Hostname: page-component-84b7d79bbc-g5fl4 Total loading time: 0 Render date: 2024-07-28T20:29:03.191Z Has data issue: false hasContentIssue false
  • English
  • Français

CRHR1 Antagonists as Novel Treatment Strategies

Published online by Cambridge University Press:  07 November 2014

Florian Holsboer
Get access Rights & Permissions [Opens in a new window]

Abstract

Research has provided considerable evidence for the hypothesis that corticotropin-releasing hormone (CRH), the key central coordinator of stress-hormone homeostasis, also plays a role in the development and course of depression and anxiety disorders. Studies using animal models of anxiety, as well as mouse mutants, in which the gene coding for the CRH type 1 receptor (CRHR1) was genetically deleted supported the notion that enhanced CRH/CRHR1 signaling underlies depression and anxiety disorders. Therefore, a number of small nonpeptide molecules that antagonize CRHR1 have been developed. In animal models, these molecules had anxiolytic and other stress-alleviating effects. An initial clinical study showed that CRHR1 antagonism has beneficial effects on depression and anxiety symptoms at doses unharmful to neuroendocrine stress responsivity.

Type
Feature Articles
Information
CNS Spectrums , Volume 6 , Issue 7: Novel Perspectives of Central CRF/HPA Axis Dysfunction , July 2001 , pp. 590 - 594
Copyright
Copyright © Cambridge University Press 2001

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

1. Owens, MJ, Nemeroff, CB. Physiology and pharmacology of corticotropinreleasing factor. Pharmacol Rev. 1991;43:425–473.Google ScholarPubMed
2. Stenzel-Poore, MP, Heinrichs, SC, Rivest, S, et al. Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior. J Neurosci. 1994;14:2579–2584.CrossRefGoogle ScholarPubMed
3. Skutella, T, Montkowski, A, Stöhr, T, et al. Corticotropin-releasing hormone (CRH) antisense oligodeoxynucleotide treatment attenuates social defeat-induced anxiety in rats. Cell Mol Neurobiol. 1994;14:579–588.CrossRefGoogle ScholarPubMed
4. Skutella, T, Probst, JC, Renner, R, et al. Corticotropin-releasing hormone receptor (type I) antisense targeting reduces anxiety. Neuroscience. 1998;85:795–805.CrossRefGoogle ScholarPubMed
5. Nemeroff, CB, Widerlov, E, Bissette, G, et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science. 1984;226:1342–1344.CrossRefGoogle ScholarPubMed
6. Gold, PW, Chrousos, G, Kellner, C, et al. Psychiatric implications of basic and clinical studies with corticotropin-releasing factor. Am J Psychiatry. 1984;141:619–627.Google ScholarPubMed
7. Holsboer, F, von Bardeleben, U, Gerken, A, et al. Blunted corticotropin and normal cortisol response to human corticotropin-releasing factor in depression. N Engl J Med. 1984;311:1127.Google ScholarPubMed
8. Mitchell, AJ. The role of corticotropin releasing factor in depressive illness: a critical review. Neurosci Biobehav Rev. 1998;22:635–651.CrossRefGoogle ScholarPubMed
9. De Bellis, MD, Gold, PW, Geracioti, TD Jr, et al. Association of fluoxetine treatment with reduction in CSF concentration of corticotropin releasing hormone and argenine vasopressin in patients with major depression. Am J Psychiatry. 1993;656:656–657.Google Scholar
10. Heuser, I, Bissette, G, Dettling, M, et al. Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: response to amitriptyline treatment. Depress Anxiety. 1998;8:71–79.3.0.CO;2-N>CrossRefGoogle ScholarPubMed
11. Banki, CM, Karmacsi, L, Bissette, G, Nemeroff, CB. CSF corticotropin-releasing hormone and somatostatin in major depression: response to antidepressant treatment and relapse. Eur Neuropsychopharmacol. 1992;2:107–113.CrossRefGoogle ScholarPubMed
12. Zobel, AW, Nickel, T, Sonntag, A, et al. Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression: a prospective study. J Psychiatr Res. 2001; in press.Google Scholar
13. Raadsheer, FC, Hoogendijk, WJG, Stam, FC, et al. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology. 1994;60:433–436.CrossRefGoogle ScholarPubMed
14. Holsboer, F, Barden, N. Antidepressants and HPA regulation. Endocr Rev. 1996;17:187–205.CrossRefGoogle Scholar
15. Reul, JMHM, Stec, I, Söder, M, Holsboer, F. Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system. Endocrinology. 1993;133:312–320.CrossRefGoogle ScholarPubMed
16. Reul, JMHM, Labeur, MS, Grigoriadis, DE, et al. Hypothalamic-pituitary-adrenocortical axis changes in the rat after long-term treatment with the reversible monoamine oxidase-A inhibitor moclobemide. Neuroendocrinology. 1994;60:509–519.CrossRefGoogle ScholarPubMed
17. Montkowski, A, Barden, N, Wotjak, C, et al. Long-term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function. J Neuroendocrinol. 1995;7:841–845.CrossRefGoogle ScholarPubMed
18. Ströhle, A, Romeo, E, Hermann, B, et al. Concentrations of 3 a-reduced neuroactive steroids and their precursors in plasma of patients with major depression and after clinical recovery. Biol Psychiatry. 1999;45:274–277.CrossRefGoogle Scholar
19. Patchev, VK, Shoaib, M, Holsboer, F, Almeida, OFX. The neurosteroid tetrahydroprogesterone counteracts CRH-induced anxiety and alters the release and gene expression of CRH in the rat hypothalamus. Neuroscience. 1994;62:265–271.CrossRefGoogle Scholar
20. Holsboer, F. The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. J Psychiatr Res. 1999;33:181–214.CrossRefGoogle ScholarPubMed
21. Rivier, J, Rivier, C, Vale, W. Synthetic competitive antagonists of corticotropin-releasing factor: effect of ACTH secretion in the rat. Science. 1984;224:889–891.CrossRefGoogle ScholarPubMed
22. Chalmers, DT, Lovenberg, TW, De Souza, EB. 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.CrossRefGoogle ScholarPubMed
23. Liebsch, G, Landgraf, R, Gerstberger, R, et al. Chronic infusion of a CRH1 receptor antisense oligodeoxynucleotide into the central nucleus of the amygdala reduced anxiety-related behavior in socially defeated rats. Regul Peptides. 1995;59:229–239.CrossRefGoogle ScholarPubMed
24. Liebsch, G, Landgraf, R, Engelmann, M, et al. Differential behavioural effects of chronic infusion of CRH1 and CRH2 receptor antisense oligonucleotides into the rat brain. J Psychiatr Res. 1999;33:153–163.CrossRefGoogle ScholarPubMed
25. Timpl, P, Spanagel, R, Sillaber, I, et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nature Genet. 1998;19:162–166.CrossRefGoogle ScholarPubMed
26. Smith, GW, Aubry, J-M, Dellu, F, et al. Corticotropin-releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron. 1998;20:1093–1102.CrossRefGoogle ScholarPubMed
27. Linthorst, ACE, Flachskamm, C, Hopkins, SJ, et al. Long-term intracere-broventricular infusion of corticotropin-releasing hormone alters neuroendocrine, neuroehemical, autonomic, behavioral, and cytokine responses to a systemic inflammatory challenge. J Neurosci. 1997;17:4448–4460.CrossRefGoogle Scholar
28. McCarthy, JR, Heinrichs, SC, Grigoriadis, DE. Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications. Curr Pharm Des. 1999;5:289–315.CrossRefGoogle ScholarPubMed
29. Schulz, DW, Mansbach, RS, Sprouse, J, et al. CP-154,526: a potent and selective nonpeptide antagonist of corticotropin releasing factor receptors. Proc Nail Acad Sci U S A. 1996;93:10477–10482.CrossRefGoogle ScholarPubMed
30. Lundkvist, J, Chai, Z, Teheranian, R, et al. A nonpeptide corticotropin releasing factor receptor antagonist attenuates fever and exhibits anxiolytic-like activity. Eur J Pharmacol. 1996;309:195–200.CrossRefGoogle Scholar
31. Mansbach, RS, Brooks, EN, Chen, YL. Antidepressant-like effects of CP-154,526, a selective CRF1 receptor antagonist. Eur J Pharmacol. 1997;323:21–26.CrossRefGoogle ScholarPubMed
32. Hikichi, T, Akiyoshi, J, Yamamoto, Y, et al. Suppression of conditioned fear by administration of CRF receptor antagonist CP-154, 526. Pharmacopsychiatry. 2000;33:189–193.CrossRefGoogle ScholarPubMed
33. Wong, M-L, Kling, A, Munson, PJ, et al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci U S A. 2000;97:325–330.CrossRefGoogle ScholarPubMed
34. Habib, KE, Weld, KP, Rice, KC, et al. Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates. Proc Natl Acad Sci U S A. 2000;97:6079–6084.CrossRefGoogle ScholarPubMed
35. Hodge, CN, Aldrich, PE, Zelda, R, et al. Corticotropin-releasing hormone receptor antagonists: framework design and synthesis guided by ligand informational studies. J Med Chem. 1999;42:819–832.CrossRefGoogle ScholarPubMed
36. Chaki, S, Okuyama, S, Nakazato, A, et al. In vitro pharmacological profile of nonpeptide CRF1 receptor antagonists, CRA1000 and CRA 1001. Eur J Pharmacol. 1999;371:205–211.Google Scholar
37. Arai, K, Ohata, H, Shibasaki, T. Non-peptide corticotropin-releasing hormone receptor type 1 antagonist reverses restraint stress-induced shortening of sodium pentobarbital-induced sleeping time of rats: evidence that an increase in arousal induced by stress is mediated through CRH receptor type 1. Neurosci Lett. 1998;255:103–106.CrossRefGoogle Scholar
38. Otagiri, A, Wakabayashi, I, Shibasaki, T. Selective corticotropin-releasing factor type 1 receptor antagonist blocks conditioned fear-induced release of noradrenaline in the hypothalamic paraventricular nucleus of rats. J Neuroendocrinology. 2000;12:1022–1026.CrossRefGoogle ScholarPubMed
39. Liebsch, G, Montkowski, A, Holsboer, F, Landgraf, R. Behavioural profiles of two Wistar rat lines selectively bred for high or low anxiety-related behaviour. Behav Brain Res. 1998;94:301–310.CrossRefGoogle ScholarPubMed
40. Keck, M, Welt, T, Wigger, A, et al. The anxiolytic effect of the CRH1 receptor antagonist R121919 depends on innate emotionality in rats. Eur J Neurosci. 2001;13:373–380.CrossRefGoogle Scholar
41.Zobel, A, Nickel, T, Künzel, HE, et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients. J Psychiatr Res. 2000;34:171–181.CrossRefGoogle ScholarPubMed
42. Künzel, HE, Zobel, AW, Sonntag, A et al. Neuroendocrine and clinical chemistry effects of a selective high affinity CRH-R1 antagonist R121919/NBI-30775 in patients with depression. J Psychiatr Res. 2001; in press.Google Scholar