Imaging sex differences in smoking-induced dopamine release via novel PET methods

描述(申请人提供)：吸烟对男性和女性的影响是不同的。男性从尼古丁中获得更大的强化和回报，而女性则倾向于吸烟是因为压力和影响调节。研究报告称，尼古丁替代疗法(NRT)对男性戒烟更有效。了解治疗效果和吸烟行为背后的神经化学机制中的性别差异将有助于推动对性别敏感的治疗发展。创新：我们将使用PET成像，这是一种将吸烟纳入扫描仪的新型实验，以及捕捉时间信息的分析，以检测大脑对吸烟的多巴胺(DA)反应的性别差异。到目前为止，吸烟的PET成像研究一直受到实验设计不佳或数据模型不充分的阻碍。我们用高分辨率扫描和高频运动校正来填补设计中的知识空白。我们用我们的创新模型LP-ntPET填补了分析方面的空白，该模型专门解释了吸烟引起的短暂和时变的DA激活。初步发现：多亏了我们的新方法，我们最近发现，男性吸烟时激活了右侧腹侧纹状体的DA传递，而女性没有。我们还确定了背侧纹状体中女性在吸烟时比男性更快地激活DA的明显区域。这些初步数据为建立行为性别差异的潜在生物学基础提供了洞察。方法：目标(1，2)：检查大量吸烟的男性和女性，以确定由于吸烟导致DA释放的位置、空间范围和时间上的性别差异。目的(3)：研究NRT戒烟对多巴胺系统影响的性别差异。目的(4)：研究Chantix对DA计时的影响，以解释其独特的作用机制。进一步的目的是寻求将DA释放的位置和时间模式(由我们的新方法产生)与吸烟期间的个人行为(例如，渴望)和临床措施(例如，依赖)联系起来。通过这种方式，我们将揭示药物的作用机制，并建立新的基于图像的成瘾关键要素时空生物标记物。将使用D2拮抗剂示踪剂11C-拉氯普利进行PET。吸烟者将在配备高频头部运动检测的高分辨率大脑扫描仪内吸烟。吸烟者将在服药1周后(NRT或Chantix)和安慰剂对照组1周后接受扫描。所有人都将被蒙在鼓里，秩序将被随机安排。LpntPET是一种新的动态PET数据模型，由研究人员开发，用于在体素水平上捕获DA动力学。这些方法新颖但经过验证，特别适合于发现性别差异的神经化学基础--对吸烟和戒烟药物的反应。

DESCRIPTION (provided by applicant): Cigarette smoking's effects are different in men vs. women. Men experience greater reinforcement and reward from the nicotine whereas women tend to smoke for stress and affect regulation. Studies report that nicotine replacement therapy (NRT) is more effective for smoking cessation in men. Understanding sex- differences in the neurochemical mechanisms underlying treatment efficacy and smoking behavior will help drive gender-sensitive treatment development. Innovation: We will use PET imaging, a novel experiment that includes smoking in the scanner, and analysis that captures temporal information to detect sex-differences in the brain's dopamine (DA) response to smoking a cigarette. To date, PET imaging studies of smoking have been hampered by suboptimal experimental designs or inadequate models of the data. We fill the knowledge gap in design with high resolution scanning and high frequency motion correction. We fill the gap in analysis with our innovative model, lp- ntPET, that specifically accounts for short-lived and time-varying DA activation caused by smoking. Preliminary Findings: Thanks to our new methods, we recently discovered that men activate DA transmission in right ventral striatum when smoking but women do not. We also identified distinct areas in dorsal striatum where women activate DA faster than men while smoking. These preliminary data provide insight into the potential biological bases for established behavioral sex differences. Approach: Aims (1, 2): To examine large cohorts of men and women smoking in order to identify sex- differences in location, spatial extent, and timing of DA release due to smoking. Aim (3): To measure sex- differences in the effect of NRT for smoking cessation on the DA system. Aim (4): To examine the effect of Chantix on DA timing as an explanation of its unique mechanism of action. Further aims seek to relate the location and temporal patterns of DA release (generated by our novel methods) to individual behaviors during smoking (e.g., craving) and to clinical measures (e.g., dependence). In this way, we will uncover mechanisms of action of medications and establish new image-based, spatiotemporal biomarkers of addiction Key elements. PET will be conducted with the D2 antagonist tracer, 11C-raclopride. Smokers will smoke cigarettes inside a high-resolution brain scanner equipped with high-frequency head-motion detection. Smokers will be scanned after 1 week of medication (NRT or Chantix) and after 1 week of placebo control. All will be blinded and order will be randomized. lpntPET is a novel model for dynamic PET data, developed by the investigators, for capturing DA kinetics at the voxel level. The methods are novel but validated and uniquely suited to discover the neurochemical bases of sex-differences in response to smoking and medications for smoking cessation.