Kaye Jesse T, Bradford Daniel E, Magruder Katherine P, Curtin John J
University of Wisconsin-Madison, Madison, Wisconsin.
J Stud Alcohol Drugs. 2017 May;78(3):353-371. doi: 10.15288/jsad.2017.78.353.
Stressors clearly contribute to addiction etiology and relapse in humans, but our understanding of specific mechanisms remains limited. Rodent models of addiction offer the power, flexibility, and precision necessary to delineate the causal role and specific mechanisms through which stressors influence alcohol and other drug use. This review describes a program of research using startle potentiation to unpredictable stressors that is well positioned to translate between animal models and clinical research with humans on stress neuroadaptations in addiction. This research rests on a solid foundation provided by three separate pillars of evidence from (a) rodent behavioral neuroscience on stress neuroadaptations in addiction, (b) rodent affective neuroscience on startle potentiation, and (c) human addiction and affective science with startle potentiation. Rodent stress neuroadaptation models implicate adaptations in corticotropin-releasing factor and norepinephrine circuits within the central extended amygdala following chronic alcohol and other drug use that mediate anxious behaviors and stress-induced reinstatement among drug-dependent rodents. Basic affective neuroscience indicates that these same neural mechanisms are involved in startle potentiation to unpredictable stressors in particular (vs. predictable stressors). We believe that synthesis of these evidence bases should focus us on the role of unpredictable stressors in addiction etiology and relapse. Startle potentiation in unpredictable stressor tasks is proposed to provide an attractive and flexible test bed to encourage tight translation and reverse translation between animal models and human clinical research on stress neuroadaptations. Experimental therapeutics approaches focused on unpredictable stressors hold high promise to identify, repurpose, or refine pharmacological and psychosocial interventions for addiction.
应激源显然在人类成瘾的病因和复发中起作用，但我们对具体机制的理解仍然有限。成瘾的啮齿动物模型提供了必要的能力、灵活性和精确性，以阐明应激源影响酒精和其他药物使用的因果作用和具体机制。这篇综述描述了一项利用惊吓增强对不可预测应激源反应的研究计划，该计划非常适合在动物模型和人类临床研究之间进行转化，以研究成瘾中的应激神经适应。这项研究建立在三个独立证据支柱提供的坚实基础之上：(a) 啮齿动物行为神经科学关于成瘾中的应激神经适应；(b) 啮齿动物情感神经科学关于惊吓增强；(c) 人类成瘾和情感科学与惊吓增强。啮齿动物应激神经适应模型表明，在长期使用酒精和其他药物后，中央扩展杏仁核内促肾上腺皮质激素释放因子和去甲肾上腺素回路会发生适应，这些适应介导了依赖药物的啮齿动物的焦虑行为和应激诱导的复吸。基础情感神经科学表明，这些相同的神经机制尤其参与对不可预测应激源（相对于可预测应激源）的惊吓增强。我们认为，综合这些证据基础应使我们关注不可预测应激源在成瘾病因和复发中的作用。在不可预测应激源任务中的惊吓增强被提议提供一个有吸引力且灵活的测试平台，以促进动物模型和人类临床研究在应激神经适应方面的紧密转化和反向转化。专注于不可预测应激源的实验治疗方法很有希望识别、重新利用或改进成瘾的药物和心理社会干预措施。
