Probing for neuroadaptations to unpredictable stressors in addiction: translational methods and emerging evidence

Abstract: 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 1) rodent behavioral neuroscience on stress neuroadaptations in addiction, 2) rodent affective neuroscience science on startle potentiation, and 3) 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 testbed to encourage tight translation and reverse translation between animal models and human clinical research on stress neuroadaptations. Experimental medicine approaches focused on unpredictable stressors holds high promise to identify, repurpose, or refine pharmacological and psychosocial interventions for addiction.

摘要：压力因素明显对人类的成瘾病因学和复吸过程产生贡献，然而，我们对特定机制的理解仍然有限。啮齿动物模型在成瘾研究中提供了必要的力量、灵活性和精确度，以阐明压力因素在酒精和其他药物使用中的因果作用及其具体机制。本综述描述了一项研究计划，该计划利用对不可预测压力的惊吓增强效应，能够有效地在动物模型与针对人类成瘾中压力神经适应的临床研究之间进行转化。该研究建立在三个独立证据支柱的坚实基础之上：1）啮齿动物行为神经科学在成瘾中的压力神经适应，2）啮齿动物情感神经科学在惊吓增强效应方面的研究，以及3）人类成瘾与情感科学中的惊吓增强效应。啮齿动物的应力神经适应模型表明，在慢性酒精和其他药物使用后，中央外延杏仁核中的促肾上腺皮质激素释放因子和去甲肾上腺素通路发生适应，这些通路介导了药物依赖啮齿动物的焦虑行为和压力诱导的复吸。基础情感神经科学表明，这些相同的神经机制在特定情况下（与可预测的压力因素相比）参与了惊吓增强效应。我们相信，这些证据基础的整合应使我们关注不可预测压力在成瘾病因学和复吸中的作用。在不可预测压力任务中的惊吓增强效应被提议为一个吸引人且灵活的测试平台，以促进动物模型与人类临床研究在压力神经适应之间的紧密转化和反向转化。专注于不可预测压力的实验医学方法在识别、重新利用或改进针对成瘾的药理和心理社会干预方面具有巨大的潜力。