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

描述(由申请人提供)：线索暴露疗法(CET)，在这种疗法中，成瘾者暴露在与药物使用有关的线索中，但被阻止反应，表现出有限的有效性。这可能是因为灭绝学习是 高度依赖于上下文--即当动物返回到最初的学习环境时，在不同于其学习的环境中熄灭的行为被重新表达或“更新”。我们合作研究计划的首要目标是通过将吸烟者真实吸烟环境中的背景线索纳入治疗中，从而防止更新，从而提高CETS的疗效。然而，为了合理地开发包含个人吸烟环境线索的新型CET，首先必须坚定地确定这些线索导致的反应性有别于标准的吸烟环境线索和传统上使用的近端线索(例如点燃的香烟)，并且它们引发吸烟行为(即自我管理)。为了完成这些初始步骤，78名成年吸烟者将接受大胆的fMRI扫描，同时观看描绘个人和实验者产生的标准吸烟和不吸烟环境的图片线索，并同时观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，个人吸烟和不吸烟环境线索对吸烟自我管理和自我报告渴望的影响将在两个实验室会议中进行评估。我们假设，除了线索反应区的大胆信号增加外，暴露于个人吸烟环境线索将导致相对于近端吸烟线索的药物上下文关联区(海马体)的更大激活，以及相对于标准吸烟环境线索的更大的自我相关加工区(mPFC，PCC)的激活。我们进一步假设，与不吸烟的环境线索相比，吸烟者将表现出更大的吸烟自我管理(即更大的吸烟概率、更短的吸烟潜伏期、更大的烟雾量)和对观看个人吸烟的渴望。此外，我们将探索在线索暴露期间行为和大脑连通性测量之间的关系。如果我们的假设得到支持，那么将个人吸烟环境纳入CET是合理的，新CET的合理开发和评估可以随之而来。此外，NIH还投资于新药物疗法的开发，这些药物疗法可以增强CET或扰乱激活的药物记忆的重新巩固；这些治疗的疗效可能会通过纳入更多生态有效和与个人相关的药物线索来提高，比如这里建议研究的那些。最后，尽管有丰富的临床前文献和300多项先前的人类线索反应性研究，但关于环境是人类吸烟行为的决定因素的了解很少。因此，这项拟议的研究，除了为治疗发展提供信息外，还将提供关于一个重要的、但尚未得到充分研究的吸毒和复发决定因素的新机制信息。 与公共健康相关：在美国，吸烟是主要的可预防的死亡和残疾原因。旨在通过减少吸烟的影响来帮助吸烟者戒烟的疗法基本上失败了--部分原因是它们没有考虑到吸烟者所处环境(例如吸烟发生的地方)的强大影响。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，并将评估环境对吸烟行为的影响。这项调查的结果将为治疗发展提供信息，应该有助于吸烟者和其他有药物滥用问题的个人。

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.