Phillips T J, Reed C, Pastor R
VA Portland Health Care System, Portland Alcohol Research Center, Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, USA; Department of Behavioral Neuroscience, Portland Alcohol Research Center, Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, USA.
Genes Brain Behav. 2015 Jan;14(1):98-135. doi: 10.1111/gbb.12189.
The results of many studies support the influence of the corticotropin-releasing factor (CRF) system on ethanol (EtOH) consumption and EtOH-induced neuroadaptations that are critical in the addiction process. This review summarizes the preclinical data in this area after first providing an overview of the components of the CRF system. This complex system involves hypothalamic and extra-hypothalamic mechanisms that play a role in the central and peripheral consequences of stressors, including EtOH and other drugs of abuse. In addition, several endogenous ligands and targets make up this system and show differences in their involvement in EtOH drinking and in the effects of chronic or repeated EtOH treatment. In general, genetic and pharmacological approaches paint a consistent picture of the importance of CRF signaling via type 1 CRF receptors (CRF(1)) in EtOH-induced neuroadaptations that result in higher levels of intake, encourage alcohol seeking during abstinence and alter EtOH sensitivity. Furthermore, genetic findings in rodents, non-human primates and humans have provided some evidence of associations of genetic polymorphisms in CRF-related genes with EtOH drinking, although additional data are needed. These results suggest that CRF(1) antagonists have potential as pharmacotherapeutics for alcohol use disorders. However, given the broad and important role of these receptors in adaptation to environmental and other challenges, full antagonist effects may be too profound and consideration should be given to treatments with modulatory effects.
许多研究结果支持促肾上腺皮质激素释放因子（CRF）系统对乙醇（EtOH）摄入以及乙醇诱导的神经适应性变化的影响，这些神经适应性变化在成瘾过程中至关重要。本综述首先概述CRF系统的组成部分，然后总结该领域的临床前数据。这个复杂的系统涉及下丘脑和下丘脑外机制，这些机制在应激源（包括乙醇和其他滥用药物）的中枢和外周影响中发挥作用。此外，几种内源性配体和靶点构成了这个系统，并且它们在参与乙醇饮用以及慢性或反复乙醇治疗的效果方面存在差异。一般来说，遗传学和药理学方法一致表明，通过1型CRF受体（CRF(1)）的CRF信号传导在乙醇诱导的神经适应性变化中具有重要作用，这些变化会导致更高的摄入量，在戒酒期间促使觅酒行为，并改变乙醇敏感性。此外，啮齿动物、非人灵长类动物和人类的遗传学研究结果提供了一些证据，表明CRF相关基因的遗传多态性与乙醇饮用有关，不过还需要更多数据。这些结果表明，CRF(1)拮抗剂有潜力作为酒精使用障碍的药物治疗方法。然而，鉴于这些受体在适应环境和其他挑战方面具有广泛而重要的作用，完全拮抗作用可能过于强烈，应考虑采用具有调节作用的治疗方法。
