Hauger Richard L, Risbrough Victoria, Brauns Olaf, Dautzenberg Frank M
San Diego VA Healthcare System, University of California San Diego, La Jolla, 929093-0603, USA.
CNS Neurol Disord Drug Targets. 2006 Aug;5(4):453-79. doi: 10.2174/187152706777950684.
Corticotropin-releasing factor (CRF) and the related urocortin peptides mediate behavioral, cognitive, autonomic, neuroendocrine and immunologic responses to aversive stimuli by activating CRF(1) or CRF(2) receptors in the central nervous system and anterior pituitary. Markers of hyperactive central CRF systems, including CRF hypersecretion and abnormal hypothalamic-pituitary-adrenal axis functioning, have been identified in subpopulations of patients with anxiety, stress and depressive disorders. Because CRF receptors are rapidly desensitized in the presence of high agonist concentrations, CRF hypersecretion alone may be insufficient to account for the enhanced CRF neurotransmission observed in these patients. Concomitant dysregulation of mechanisms stringently controlling magnitude and duration of CRF receptor signaling also may contribute to this phenomenon. While it is well established that the CRF(1) receptor mediates many anxiety- and depression-like behaviors as well as HPA axis stress responses, CRF(2) receptor functions are not well understood at present. One hypothesis holds that CRF(1) receptor activation initiates fear and anxiety-like responses, while CRF(2) receptor activation re-establishes homeostasis by counteracting the aversive effects of CRF(1) receptor signaling. An alternative hypothesis posits that CRF(1) and CRF(2) receptors contribute to opposite defensive modes, with CRF(1) receptors mediating active defensive responses triggered by escapable stressors, and CRF(2) receptors mediating anxiety- and depression-like responses induced by inescapable, uncontrollable stressors. CRF(1) receptor antagonists are being developed as novel treatments for affective and stress disorders. If it is confirmed that the CRF(2) receptor contributes importantly to anxiety and depression, the development of small molecule CRF(2) receptor antagonists would be therapeutically useful.
促肾上腺皮质激素释放因子（CRF）及相关的尿皮质素肽通过激活中枢神经系统和垂体前叶中的CRF(1)或CRF(2)受体，介导对厌恶刺激的行为、认知、自主神经、神经内分泌和免疫反应。在焦虑、应激和抑郁症患者亚群中，已发现中枢CRF系统功能亢进的标志物，包括CRF分泌过多和下丘脑-垂体-肾上腺轴功能异常。由于在高激动剂浓度存在的情况下，CRF受体会迅速脱敏，因此仅CRF分泌过多可能不足以解释在这些患者中观察到的CRF神经传递增强。严格控制CRF受体信号强度和持续时间的机制同时失调也可能导致这一现象。虽然CRF(1)受体介导许多焦虑和抑郁样行为以及HPA轴应激反应已得到充分证实，但目前对CRF(2)受体的功能了解尚少。一种假说是，CRF(1)受体激活引发恐惧和焦虑样反应，而CRF(2)受体激活通过抵消CRF(1)受体信号的厌恶作用来重新建立内稳态。另一种假说认为，CRF(1)和CRF(2)受体促成相反的防御模式，CRF(1)受体介导由可逃避应激源触发的主动防御反应，而CRF(2)受体介导由不可逃避、无法控制的应激源诱导的焦虑和抑郁样反应。CRF(1)受体拮抗剂正在被开发为治疗情感和应激障碍的新型药物。如果证实CRF(2)受体对焦虑和抑郁有重要作用，那么开发小分子CRF(2)受体拮抗剂将具有治疗价值。
