Therapeutic utility of non-peptidic CRF1 receptor antagonists in anxiety, depression, and stress-related disorders: evidence from animal models.
Therapeutic utility of non-peptidic CRF1 receptor antagonists in anxiety, depression, and stress-related disorders: evidence from animal models.
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DOI：
10.1016/j.pharmthera.2010.08.011
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发表时间：
2010-12
影响因子：
13.5
通讯作者：
Cain, Christopher K.
中科院分区：
文献类型：
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作者：
Kehne, John H.;Cain, Christopher K.
对威胁性压力源的适应性反应对生存至关重要。促肾上腺皮质激素释放因子1型（CRF1）受体在应激反应系统通路中的功能失调过度激活与应激相关的精神病理有关，CRF1受体拮抗剂（CRAs）已被提出作为一种新的治疗药物。本文回顾了CRA在多种应激动物模型中检测抗焦虑药和/或抗抑郁药的作用，目的是评估其在抑郁、焦虑和其他应激相关疾病中的潜在治疗效用。CRAs在动物中具有独特的表型，与经典抗抑郁药和抗焦虑药既有相似之处，也有不同之处。cra通常是行为沉默的，这表明CRF1受体通常处于低基础激活状态。CRAs通过阻断垂体和可能的脑CRF1受体来减少应激源诱导的HPA轴激活，这可能改善慢性应激诱导的病理。在对抗焦虑药和/或抗抑郁药敏感的动物模型中，cra通常在高应激水平的动物中更活跃，这可能会最大化CRF1受体的过度激活。临床研究表明，CRAs具有良好的耐受性和安全性，但迄今为止在重度抑郁症、广泛性焦虑症或肠易激综合征方面缺乏令人信服的疗效。cra可能最适合于应激源明显导致潜在病理的疾病（例如，创伤后应激障碍，早期生活创伤，戒断/戒断成瘾物质），尽管需要进行大量工作来探索这些可能性。在提高当前动物模型的翻译价值的背景下，探讨CRF1受体功能障碍与应激相关精神病理之间的遗传、发育和环境因素的不断发展的文献。
Adaptive responding to threatening stressors is of fundamental importance for survival. Dysfunctional hyperactivation of corticotropin releasing factor type-1 (CRF1) receptors in stress response system pathways is linked to stress-related psychopathology and CRF1 receptor antagonists (CRAs) have been proposed as novel therapeutic agents. CRA effects in diverse animal models of stress that detect anxiolytics and/or antidepressants are reviewed, with the goal of evaluating their potential therapeutic utility in depression, anxiety, and other stress-related disorders. CRAs have a distinct phenotype in animals that has similarities to, and differences from, those of classic antidepressants and anxiolytics. CRAs are generally behaviorally silent, indicating that CRF1 receptors are normally in a state of low basal activation. CRAs reduce stressor-induced HPA axis activation by blocking pituitary and possibly brain CRF1 receptors which may ameliorate chronic stress-induced pathology. In animal models sensitive to anxiolytics and/or antidepressants, CRAs are generally more active in those with high stress levels, conditions which may maximize CRF1 receptor hyperactivation. Clinically, CRAs have demonstrated good tolerability and safety, but have thus far lacked compelling efficacy in major depressive disorder, generalized anxiety disorder, or irritable bowel syndrome. CRAs may be best suited for disorders in which stressors clearly contribute to the underlying pathology (e.g. posttraumatic stress disorder, early life trauma, withdrawal/abstinence from addictive substances), though much work is needed to explore these possibilities. An evolving literature exploring the genetic, developmental and environmental factors linking CRF1 receptor dysfunction to stress-related psychopathology is discussed in the context of improving the translational value of current animal models.
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影响因子：
4.1
作者：
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通讯作者：
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