain Res. 1993, 616, 114–125.
39. Campbell, B.M.; Morrison, J.L.; Walker, E.L.; Merchant, K.M. Differential regulation of behavioral, genomic, and neuroendocrine responses by CRF infusions in rats. Pharmacol. Biochem. Behav. 2004, 77, 447–455.
40. Sutton, R.E.; Koob, G.F.; Le Moal, M.; Rivier, J.; Vale, W. Corticotropin releasing factor produces behavioural activation in rats. Nature 1982, 297, 331–333.
41. Dunn, A. Physiological and behavioral responses to corticotropin-releasing factor administration: Is CRF a mediator of anxiety or stress responses. Brain Res. Rev. 1990, 15, 71–100.
42. Rivest, S.; Deshaies, Y.; Richard, D. Effects of corticotropin-releasing factor on energy balance in rats are sex dependent. Am. J. Phys. 1989, 257, R1417–R1422.
43. Glowa, J.R.; Barrett, J.E.; Russell, J.; Gold, P.W. Effects of corticotropin releasing hormone on appetitive behaviors. Peptides 1992, 13, 609–621.
44. Sherman, J.E.; Kalin, N.H. ICV-CRH alters stress-induced freezing behavior without affecting pain sensitivity. Pharmacol. Biochem. Behav. 1988, 30, 801–807.
45. Britton, K.T.; Lee, G.; Vale, W.; Rivier, J.; Koob, G.F. Corticotropin releasing factor CRF receptor antagonist blocks activating and “anxiogenic” actions of CRF in the rat. Brain Res. 1986, 369, 303–306.
46. Heinrichs, S.C.; Pich, E.M.; Miczek, K.A.; Britton, K.T.; Koob, G.F. Corticotropin-releasing factor antagonist reduces emotionality in socially defeated rats via direct neurotropic action. Brain Res. 1992, 581, 190–197.
47. Kalin, N.H.; Sherman, J.E.; Takahashi, L.K. Antagonism of endogenous CRH systems attenuates stress-induced freezing behavior in rats. Brain Res. 1988, 457, 130–135.
48. Heinrichs, S.C.; Lapsansky, J.; Lovenberg, T.W.; De Souza, E.B.; Chalmers, D.T. Corticotropin-releasing factor CRF1, but not CRF2, receptors mediate anxiogenic-like behavior. Regul. Pept. 1997, 71, 15–21.
49. Liebsch, G.; Landgraf, R.; Engelmann, M.; Lörscher, P.; Holsboer, F. Differential behavioural effects of chronic infusion of CRH 1 and CRH 2 receptor antisense oligonucleotides into the rat brain. J. Psychiatr. Res. 1999, 33, 153–163.
50. Bagosi, Z.; Jászberényi, M.; Szabó, G.; Telegdy, G. The effects of CRF and the urocortins on [3H]GABA release from the rat amygdala—An in vitro superfusion study. Brain Res. Bull. 2008, 75, 15–17.
51. Bagosi, Z.; Csabafi, K.; Jászberényi, M.; Telegdy, G. The effects of corticotropin-releasing factor and the urocortins on hypothalamic gamma-amino butyric acid release—The impacts on the hypothalamic-pituitary-adrenal axis. Neurochem. Int. 2012, 60, 350–354.
52. Rainnie, D.G.; Bergeron, R.; Sajdyk, T.J.; Patil, M.; Gehlert, D.R.; Shekhar, A. Corticotrophin releasing factor-induced synaptic plasticity in the amygdala translates stress into emotional disorders. J. Neurosci. 2004, 24, 3471–3479.
53. Valdez, G.R.; Inoue, K.; Koob, G.F.; Rivier, J.; Vale, W.; Zorrilla, E.P. Human urocortin II: Mild locomotor suppressive and delayed anxiolytic-like effects of a novel corticotropin-releasing factor related peptide. Brain Res. 2002, 943, 142–150.
54. Valdez, G.R.; Zorrilla, E.P.; Rivier, J.; Vale, W.W.; Koob, G.F. Locomotor suppressive and anxiolytic-like effects of urocortin 3, a highly selective type 2 corticotropin-releasing factor agonist. Brain Res. 2003, 980, 206–212.
55. Pelleymounter, M.A.; Joppa, M.; Ling, N.; Foster, A.C. Behavioral and neuroendocrine effects of the selective CRF2 receptor agonists urocortin II and urocortin III. Peptides 2004, 25, 659–666.
56. Chen, P.; Vaughan, J.; Donaldson, C.; Vale, W.; Li, C. Injection of Urocortin 3 into the ventromedial hypothalamus modulates feeding, blood glucose levels, and hypothalamic POMC gene expression but not the HPA axis. Am. J. Physiol-Endoc. Metab. 2010, 298, E337–E345.
57. Muglia, L.; Jacobson, L.; Majzoub, J.A. Production of corticotropin-releasing hormone-deficient mice by targeted mutation in embryonic stem cells. Ann. NY Acad. Sci. 1996, 780, 49–59.
58. Muglia, L.; Jacobson, L.; Dikkes, P.; Majzoub, J.A. Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need. Nature 1995, 373, 427–432.
59. Weninger, S.C. Stress-induced behaviors require the corticotropin-releasing hormone (CRH) receptor, but not CRH. Proc. Natl. Acad. Sci. USA 1999, 96, 8283–8288.
60. Dunn, A.J.; Swiergiel, A.H. Behavioral responses to stress are intact in CRF-deficient mice. Brain Res. 1999, 845, 14–20.
61. Stenzel-Poore, M.P.; Cameron, V.A.; Vaughan, J.; Sawchenko, P.E.; Vale, W. Development of Cushing’s syndrome in corticotropin-releasing factor transgenic mice. Endocrinology 1992, 130, 3378–3386.
62. Dirks, A.; Groenink, L.; Schipholt, M.I.; van der Gugten, J.; Hijzen, T.H.; Geyer, M.A.; Olivier, B. Reduced startle reactivity and plasticity in transgenic mice overexpressing corticotropin-releasing hormone. Biol. Psychiatr. 2002, 51, 583–590.
63. Lu, S.; Steiner, M.A.; Whittle, N.; Vogl, A.M.; Walser, S.M.; Ableitner, M.; Refojo, D.; Ekker, M.; Rubenstein, J.L.; Stalla, G.K.; et al. Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior. Mol. Psychiatr. 2008, 13, 1028–1042.
64. Dedic, N.; Touma, C.; Romanowski, C.P.; Schieven, M.; Kühne, C.; Ableitner, M.; Lu, A.; Holsboer, F.; Wurst, W.; Kimura, M.; Deussing, J.M. Assessing behavioural effects of chronic HPA axis activation using conditional CRH-overexpressing mice. Cell Mol. Neurobiol. 2011, [Epub ahead of print].
65. Groenink, L.; Dirks, A.; Verdouw, P.M.; Schipholt, M.L.; Veening, J.G.; van der Gugten, J.; Olivier, B. HPA axis dysregulation in mice overexpressing corticotropin releasing hormone. Biol. Psychiatr. 2002, 51, 875–881.
66. Stenzel-Poore, M.P.; Heinrichs, S.C.; Rivest, S.; Koob, G.F.; Vale, W.W. Overproduction of corticotropin-releasing factor in transgenic mice: A genetic model of anxiogenic behavior. J. Neurosci. 1994, 14, 2579–2584.
67. van Gaalen, M.M.; Stenzel-Poore, M.P.; Holsboer, F.; Steckler, T. Effects of transgenic overproduction of CRH on anxiety-like behaviour. Eur. J. Neurosci. 2002, 15, 2007–2015.
68. Heinrichs, S.C.; Min, H.; Tamraz, S.; Carmouché, M.; Boehme, S.A.; Vale, W.W. Anti-sexual and anxiogenic behavioral consequences of corticotropin-releasing factor overexpression are centrally mediated. Psychoneuroendocrinology 1997, 22, 215–224.
69. Dirks, A.; Groenink, L.; Bouwknecht, J.A.; Hijzen, T.H.; van der Gugten, J.; Ronken, E.; Verbeek, J.S.; Veening, J.G.; Dederen, P.J.W.C.; Korosi, A.; et al. Overexpression of corticotropin-releasing hormone in transgenic mice and chronic stress-like autonomic and physiological alterations. Eur. J. Neurosci. 2002, 16, 1751–1760.
70. Palmer, A.A.; Sharpe, A.L.; Burkhart-Kasch, S.; McKinnon, C.S.; Coste, S.C.; Stenzel-Poore, M.P.; Phillips, T.J. Corticotropin-releasing factor overexpression decreases ethanol drinking and increases sensitivity to the sedative effects of ethanol. Psychopharmacology 2004, 176, 386–397.
71. Hansson, A.C.; Cippitelli, A.; Sommer, W.H.; Fedeli, A.; Björk, K.; Soverchia, L.; Terasmaa, A.; Massi, M.; Heilig, M.; Ciccocioppo, R. Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress. Proc. Natl. Acad. Sci. USA 2006, 103, 15236–15241.
72. Treutlein, J.; Kissling, C.; Frank, J.; Wiemann, S.; Dong, L.; Depner, M.; Saam, C.; Lascorz, J.; Soyka, M.; Preuss, U.W.; et al. Genetic association of the human corticotropin releasing hormone receptor 1 CRHR1 with binge drinking and alcohol intake patterns in two independent samples. Mol. Psychiatr. 2006, 11, 594–602.
73. Heilig, M.; Koob, G.F. A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci. 2007, 30, 399–406.
74. Vinkers, C.H.; Hendriksen, H.; van Oorschot, R.; Cook, J.M.; Rallipalli, S.; Huang, S.; Millan, M.J.; Olivier, B.; Groenink, L. Lifelong CRF overproduction is associated with altered gene expression and sensitivity of discrete GABA(A) and mGlu receptor subtypes. Psychopharmacology 2012, 219, 897–908.
75. 1 modulates early-life stress-programmed cognitive deficits. J. Neurosci. 2011, 31, 13625–13634.
76. Kimura, M.; Müller-Preuss, P.; Lu, A.; Wiesner, E.; Flachskamm, C.; Wurst, W.; Holsboer, F.; Deussing, J.M. Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep. Mol. Psychiatr. 2010, 15, 154–165.
77. Kolber, B.J.; Boyle, M.P.; Wieczorek, L.; Kelley, C.L.; Onwuzurike, C.C.; Nettles, S.A.; Vogt, S.K.; Muglia, L.J. Transient early-life forebrain corticotropin-releasing hormone elevation causes long-lasting anxiogenic and despair-like changes in mice. J. Neurosci. 2010, 30, 2571–2581.
78. Vicentini, E.; Arban, R.; Angelici, O.; Maraia, G.; Perico, M.; Mugnaini, M.; Ugolini, A.; Large, C.; Domenici, E.; Gerrard, P.; et al. Transient forebrain over-expression of CRF induces plasma corticosterone and mild behavioural changes in adult conditional CRF transgenic mice. Pharmacol. Biochem. Behav. 2009, 93, 17–24.
79. Smith, G.W.; Aubry, J.M.; Dellu, F.; Contarino, A.; Bilezikjian, L.M.; Gold, L.H.; Chen, R.; Marchuk, Y.; Hauser, C.; Bentley, C.A.; et al. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 1998, 20, 1093–1102.
80. Contarino, A.; Dellu, F.; Koob, G.F.; Smith, G.W.; Lee, K.F.; Vale, W.; Gold, L.H. Reduced anxiety-like and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1. Brain Res. 1999, 835, 1–9.
81. Timpl, P.; Spanagel, R.; Sillaber, I.; Kresse, A.; Reul, J.M.; Stalla, G.K.; Blanquet, V.; Steckler, T.; Holsboer, F.; Wurst, W. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nat. Gen. 1998, 19, 162–166.
82. Müller, M.B.; Zimmermann, S.; Sillaber, I.; Hagemeyer, T.P.; Deussing, J.M.; Timpl, P.; Kormann, M.S.D.; Droste, S.K.; Kühn, R.; Reul, J.M.H.M.; et al. Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat. Neurosci. 2003, 6, 1100–1107.
83. Nguyen, N.K.; Keck, M.E.; Hetzenauer, A.; Thoeringer, C.K.; Wurst, W.; Deussing, J.M.; Holsboer, F.; Müller, M.B.; Singewald, N. Conditional CRF receptor 1 knockout mice show altered neuronal activation pattern to mild anxiogenic challenge. Psychopharmacology 2006, 188, 374–385.
84. Wang, X.D.; Chen, Y.; Wolf, M.; Wagner, K.V.; Liebl, C.; Scharf, S.H.; Harbich, D.; Mayer, B.; Wurst, W.; Holsboer, F.; et al. Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling. Neurobiol. Dis. 2011, 42, 300–310.
85. Molander, A.; Vengeliene, V.; Heilig, M.; Wurst, W.; Deussing, J.M.; Spanagel, R. Brain-specific inactivation of the Crhr1 gene inhibits post-dependent and stress-induced alcohol intake, but does not affect relapse-like drinking. Neuropsychopharmacology 2012, 37, 1047–1056.
86. Schmidt, M.V.; Deussing, J.M.; Oitzl, M.S.; Ohl, F.; Levine, S.; Wurst, W.; Holsboer, F.; Müller, M.B.; de Kloet, E.R. Differential disinhibition of the neonatal hypothalamic- pituitary-adrenal axis in brain-specific CRH receptor 1-knockout mice. Eur. J. Neurosci.2006, 24, 2291–2298.
87. Schmidt, M. Regulation of the developing hypothalamic-pituitary-adrenal axis in corticotropin releasing hormone receptor 1-deficient mice, Neuroscience 2003, 119, 589–595.
88. Müller, M.B.; Preil, J.; Renner, U.; Zimmermann, S.; Kresse, A.E.; Stalla, G.K.; Keck, M.E.; Holsboer, F.; Wurst, W. Expression of CRHR1 and CRHR2 in mouse pituitary and adrenal gland: Implications for HPA system regulation. Endocrinology 2001, 142, 4150–4153.
89. Coste, S.C.; Kesterson, R.A.; Heldwein, K.A.; Stevens, S.L.; Heard, A.D.; Hollis, J.H.; Murray, S.E.; Hill, J.K.; Pantely, G.A.; Hohimer, A.R.; et al. Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nat. Gen. 2000, 24, 403–409.
90. Bale, T.L.; Contarino, A.; Smith, G.W.; Chan, R.; Gold, L.H.; Sawchenko, P.E.; Koob, G.F.; Vale, W.W.; Lee, K.F. Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat. Gen. 2000, 24, 410–414.
91. Kishimoto, T.; Radulovic, J.; Radulovic, M.; Lin, C.R.; Schrick, C.; Hooshmand, F.; Hermanson, O.; Rosenfeld, M.G.; Spiess, J. Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2. Nat. Gen. 2000, 24, 415–419.
92. Todorovic, C.; Sherrin, T.; Pitts, M.; Hippel, C.; Rayner, M.; Spiess, J. Suppression of the MEK/ERK signaling pathway reverses depression-like behaviors of CRF2-deficient mice. Neuropsychopharmacology 2009, 34, 1416–1426.
93. Bale, T.L.; Vale, W.W. Increased depression-like behaviors in corticotropin-releasing factor receptor-2-deficient mice: Sexually dichotomous responses. J. Neurosci. 2003, 23, 5295–5301
94. Gresack, J.; Powell, S.; Geyer, M.; Poore, M.S.; Coste, S.; Risbrough, V. CRF2 null mutation increases sensitivity to isolation rearing effects on locomotor activity in mice. Neuropeptides 2010, 44, 349–353.
95. Bale, T.L.; Picetti, R.; Contarino, A.; Koob, G.F.; Vale, W.W.; Lee, K.F. Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety-like behavior. J. Neurosci. 2002, 22, 193–199.
96. Gysling, K.; Forray, M.I.; Haeger, P.; Daza, C.; Rojas, R. Corticotropin-releasing hormone and urocortin: Redundant or distinctive functions? Brain Res. Rev. 2004, 47, 116–125.
97. Wang, X.; Su, H.; Copenhagen, L.D.; Vaishnav, S.; Pieri, F.; Shope, C.D.; Brownell, W.E.; De Biasi, M.; Paylor, R.; Bradley, A. Urocortin-deficient mice display normal stress-induced anxiety behavior and autonomic control but an impaired acoustic startle response. Mol. Cell. Biol. 2002, 22, 6605–6610.
98. Vetter, D.E.; Li, C.; Zhao, L.; Contarino, A.; Liberman, M.C.; Smith, G.W.; Marchuk, Y.; Koob, G.F.; Heinemann, S.F.; Vale, W.; Lee, K.F. Urocortin-deficient mice show hearing impairment and increased anxiety-like behavior. Nat. Gen. 2002, 31, 363–369.
99. Giardino, W.J.; Cocking, D.L.; Kaur, S.; Cunningham, C.L.; Ryabinin, A.E. Urocortin-1 within the centrally-projecting Edinger-Westphal nucleus is critical for ethanol preference. PLoS One 2011, 6, e26997.
100. Chen, A.; Zorrilla, E.; Smith, S.; Rousso, D.; Levy, C.; Vaughan, J.; Donaldson, C.; Roberts, A.; Lee, K.F.; Vale, W. Urocortin 2-deficient mice exhibit gender-specific alterations in circadian hypothalamus-pituitary-adrenal axis and depressive-like behavior. J. Neurosci. 2006, 26, 5500–5510.
101. Neufeld-Cohen, A.; Evans, A.K.; Getselter, D.; Spyroglou, A.; Hill, A.; Gil, S.; Tsoory, M.; Beuschlein, F.; Lowry, C.A.; Vale, W.; Chen, A. Urocortin-1 and -2 double-deficient mice show robust anxiolytic phenotype and modified serotonergic activity in anxiety circuits. Mol. Psychiatr. 2010, 15, 426–441.
102. Deussing, J.M.; Breu, J.; Kühne, C.; Kallnik, M.; Bunck, M.; Glasl, L.; Yen, Y.C.; Schmidt, M.V.; Zurmühlen, R.; Vogl, A.M.; et al. Urocortin 3 modulates social discrimination abilities via corticotropin-releasing hormone receptor type 2. J. Neurosci. 2010, 30, 9103–9116.
103. Neufeld-cohen, A.; Tsoory, M.M.; Evans, A.K.; Getselter, D.; Gil, S. A triple urocortin knockout mouse model reveals an essential role for urocortins in stress recovery. Proc. Natl. Acad. Sci. USA 2010, 107, 19020–19025.
104. Lovejoy, D.A.; Aubry, J.M.; Turnbull, A.; Sutton, S.; Potter, E.; Yehling, J.; Rivier, C.; Vale, W.W. Ectopic expression of the CRF-binding protein: Minor impact on HPA axis regulation but induction of sexually dimorphic weight gain. J. Neuroendocrinol. 1998, 10, 483–491.
105. Burrows, H.L.; Nakajima, M.; Lesh, J.S.; Goosens, K.A.; Samuelson, L.C.; Inui, A.; Camper, S.A.; Seasholtz, A.F. Excess corticotropin releasing hormone-binding protein in the hypothalamic-pituitary-adrenal axis in transgenic mice. J. Clin. Invest. 1998, 101, 1439–1447.
106. Karolyi, I.J.; Burrows, H.L.; Ramesh, T.M.; Nakajima, M.; Lesh, J.S.; Seong, E.; Camper, S.A.; Seasholtz, A.F. Altered anxiety and weight gain in corticotropin-releasing hormone-binding protein-deficient mice. Proc. Natl. Acad. Sci. USA 1999, 96, 11595–11600.
107. Regev, L.; Neufeld-Cohen, A.; Tsoory, M.; Kuperman, Y.; Getselter, D.; Gil, S.; Chen, A. Prolonged and site-specific over-expression of corticotropin-releasing factor reveals differential roles for extended amygdala nuclei in emotional regulation. Mol. Psychiatr. 2010, 16, 714–728.
108. Regev, L.; Tsoory, M.; Gil, S.; Chen, A. Site-Specific Genetic Manipulation of Amygdala Corticotropin-Releasing Factor Reveals Its Imperative Role in Mediating Behavioral Response to Challenge. Biol. Psychiatr. 2011, 71, 317–326.
109. Flandreau, E.I.; Ressler, K.J.; Owens, M.J.; Nemeroff, C.B. Chronic overexpression of corticotropin-releasing factor from the central amygdala produces HPA axis hyperactivity and behavioral anxiety associated with gene-expression changes in the hippocampus and paraventricular nucleus of the hypothalamus. Psychoneuroendocrinology 2012, 37, 27–38.
110. Keen-Rhinehart, E.; Michopoulos, V.; Toufexis, D.J.; Martin, E.I.; Nair, H.; Ressler, K.J.; Davis, M.; Owens, M.J.; Nemeroff, C.B.; Wilson, M.E. Continuous expression of corticotropin-releasing factor in the central nucleus of the amygdala emulates the dysregulation of the stress and reproductive axes. Mol. Psychiatr. 2009, 14, 37–50.
111. Sink, K.S.; Walker, D.L.; Freeman, S.M.; Flandreau, E.I.; Ressler, K.J.; Davis, M. Effects of continuously enhanced corticotropin releasing factor expression within the bed nucleus of the stria terminalis on conditioned and unconditioned anxiety. Mol. Psychiatr. 2012, doi:10.1038/mp.2011.188.
112. Sztainberg, Y.; Kuperman, Y.; Tsoory, M.; Lebow, M.; Chen, A. The anxiolytic effect of environmental enrichment is mediated via amygdalar CRF receptor type 1. Mol. Psychiatr. 2010, 15, 905–917.
113. Sztainberg, Y.; Kuperman, Y.; Justice, N.; Chen, A. An anxiolytic role for CRF receptor type 1 in the globus pallidus. J. Neurosci. 2011, 31, 17416–17424.
114. Kuperman, Y.; Issler, O.; Regev, L.; Musseri, I.; Navon, I.; Neufeld-Cohen, A.; Gil, S.; Chen, A. Perifornical Urocortin-3 mediates the link between stress-induced anxiety and energy homeostasis. Proc. Natl. Acad. Sci. USA 2010, 107, 8393–8398.
115. Smoller, J.W.; Rosenbaum, J.F.; Biederman, J.; Kennedy, J.; Dai, D.; Racette, S.R.; Laird, N.M.; Kagan, J.; Snidman, N.; Hirshfeld-Becker, D. Association of a genetic marker at the corticotropin-releasing hormone locus with behavioral inhibition. Biol. Psychiatr. 2003, 54, 1376–1381.
116. Smoller, J.W.; Yamaki, L.H.; Fagerness, J.A.; Biederman, J.; Racette, S.; Laird, N.M.; Kagan, J.; Snidman, N.; Faraone, S.V.; Hirshfeld-Becker, D.; et al. The corticotropin-releasing hormone gene and behavioral inhibition in children at risk for panic disorder. Biol. Psychiatr. 2005, 57, 1485–1492.
117. Bradley, R.G.; Binder, E.B.; Epstein, M.P.; Tang, Y.; Nair, H.P.; Liu, W.; Gillespie, C.F.; Berg, T.; Evces, M.; Newport, D.J.; et al. Influence of child abuse on adult depression: Moderation by the corticotropin-releasing hormone receptor gene. Arch. Gen. Psychiatr. 2008, 65, 190–200.
118. Kranzler, H.R.; Feinn, R.; Nelson, E.C.; Covault, J.; Anton, R.F.; Farrer, L.; Gelernter, J.A. CRHR1 haplotype moderates the effect of adverse childhood experiences on lifetime risk of major depressive episode in African-American women. Am. J. Med. Genet. B 2011, 156B, 960–968.
119. Tyrka, A.R.; Price, L.H.; Gelernter, J.; Schepker, C.; Anderson, G.M.; Carpenter, L.L. Interaction of childhood maltreatment with the corticotropin-releasing hormone receptor gene: Effects on hypothalamic-pituitary-adrenal axis reactivity. Biol. Psychiatr. 2009, 66, 681–685.
120. Heim, C.; Bradley, B.; Mletzko, T.C.; Deveau, T.C.; Musselman, D.L.; Nemeroff, C.B.; Ressler, K.J.; Binder, E.B. Effect of childhood trauma on adult depression and neuroendocrine function: Sex-specific moderation by CRH receptor 1 gene. Front. Behav. Neurosci. 2009, 3, 41.
121. Polanczyk, G.; Caspi, A.; Williams, B.; Price, T.S.; Danese, A.; Sugden, K.; Uher, R.; Poulton, R.; Moffitt, T.E. Protective effect of CRHR1 gene variants on the development of adult depression following childhood maltreatment: Replication and extension. Arch. Gen. Psychiatr. 2009, 66, 978–985.
122. Grabe, H.J.; Schwahn, C.; Appel, K.; Mahler, J.; Schulz, A.; Spitzer, C.; Fenske, K.; Barnow, S.; Lucht, M.; Freyberger, H.J.; et al. Childhood maltreatment, the corticotropin-releasing hormone receptor gene and adult depression in the general population. Am. J. Med. Genet. B 2010, 153B, 1483–1493.
123. Pitts, M.W.; Todorovic, C.; Blank, T.; Takahashi, L.K. The central nucleus of the amygdala and corticotropin-releasing factor: Insights into contextual fear memory. J. Neurosci. 2009, 29, 7379–7388.
124. Roozendaal, B.; Schelling, G.; McGaugh, J.L. Corticotropin-releasing factor in the basolateral amygdala enhances memory consolidation via an interaction with the beta-adrenoceptor-cAMP pathway: Dependence on glucocorticoid receptor activation. J. Neurosci. 2008, 28, 6642–6651.
125. Papiol, S.; Arias, B.; Gastó, C.; Gutiérrez, B.; Catalán, R.; Fañanás, L. Genetic variability at HPA axis in major depression and clinical response to antidepressant treatment. J. Affect. Disord. 2007, 104, 83–90.
126. Licinio, J.; O’Kirwan, F.; Irizarry, K.; Merriman, B.; Thakur, S.; Jepson, R.; Lake, S.; Tantisira, K.G.; Weiss, S.T.; Wong, M.L. Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans. Mol. Psychiatr. 2004, 9, 1075–1082.
127. Liu, Z.; Zhu, F.; Wang, G.; Xiao, Z.; Tang, J.; Liu, W.; Wang, H.; Liu, H.; Wang, X.; Wu, Y.; et al. Association study of corticotropin-releasing hormone receptor1 gene polymorphisms and antidepressant response in major depressive disorders. Neurosci. Lett. 2007, 414, 155–158.
128. Xiao, Z.; Liu, W.; Gao, K.; Wan, Q.; Yang, C.; Wang, H.; Wang, X.; Wang, G.; Liu, Z. Interaction between CRHR1 and BDNF genes increases the risk of recurrent major depressive disorder in Chinese population. PLoS One 2011, 6, e28733.
129. Blomeyer, D.; Treutlein, J.; Esser, G.; Schmidt, M.H.; Schumann, G.; Laucht, M. Interaction between CRHR1 gene and stressful life events predicts adolescent heavy alcohol use. Biol. Psychiatr. 2008, 63, 146–151.
130. Schmid, B.; Blomeyer, D.; Treutlein, J.; Zimmermann, U.S.; Buchmann, A.F.; Schmidt, M.H.; Esser, G.; Rietschel, M.; Banaschewski, T.; Schumann, G.; Laucht, M. Interacting effects of CRHR1 gene and stressful life events on drinking initiation and progression among 19-year-olds. Int. J. Neuropsychopharmacol. 2010, 13, 703–714.
131. Barr, C.S.; Dvoskin, R.L.; Yuan, Q.; Lipsky, R.H.; Gupte, M.; Hu, X.; Zhou, Z.; Schwandt, M.L.; Lindell, S.G.; McKee, M.; et al. CRH haplotype as a factor influencing cerebrospinal fluid levels of corticotropin-releasing hormone, hypothalamic-pituitary-adrenal axis activity, temperament, and alcohol consumption in rhesus macaques. Arch. Gen. Psychiatr. 2008, 65, 934–944.
132. Dahl, J.P.; Doyle, G.A.; Oslin, D.W.; Buono, R.J.; Ferraro, T.N.; Lohoff, F.W.; Berrettini, W.H. Lack of association between single nucleotide polymorphisms in the corticotropin releasing hormone receptor 1 (CRHR1) gene and alcohol dependence. J. Psychiatr. Res. 2005, 39, 475–479.
133. Soyka, M.; Preuss, U.W.; Koller, G.; Zill, P.; Hesselbrock, V.; Bondy, B. No association of CRH1 receptor polymorphism haplotypes, harm avoidance and other personality dimensions in alcohol dependence: Results from the Munich gene bank project for alcoholism. Addict. Biol. 2004, 9, 73–79.
134. Ribbe, K.; Ackermann, V.; Schwitulla, J.; Begemann, M.; Papiol, S.; Grube, S.; Sperling, S.; Friedrichs, H.; Jahn, O.; Sillaber, I.; et al. Prediction of the risk of comorbid alcoholism in schizophrenia by interaction of common genetic variants in the corticotropin-releasing factor system. Arch. Gen. Psychiatr. 2011, 68, 1247–1256.
135. Wasserman, D.; Sokolowski, M.; Rozanov, V.; Wasserman, J. The CRHR1 gene: A marker for suicidality in depressed males exposed to low stress. Genes Brain Behav. 2008, 7, 14–19.
136. De Luca, V.; Tharmalingam, S.; Kennedy, J.L. Association study between the corticotropin-releasing hormone receptor 2 gene and suicidality in bipolar disorder. Eur. Psychiatr. 2007, 22, 282–287.
137. Claes, S.; Villafuerte, S.; Forsgren, T.; Sluijs, S.; Del-Favero, J.; Adolfsson, R.; van Broeckhoven, C. The corticotropin-releasing hormone binding protein is associated with major depression in a population from Northern Sweden. Biol. Psychiatr. 2003, 54, 867–872.
138. Ray, L.A. Stress-induced and cue-induced craving for alcohol in heavy drinkers: Preliminary evidence of genetic moderation by the OPRM1 and CRH-BP genes. Alcohol Clin. Exp. Res. 2011, 35, 166–174.
139. De Luca, V.; Tharmalingam, S.; Zai, C.; Potapova, N.; Strauss, J.; Vincent, J.; Kennedy, J.L. Association of HPA axis genes with suicidal behaviour in schizophrenia. J. Psychopharmacol. 2010, 24, 677–682.
140. Claes, S.J. Corticotropin-releasing hormone (CRH) in psychiatry: From stress to psychopathology. Ann. Med. 2004, 36, 50–61.
141. Austin, M.C.; Janosky, J.E.; Murphy, H.A. Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men. Mol. Psychiatr. 2003, 8, 324–332.
142. Zobel, A. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: The first 20 patients treated. J. Psychiatr. Res. 2000, 34, 171–181.
143. Held, K.; Künzel, H.; Ising, M.; Schmid, D.A.; Zobel, A.; Murck, H.; Holsboer, F.; Steiger, A. Treatment with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with depression. J. Psychiatr. Res. 2004, 38, 129–136.
144. Künzel, H.E.; Zobel, A.W.; Nickel, T.; Ackl, N.; Uhr, M.; Sonntag, A.; Ising, M.; Holsboer, F. Treatment of depression with the CRH-1-receptor antagonist R121919: Endocrine changes and side effects. J. Psychiatr. Res. 2003, 37, 525–533.
145. Coric, V.; Feldman, H.H.; Oren, D.A.; Shekhar, A.; Pultz, J.; Dockens, R.C.; Wu, X.; Gentile, K.A.; Huang, S.P.; Emison, E.; et al. Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. Depress. Anxiety 2010, 27, 417–425.
146. Binneman, B.; Feltner, D.; Kolluri, S.; Shi, Y.; Qiu, R.; Stiger, T. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am. J. Psychiatr. 2008, 165, 617–620.