Dynamic Dopamine Images: A New View of the Neurochemistry of Smoking

描述（由申请人提供）：吸烟是一种严重的成瘾，它继续使国家付出高昂的代价，无论是在金钱上，还是在生产力损失和过早死亡方面（美国人类服务部，2008年）。对给予尼古丁（iv或sc）的动物进行的微透析研究表明，尼古丁诱导多巴胺（DA）释放（Di Chiara和Imperato， 1988），这种反应被认为是药物成瘾性的核心（Imperato等人，1986）。人类吸烟者的正电子发射断层扫描（PET）成像在通过DA系统工作的戒烟新药物的急需开发中发挥作用。然而，为了使PET发挥最大的作用，将需要新型的图像分析，产生对吸烟引起的DA效应敏感的端点，这些效应在时间和/或空间上高度局部化。利用可置换d2受体示踪剂（即对DA波动敏感的示踪剂）对PET扫描进行分析的传统方法通常是通过计算结合电位（BP）的变化，或通过感兴趣区域（ROI）分析，对随时间推移的数据进行平均。我们最近介绍了一种新型的PET图像分析（“ntPET”），其终点是多巴胺图像的动态序列，不依赖于roi范围内的现象，但对DA的瞬时效应很敏感。相反，它是一种基于体素的方法，不像计算BP那样依赖于时间平均或平衡。我们提出了当前提案中对吸烟反应的“动态多巴胺图像”（DDI）的第一个实例。我们已经初步证明，DDI包含纹状体在体素水平上对吸烟多支香烟的个体反应

DESCRIPTION (provided by applicant): Cigarette smoking is a serious addiction that continues to cost the country dearly, both monetarily and in terms of lost productivity and premature death (U.S. Dept. of Human Services, 2008). Microdialysis studies in animals administered nicotine (iv or sc) indicate that nicotine induces dopamine (DA) release (Di Chiara and Imperato, 1988) and this response is believed to be central to the addictive quality of the drug (Imperato et al., 1986). Positron Emission Tomography (PET) imaging of human smokers has a role to play in the much-needed development of new medications for smoking cessation that work through the DA system. For PET to be maximally useful, however, will require new types of image analysis that yield endpoints that are sensitive to smoking-induced DA effects that are highly localized in time and/or space. Conventional methods of analysis of PET scans with displaceable D2-receptor tracers (i.e., that are sensitive to fluctuations in DA) typically rey on averaging data over time, via calculation of changes in Binding Potential (BP), or over space, via region-of-interest (ROI) analysis. We have recently introduced a new type of PET image analysis ('ntPET') whose endpoint is a dynamic sequence of dopamine images that does not rely on ROI-wide phenomena but is sensitive to transient effects of DA. Rather, it is a voxel-based-method which does not rely on time-averaging or equilibrium, as is the case for calculation of BP. We present the first instance of a "dynamic dopamine image" (DDI) of the response to smoking in the current proposal. We have preliminarily demonstrated that the DDI contains the individual responses at the voxel level in the striatum to smoking multiple cigarettes in the PET scanner. The DDI has the potential to be a detailed spatio- temporal biomarker of the effect of smoking cigarettes on the brain's DA system. We envision using such a biomarker as an indicator of the progression of dependence or the response to therapy. As with the development of any new method, a key question to ask is whether or not the output of the method is reproducible. The primary goal of the current proposal is to address the issue of reproducibility. We have configured a test/retest imaging paradigm with dependent smokers to quantify the consistency and reproducibility of the DDI of smoking in each individual from one scan session to the next. We believe that the proposed project is well constructed to test and validate a new tool that could, in turn, aid in the understanding and treatment of smoking. PUBLIC HEALTH RELEVANCE: In this study, we will use newly established mathematical techniques to produce detailed, time-sequences of images of the brain's dopamine system responding to cigarette smoking. The images, which have not been created before, will be derived from dynamic PET imaging data and will reveal much new information about the location and timing of the dopaminergic response to smoking in the brains of dependent smokers. The primary goal of the study will be to investigate how reproducible are the series of dopamine images and thus to gauge how useful they might be as a new tool for understanding the neurochemistry of smoking.