Blocking metabotropic glutamate receptor subtype 5 relieves maladaptive chronic stress consequences
Blocking metabotropic glutamate receptor subtype 5 relieves maladaptive chronic stress consequences
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DOI：
10.1016/j.bbi.2016.08.007
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发表时间：
2017-01
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通讯作者：
D. Peterlik;Christina Stangl;Amélie Bauer;A. Bludau;J. Keller;Dominik Grabski;Tobias Killian;D. Schmidt;Franziska Zajicek;G. Jaeschke;L. Lindemann;S. Reber;P. Flor;Nicole Uschold-Schmidt
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作者：
D. Peterlik;Christina Stangl;Amélie Bauer;A. Bludau;J. Keller;Dominik Grabski;Tobias Killian;D. Schmidt;Franziska Zajicek;G. Jaeschke;L. Lindemann;S. Reber;P. Flor;Nicole Uschold-Schmidt
与压力有关的精神疾病和躯体形式障碍的病因学和药物治疗是高度未满足的医疗需求领域。因此，具有慢性和心理社会因素的压力源对健康的风险最大。尽管代谢型谷氨酸受体亚型5（mGlu 5）在急性应激诱导的行为和生理学方面得到了很好的研究，但实际上对其在慢性心理社会应激中的潜在参与一无所知。使用mGlu 5负变构调节剂CTEP（2-氯-4-[2-[2，5-二甲基-1-[4-（三氟甲氧基）苯基]咪唑-4基]乙炔基]吡啶），临床活性药物Basimglurant的密切类似物-但针对啮齿动物研究以及mGlu 5进行了优化缺陷小鼠与雄性从属小鼠模型相结合（称为CSC，慢性下属殖民地住房），我们表明，mGlu 5介导多种生理，免疫和行为后果的慢性心理社会应激暴露。例如，CTEP剂量依赖性地缓解下丘脑-垂体-肾上腺轴功能障碍、结肠炎症以及CSC诱导的先天性焦虑增加;小鼠中mGlu 5的基因消融在很大程度上再现了CTEP的应激保护作用，并且还改善了CSC诱导的生理性焦虑。有趣的是，CSC还诱导了海马体中mGlu 5的上调，海马体是一个调节压力的大脑区域。总之，我们的研究结果提供的证据表明，mGlu 5是一个重要的调解人的范围广泛的慢性心理社会压力引起的变化和一个潜在的有价值的药物靶点，用于治疗慢性压力相关的病理在男人。
Etiology and pharmacotherapy of stress-related psychiatric conditions and somatoform disorders are areas of high unmet medical need. Stressors holding chronic plus psychosocial components thereby bear the highest health risk. Although the metabotropic glutamate receptor subtype 5 (mGlu5) is well studied in the context of acute stress-induced behaviors and physiology, virtually nothing is known about its potential involvement in chronic psychosocial stress. Using the mGlu5 negative allosteric modulator CTEP (2-chloro-4-[2-[2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]imidazol-4yl]ethynyl]pyridine), a close analogue of the clinically active drug basimglurant – but optimized for rodent studies, as well as mGlu5-deficient mice in combination with a mouse model of male subordination (termed CSC, chronic subordinate colony housing), we demonstrate that mGlu5 mediates multiple physiological, immunological, and behavioral consequences of chronic psychosocial stressor exposure. For instance, CTEP dose-dependently relieved hypothalamo-pituitary-adrenal axis dysfunctions, colonic inflammation as well as the CSC-induced increase in innate anxiety; genetic ablation of mGlu5 in mice largely reproduced the stress-protective effects of CTEP and additionally ameliorated CSC-induced physiological anxiety. Interestingly, CSC also induced an upregulation of mGlu5 in the hippocampus, a stress-regulating brain area. Taken together, our findings provide evidence that mGlu5 is an important mediator for a wide range of chronic psychosocial stress-induced alterations and a potentially valuable drug target for the treatment of chronic stress-related pathologies in man.