A new addiction model: Relapse triggered by cognitive stress

描述(由申请人提供)：目前，临床医生对精神刺激剂上瘾的人几乎没有希望-多达10人中有9人会在完成康复计划的第一年内复发。人类对成瘾的研究通过用心理应激源诱导复吸来模拟真实世界的体验。遗憾的是，目前缺乏有效的方法来诱导啮齿动物的心理应激，大多数研究依赖于生理应激源。这一需求在这里通过认知压力(成本)诱导的恢复模型来解决，该模型使用非侵入性方法来诱导认知应激(例如，不需要脚部电击等生理应激源)。中心假设是，心理压力将模拟药物滥用者在康复后所经历的认知压力，并恢复成年动物的寻药行为。除了是在成年后引发认知压力的一种方式外，我们使用早期生活压力提醒作为压力来源之一，与成瘾有直接联系。在吸毒者中，自我报告童年虐待和忽视的比例非常高，高达80%-90%。与此一致的是，早期生活压力的动物模型显示，成年后对滥用药物的易感性增加。该项目将确定最有效地恢复寻药行为的认知应激源，以及确定由成本诱导的恢复行为所激活的大脑区域。工作假设是，急性心理压力源或嗅觉提醒早期生活压力将有效地恢复成年啮齿动物的药物寻找，并招募对情绪记忆和基于奖励的策略至关重要的大脑区域。该方法包括将常见和广泛使用的行为应激源(例如新生儿隔离)与恢复寻求毒品简单结合起来。此外，通过对特定神经元亚型活动的细胞成像，将识别由成本诱导的恢复所激活的大脑区域。这项拟议的研究的贡献很简单，但影响很大-S希望产生第一个通过心理压力恢复寻药行为的动物模型。通过反映药物滥用者在康复后所经历的压力，成本诱导的恢复将为治疗发现工作提供一个具有前所未有的临床相关性的新平台。这一模式将向整个FID提供，加快NIDA和NIAAA治疗与药物和酒精有关的滥用和成瘾的任务。这一方法的进一步创新在于整合和提升了完善的行为方案，以一种全新的方式调查吸毒复发；一种反映成瘾个人经历的康复后斗争的方式。重要的是 出于同样的原因，这种方法成功的可能性很高--它涉及到由在行为操纵和成瘾研究方面拥有丰富经验的实验室直接整合完善的行为规范。 公共卫生相关性：通过提供第一种模拟心理压力引起的复发的方法，拟议的项目有望提高基础研究工作的临床相关性。预计这将深刻影响该领域识别小说的能力 预防复发的治疗靶点。重要的是，这一无价工具将向该领域的所有研究人员提供，为NIDA和NIAAA努力开发有效的药物滥用复发治疗方法做出重大贡献。

DESCRIPTION (provided by applicant): Currently, clinicians can offer little hope to people addicted to psychostimulants - as many as 9 out of 10 will relapse within the first year of completing a rehabilitation program. Human studies of addiction model real world experience by inducing relapse with psychological stressors. Unfortunately, effective methods for inducing psychological stress in rodents are lacking at present, with most studies relying on physiological stressors. This need is addressed here with a Cognitive Stress (CoSt)-induced reinstatement model that uses non- invasive methods to induce cognitive stress (e.g. no need for physiologic stressors such as foot shock). The central hypothesis is that psychological stress will model the cognitive stress experienced by substance abusers after rehabilitation and reinstate drug seeking behavior in adult animals. In addition to being a means to elicit cognitive stress in adulthood, our use of early life stress reminders as one of the stressors has direct connections to addiction. Self-reports of childhood abuse and neglect are extremely high in addicts, up to 80- 90%. Consistent with this, animal models of early life stress reveal an increased vulnerability to drugs of abuse in adulthood. This project will determine the cognitive stressors that most effectively reinstate drug seeking behavior, as well as identify the brain regions that are activated by CoSt-induced reinstatement. The working hypothesis is that an acute psychological stressor or an olfactory reminder of early life stress will effectively reinstate drug seeking in ault rodents and recruit brain regions critical for emotional memory and reward- based strategies. The approach involves the simple union of common and widely used behavioral stressors (e.g. neonatal isolation) with reinstatement of drug seeking. In additional, through cellular imaging of activity in specific neuronal subtypes, the brain regions activated by CoSt-induced reinstatement will be identified. The contribution of the proposed research is simple, yet highly impactful - it s expected to yield the first animal model in which drug seeking behavior is reinstated by psychological stress. By mirroring the stress that substance abusers experience after rehabilitation, CoSt-induced reinstatement will provide a new platform with unprecedented clinical relevance for therapeutic discovery efforts. This model will be available to the entire fild, accelerating the missions of NIDA and NIAAA to treat substance and alcohol-related abuse and addiction. Further innovation of this approach lies in the integration and elevation of well-established behavior proto- cols to investigate relapse to drug seeking in an entirely new way; one that mirrors the post-rehabilitation struggle experienced by addicted individuals. Importantly, this approach has a high likelihood of success for the same reason - it involves the straightforward integration of well-established behavior protocols by a laboratory that has extensive experience with behavioral manipulations and addiction research. PUBLIC HEALTH RELEVANCE: By providing the first method to model relapse induced by psychological stress, the proposed project is anticipated to improve the clinical relevance of basic research efforts. This is expected to profoundly impact the field's ability to identify novel therapeutic targets for relapse prevention. Importantly, this invaluable tool will be available to ll researchers in the field, contributing significantly to the NIDA and NIAAA efforts towards developing effective treatments for substance abuse relapse.