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CRH signaling. Molecular specificity for drug targeting in the CNS.
Ann N Y Acad Sci 2009; 1179:106-19AN

Abstract

There is an urgent need to generate new drugs or improve existing ones in the pharmacology of mood disorders. The corticotropin-releasing hormone (CRH) system is closely involved in the development and course of depression, and drugs targeting this system arguably offer hope to improve the current tools for drug treatment of depression. Recent clinical studies in depressed patients showed that CRHR1 antagonists improve clinical symptoms of anxiety and depression and reduce stress hormone release following psychosocial stress. These effects of CRHR1 antagonists were not associated with reduced secretory capacity of corticotrophic cells because of CRH receptor abundance at the pituitary level, which contrasts with CRH receptors in the brain. This is in accordance with previous studies showing that CRH injections into the mouse brain activate MAPK pathways in a brain region-specific manner pointing toward differences in signaling pathways beyond the receptor level. We will highlight this and discuss how these brain area-specific differences may offer opportunities for drug discovery. An additional puzzle in the search of new targets for depression is the lack of bona fide animal models helping to discover the antidepressants that are not monoamine based. We recently developed a conditional mouse model that overexpresses CRH in a spatio-temporal-regulated fashion and permits to dissect precisely the contribution of different brain areas to the CRH-dependent behaviors. Recent findings obtained with this mouse model and its usefulness in the context of the CRH-dependent, region-specific changes in depression will be discussed.

Authors+Show Affiliations

Max-Planck Institute of Psychiatry, Munich, Germany. holsboer@mpipsykl.mpg.deNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

19906235

Citation

Refojo, Damian, and Florian Holsboer. "CRH Signaling. Molecular Specificity for Drug Targeting in the CNS." Annals of the New York Academy of Sciences, vol. 1179, 2009, pp. 106-19.
Refojo D, Holsboer F. CRH signaling. Molecular specificity for drug targeting in the CNS. Ann N Y Acad Sci. 2009;1179:106-19.
Refojo, D., & Holsboer, F. (2009). CRH signaling. Molecular specificity for drug targeting in the CNS. Annals of the New York Academy of Sciences, 1179, pp. 106-19. doi:10.1111/j.1749-6632.2009.04983.x.
Refojo D, Holsboer F. CRH Signaling. Molecular Specificity for Drug Targeting in the CNS. Ann N Y Acad Sci. 2009;1179:106-19. PubMed PMID: 19906235.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CRH signaling. Molecular specificity for drug targeting in the CNS. AU - Refojo,Damian, AU - Holsboer,Florian, PY - 2009/11/13/entrez PY - 2009/11/13/pubmed PY - 2009/12/16/medline SP - 106 EP - 19 JF - Annals of the New York Academy of Sciences JO - Ann. N. Y. Acad. Sci. VL - 1179 N2 - There is an urgent need to generate new drugs or improve existing ones in the pharmacology of mood disorders. The corticotropin-releasing hormone (CRH) system is closely involved in the development and course of depression, and drugs targeting this system arguably offer hope to improve the current tools for drug treatment of depression. Recent clinical studies in depressed patients showed that CRHR1 antagonists improve clinical symptoms of anxiety and depression and reduce stress hormone release following psychosocial stress. These effects of CRHR1 antagonists were not associated with reduced secretory capacity of corticotrophic cells because of CRH receptor abundance at the pituitary level, which contrasts with CRH receptors in the brain. This is in accordance with previous studies showing that CRH injections into the mouse brain activate MAPK pathways in a brain region-specific manner pointing toward differences in signaling pathways beyond the receptor level. We will highlight this and discuss how these brain area-specific differences may offer opportunities for drug discovery. An additional puzzle in the search of new targets for depression is the lack of bona fide animal models helping to discover the antidepressants that are not monoamine based. We recently developed a conditional mouse model that overexpresses CRH in a spatio-temporal-regulated fashion and permits to dissect precisely the contribution of different brain areas to the CRH-dependent behaviors. Recent findings obtained with this mouse model and its usefulness in the context of the CRH-dependent, region-specific changes in depression will be discussed. SN - 1749-6632 UR - https://www.unboundmedicine.com/medline/citation/19906235/CRH_signaling__Molecular_specificity_for_drug_targeting_in_the_CNS_ L2 - https://doi.org/10.1111/j.1749-6632.2009.04983.x DB - PRIME DP - Unbound Medicine ER -