Lu A, Steiner M A, Whittle N, Vogl A M, Walser S M, Ableitner M, Refojo D, Ekker M, Rubenstein J L, Stalla G K, Singewald N, Holsboer F, Wotjak C T, Wurst W, Deussing J M
Max Planck Institute of Psychiatry, Munich, Germany.
Mol Psychiatry. 2008 Nov;13(11):1028-42. doi: 10.1038/mp.2008.51. Epub 2008 May 13.
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.
中枢促肾上腺皮质激素释放激素（CRH）分泌过多与情感障碍的病理生理学有关。基础研究和临床研究均表明，通过1型CRH受体（CRH-R1）破坏CRH信号传导可改善与应激相关的临床状况。为了研究CRH-R1阻断对CRH引发的行为和神经化学变化的影响，我们创建了不同的小鼠品系，这些品系以不同的空间限制模式过表达CRH。在整个中枢神经系统中过表达CRH，但在特定前脑区域过表达时则不会，会导致应激激素的应激诱导性分泌过多，并增加主动应激应对行为，这在强迫游泳试验和悬尾试验中表现为不动时间减少。这些变化与过表达CRH的急性效应有关，因为它们通过CRH-R1拮抗剂治疗得以恢复正常，并重现了应激诱导的内源性CRH系统激活的效应。此外，我们确定增强的去甲肾上腺素能活性是这些动物中观察到的主动应激应对行为增加的潜在分子机制。因此，这些转基因小鼠品系可作为应激引发的病理和针对中枢CRH系统的治疗的动物模型。
