Environments as Smoking Cues: Imaging Brain Substrates, Developing New Treatments

描述（由申请人提供）：线索暴露治疗（CET），其中成瘾个体暴露于与药物使用相关的线索，但阻止响应，已证明有效性有限。这可能是由于灭绝学习是一种 高度依赖于环境--即，当动物返回到最初的学习环境时，在环境中消失而不是在学习环境中消失的行为被重新表达或“更新”。我们的合作研究计划的总体目标是通过将吸烟者真实吸烟环境的上下文线索纳入治疗来提高CET的疗效，从而防止更新。然而，为了合理地开发结合个人吸烟环境线索的新型CET，首先必须牢固地确立这样的线索导致与标准吸烟环境线索和传统上使用的近端线索（例如点燃的香烟）不同的反应性，并且它们引起吸烟行为（即自我施用）。为了实现这些初始步骤，78名（n=78）成年吸烟者将接受BOLD fMRI扫描，同时他们查看描绘个人和实验者生成的标准吸烟和不吸烟环境的图片线索，同时查看吸烟和不吸烟的近端线索。个人环境线索将通过训练吸烟者在现实世界中拍照来获得。此外，个人吸烟和非吸烟环境线索对香烟烟雾自我管理和自我报告的渴望的影响将在两个实验室会议中进行评估。我们假设，除了增加BOLD信号的线索反应区，暴露于个人吸烟环境的线索将导致更大的激活药物上下文关联区（海马）相对于近端吸烟线索;和更大的激活自我相关处理区（mPFC，PCC）相对于标准吸烟环境的线索。我们进一步假设，吸烟者将表现出更大的烟雾自我管理（即吸烟的可能性更大，吸烟的潜伏期减少，更大的烟量）和渴望响应于查看个人吸烟相比，非吸烟环境的线索。此外，我们将探讨线索暴露过程中行为和大脑连接措施之间的关系。如果我们的假设得到支持，那么个人吸烟环境纳入大学英语四级考试是有道理的，合理的开发和评估新的大学英语四级考试可以遵循。此外，美国国立卫生研究院还投资于开发新的药物疗法，增强CET或破坏激活的药物记忆的重新巩固;这些治疗的疗效可以通过纳入更多生态有效和个人相关的药物线索来改善，例如本文提出的研究。最后，尽管有丰富的临床前文献和300多个先前的人类线索反应性研究，但关于环境作为人类吸烟行为的决定因素的知之甚少。因此，除了为治疗开发提供信息外，拟议的研究还将提供关于吸毒和复发的重要但未充分研究的决定因素的新机制信息。 公共卫生相关性：在美国，吸烟是导致死亡和残疾的主要可预防原因。旨在通过减少吸烟“触发因素”的影响来帮助吸烟者戒烟的治疗方法在很大程度上都失败了，部分原因是它们没有考虑到吸烟者所处环境的强大影响（例如吸烟的地方）。在这个翻译项目中，我们将探索大脑如何处理有关吸烟环境的信息，并评估环境对吸烟行为的影响。这项调查的结果将为治疗的发展提供信息，帮助吸烟者和其他有药物滥用问题的人。

DESCRIPTION (provided by applicant): Cue-exposure treatments (CETs) in which addicted individuals are exposed to cues associated with drug use, but prevented from responding, have demonstrated limited effectiveness. This is potentially due to the fact that extinction learning is highly context dependent-i.e. behavior extinguished in a context other than the one in which it was learned, is re-expressed or 'renewed' when the animal returns to the original learning context. The overarching goal of our collaborative research program is to increase the efficacy of CETs by incorporating contextual cues from the smoker's real-world smoking environment into treatment, thereby preventing renewal. However, in order to rationally develop novel CETs that incorporate personal smoking environment cues, it is first necessary to firmly establish that such cues result in reactivity distinct from standard smoking environment cues and traditionally used proximal cues (e.g. lit cigarette) and that they provoke smoking behavior (i.e. self- administration). In order to achieve these initial steps, seventy-eight (n=78) adult smokers will undergo BOLD fMRI scanning while they view picture cues depicting personal and experimenter generated standard smoking and nonsmoking environments and while viewing smoking and nonsmoking proximal cues. Personal environment cues will be acquired by training smokers to take pictures in real-world settings. In addition, the effects of personal smoking and nonsmoking environment cues on cigarette smoke self-administration and self-reported craving will be assessed in two lab sessions. We hypothesize that in addition to increased BOLD signal in cue-reactivity areas, exposure to personal smoking environment cues will result in greater activation of a drug-context association area (hippocampus) relative to proximal smoking cues; and greater activation of self-relevance processing areas (mPFC, PCC) relative to standard smoking environment cues. We further hypothesize that smokers will exhibit greater smoke self-administration (i.e. greater probability of smoking, decreased latency to smoke, greater puff volume) and craving in response to viewing personal smoking as compared to nonsmoking environment cues. Additionally, we will explore relations between behavioral and brain measures of connectivity during cue-exposure. If our hypotheses are supported, then the incorporation of personal smoking environments into CET is warranted and the rational development and evaluation of novel CETs can follow. In addition, the NIH is invested in the development of novel pharmacotherapies that enhance CET or disrupt reconsolidation of activated drug memories; the efficacy of these treatments can potentially be improved by incorporating more ecologically valid and personally relevant drug cues such as those proposed for study here. Finally, despite a rich preclinical literature and over 300 prior human cue-reactivity studies, very little is known regarding the environment as a determinant of smoking behavior in humans. As such, the proposed research, in addition to informing treatment development, will provide novel mechanism information regarding an important, yet understudied, determinant of drug taking and relapse. PUBLIC HEALTH RELEVANCE: Cigarette smoking is the leading preventable cause of death and disability in the U.S. Treatments designed to help smokers quit by reducing the impact of smoking 'triggers' have largely failed-in part because they do not take into account the powerful effect of the smoker's environment (e.g. places where smoking occurs). In this translational project we will explore how the brain processes information about smoking environments and will also evaluate the effects of environments on smoking behavior. The results of this investigation will inform treatment development that should help smokers and other individuals with substance abuse problems.