A new addiction model: Relapse triggered by cognitive stress

描述（由申请人提供）：目前，临床医生对精神兴奋剂成瘾者几乎没有希望-多达十分之九的人将在完成康复计划的第一年内复发。成瘾模型真实的世界经验的人类研究通过心理应激诱导复吸。不幸的是，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。在此，该需求通过认知应激（CoSt）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，不需要生理应激源，诸如足部电击）。中心假设是，心理压力将模拟物质滥用者在康复后所经历的认知压力，并恢复成年动物的药物寻求行为。除了作为成年后引发认知压力的一种手段，我们使用早期生活压力提醒作为压力源之一与成瘾有直接联系。成瘾者自我报告的童年虐待和忽视的比例极高，高达80- 90%。与此相一致的是，早期生活压力的动物模型揭示了成年后对滥用药物的脆弱性增加。该项目将确定最有效地恢复药物寻求行为的认知应激源，以及确定由成本诱导的恢复激活的大脑区域。工作假设是，急性心理压力或早期生活压力的嗅觉提醒将有效地恢复攻击啮齿动物的药物寻求，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。该方法涉及常见和广泛使用的行为应激源（如新生儿隔离）与恢复药物寻求的简单结合。此外，通过对特定神经元亚型的活动进行细胞成像，将识别由Cost-induced恢复激活的脑区。这项研究的贡献很简单，但却很有影响力--它有望产生第一个通过心理压力恢复药物寻求行为的动物模型。通过反映物质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意义的新平台。这种模式将适用于整个领域，加速NIDA和NIAAA治疗物质和酒精相关滥用和成瘾的使命。这种方法的进一步创新在于整合和提升完善的行为原型，以全新的方式研究药物寻求的复发;这反映了成瘾个体经历的康复后斗争。重要的是， 由于同样的原因，这种方法具有很高的成功可能性--它涉及由在行为操纵和成瘾研究方面具有丰富经验的实验室对完善的行为规程的直接整合。 公共卫生相关性：通过提供第一种方法来模拟由心理压力引起的复发，预计该项目将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新的 预防复发的治疗目标。重要的是，这一宝贵的工具将提供给该领域的所有研究人员，大大有助于NIDA和NIAAA努力开发有效的药物滥用复发治疗方法。

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.