Conditional mouse mutants highlight mechanisms of corticotropin-releasing hormone effects on stress-coping behavior

被引：107

作者：

Lu, A. ^{[1
]}

Steiner, M. A. ^{[1
]}

Whittle, N. ^{[2
]}

Vogl, A. M. ^{[1
]}

Walser, S. M. ^{[1
]}

Ableitner, M. ^{[1
]}

Refojo, D. ^{[1
]}

Ekker, M. ^{[3
]}

Rubenstein, J. L. ^{[4
]}

Stalla, G. K. ^{[1
]}

Singewald, N. ^{[2
]}

Holsboer, F. ^{[1
]}

Wotjak, C. T. ^{[1
]}

Wurst, W. ^{[1
,5
]}

Deussing, J. M. ^{[1
]}

机构：

[1] Max Planck Inst Psychiat, D-80804 Munich, Germany

[2] Univ Innsbruck, Dept Pharmacol & Toxicol, A-6020 Innsbruck, Austria

[3] Univ Ottawa, Dept Biol, Ctr Adv Res Environm Genom, Ottawa, ON, Canada

[4] Univ Calif San Francisco, Nina Ireland Lab Dev Neurobiol, San Francisco, CA USA

[5] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Dev Genet, Neuherberg, Germany

来源：

MOLECULAR PSYCHIATRY | 2008年 / 13卷 / 11期

关键词：

corticotropin-releasing hormone; depression; forced swim test; HPA axis; ROSA26; DMP696;

D O I：

10.1038/mp.2008.51

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Hypersecretion of central corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of affective disorders. Both, basic and clinical studies suggested that disrupting CRH signaling through CRH type 1 receptors (CRH-R1) can ameliorate stress-related clinical conditions. To study the effects of CRH-R1 blockade upon CRH-elicited behavioral and neurochemical changes we created different mouse lines overexpressing CRH in distinct spatially restricted patterns. CRH overexpression in the entire central nervous system, but not when overexpressed in specific forebrain regions, resulted in stress-induced hypersecretion of stress hormones and increased active stress-coping behavior reflected by reduced immobility in the forced swim test and tail suspension test. These changes were related to acute effects of overexpressed CRH as they were normalized by CRH-R1 antagonist treatment and recapitulated the effect of stress-induced activation of the endogenous CRH system. Moreover, we identified enhanced noradrenergic activity as potential molecular mechanism underlying increased active stress-coping behavior observed in these animals. Thus, these transgenic mouse lines may serve as animal models for stress-elicited pathologies and treatments that target the central CRH system.

引用

页码：1028 / 1042

页数：15

共 60 条

[1] IMMUNOCYTOCHEMICAL EVIDENCE FOR STIMULATORY CONTROL BY THE VENTRAL NORADRENERGIC BUNDLE OF PARVOCELLULAR NEURONS OF THE PARAVENTRICULAR NUCLEUS SECRETING CORTICOTROPIN RELEASING HORMONE AND VASOPRESSIN IN RATS [J].