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，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（美国卫生部）。人类服务，2008年）。在施用尼古丁（iv或sc）的动物中的微透析研究表明，尼古丁诱导多巴胺（DA）释放（Di Chiara和Imperato，1988），并且这种反应被认为是药物成瘾性的核心（Imperato等人，1986年）。人类吸烟者的正电子发射断层扫描（PET）成像在急需开发通过DA系统起作用的戒烟新药中发挥作用。然而，要使PET发挥最大的作用，需要新型的图像分析，这些图像分析产生的终点对吸烟引起的DA效应敏感，这些效应在时间和/或空间上高度局部化。用可置换的D2受体示踪剂分析PET扫描的常规方法（即，对DA的波动敏感）通常依赖于通过计算结合电位（BP）的变化对时间上的数据进行平均，或者通过感兴趣区域（ROI）分析对空间上的数据进行平均。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范围的现象，但对DA的瞬态效应敏感。相反，它是一种基于体素的方法，不依赖于时间平均或平衡，如BP计算的情况。我们提出了第一个实例的“动态多巴胺图像”（DDI）的响应吸烟在目前的建议。我们初步证明了在体素水平上，DDI包含了纹状体对吸烟的个体反应 在PET扫描仪上。DDI有可能成为吸烟对大脑DA系统影响的详细时空生物标志物。我们设想使用这样的生物标志物作为依赖性进展或对治疗的反应的指标。与任何新方法的开发一样，要问的一个关键问题是该方法的输出是否可重现。当前提案的主要目标是解决再现性问题。我们已经配置了一个测试/再测试成像范例与依赖吸烟者量化的一致性和再现性的DDI吸烟在每个人从一个扫描会话到下一个。我们认为，拟议的项目是很好的建设，以测试和验证一个新的工具，可以反过来，在吸烟的理解和治疗援助。

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.