Targeting Foundational Memory Processes in Nicotine Addiction: A Translational Clinical Neuroscience Study of a Retrieval-Extinction Intervention to Reduce Craving & Smoking Behavior

项目摘要：我们最近发表了NIDA资助的一项简短行为研究的结果 旨在减少吸烟者在尝试吸烟时遇到的麻烦渴望的治疗方法 戒烟吧。这种干预是基于越来越多的神经科学研究表明，记忆 对于先前的学习，可以通过呈现与该学习有关的线索来检索。检索到后， 记忆进入一个短暂的脆弱时期，在此期间，它们可以被修改，但在此之后，它们将被修改 重新整合(重新稳定)回长期存储。这种现象的治疗潜力是 最初是在一份科学报告中展示的，在这份报告中，住院海洛因成瘾者短暂地接触到了线索 与海洛因使用相关联，以促使海洛因使用记忆进入脆弱状态。一旦 在记忆处于这种状态时，海洛因成瘾者接受了由长期接触 与海洛因有关的线索。有人争辩说，灭绝会改变记忆，这样线索就不会 不再与海洛因的使用和奖励联系在一起。值得注意的是，在仅仅两次检索之后- 在灭绝训练(RET)中，研究人员发现，对海洛因线索做出反应的渴望实质上是 减少最多6个月的治疗后。这种效果是相对于对照组观察到的，对照组接受了 涉及非海洛因线索的提取，然后消失。这些令人印象深刻的初步发现促使我们重复 并将这项研究扩展到吸烟者身上。在我们的研究中，一组吸烟者接受了两次RET 而控制组则接受相同的训练，只是提取包括简短的 接触中性的、与吸烟无关的线索。对熟悉和新奇的吸烟线索的渴望和其他反应 在干预后24小时、2周和1个月的测试中进行评估；吸烟行为 并进行了超过1个月的随访评估。值得注意的是，在1个月的随访中，渴望熟悉和 在接受R-E训练的组中，新的吸烟线索显著低于对照组。更引人注目的是 与对照组相比，RET组每天吸烟的数量减少了25%。[亦为 有意义的是，与对照组参与者相比，RET组中有更多的参与者 实现吸烟减少60%(与治疗前水平相比)]。拟议的项目将复制和 通过1)增加干预剂量以支持观察到的治疗效果来扩大这些发现， 2)使用脑成像方法来识别与 干预和潜在的治疗结果预测，3)增加一个对照组，这将增强 了解RET的影响，以及4)延长随访期，以更完整地记录长期的 RET的期限效应。这项研究的积极发现可能会导致开发一种简短、有效的 行为干预，以减轻吸烟对社会造成的负担。重要的是，这种干预 可以很容易地适应于治疗其他形式的成瘾和共生的焦虑症，如创伤后应激障碍。

PROJECT SUMMARY: We recently published results from a NIDA-funded study of a brief behavioral treatment that was designed to reduce the troublesome cravings that smokers encounter when they attempt to quit smoking. This intervention was based on a growing body of neuroscience studies showing that memories for prior learning can be retrieved by the presentation of cues involved in that learning. Once retrieved, the memories enter into a brief period of vulnerability, during which they can be modified, but after which they are reconsolidated (restabilized) back into long-term storage. The treatment potential of this phenomenon was initially demonstrated in a Science report in which inpatient heroin addicts were briefly exposed to cues associated with heroin use in order to prompt the heroin use memories into a vulnerable state. Once the memories were in this state, the heroin addicts received extinction training consisting of protracted exposure to heroin associated cues. It was argued that extinction would change the memories such that the cues would no longer be associated with heroin administration and reward. Remarkably, after just two sessions of retrieval- extinction training (RET), the investigators found that craving in response to heroin cues was substantially reduced for up to 6-months post-treatment. This effect was observed relative to a control group that received retrieval involving non-heroin cues, followed by extinction. These impressive initial findings led us to replicate and extend the study in cigarette smokers. In our study, one group of smokers received two sessions of RET with smoking cues whereas a control group received the same training except that retrieval consisted of brief exposure to neutral, smoking-unrelated cues. Craving and other reactions to familiar and novel smoking cues were assessed in test sessions performed 24-hrs, 2-weeks and 1-month after intervention; smoking behavior was also assessed over 1-month follow-up. Remarkably, at 1-month follow-up, craving to both familiar and novel smoking cues was significantly lower in the group receiving R-E training vs. control. Even more striking was the 25% reduction in the number of cigarettes smoked per day in the RET group vs. control. [Also of significance was suggestive evidence that, relative to control participants, more participants in the RET group achieved a 60% reduction in smoking (from pretreatment levels)]. The proposed project will replicate and extend these findings by 1) increasing the dose of intervention so as to bolster the observed treatment effects, 2) employing brain imaging methods to identify patterns of brain activity uniquely associated with the intervention and potentially predictive of treatment outcome, 3) adding a control group that will enhance understanding of the effects of RET, and 4) extending follow-up period to more completely document the long- term effects of RET. Positive findings from this study could lead to the development of a brief, effective behavioral intervention to reduce the burden levied against society by smoking. Importantly, this intervention could be easily adapted to treat other forms of addiction and co-occurring anxiety disorders, such as PTSD.