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

通过新型 PET 方法对吸烟引起的多巴胺释放的性别差异进行成像

• 批准号: 9276632
• 负责人: Evan D Morris
• 金额: $ 73.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276632
• 关键词: Address; Affect; Amphetamines; Area; Behavior; Behavioral; Biological; Biological Markers; Blinded; Brain; Cessation Research; Chantix; Cigarette; Clinical; Corpus striatum structure; Data; Dependence; Detection; Development; Dopamine; Dorsal; Double-Blind Method; Elements; Event; Experimental Designs; Frequencies; Funding; Gender; Goals; Head; Human; Image; Image Analysis; Individual; Investigation; Kinetics; Knowledge; Libido; Light; Location; Mathematics; Measures; Methods; Microdialysis; Modeling; Motion; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Pattern; Pharmaceutical Preparations; Placebo Control; Placebos; Positron-Emission Tomography; Psychological reinforcement; Raclopride; Randomized; Regulation; Relapse; Reporting; Research Personnel; Resolution; Rewards; Scanning; Sex Characteristics; Smoke; Smoker; Smoking; Smoking Behavior; Speed; Statistical Data Interpretation; Stimulus; Stress; System; Techniques; Testing; Time; Tobacco smoke; Tracer; Treatment Efficacy; Ventral Striatum; Woman; Work; addiction; amphetamine use; base; behavior measurement; cigarette smoking; cohort; craving; data modeling; design; dopamine system; experience; experimental study; follow-up; imaging study; imaging system; in vivo; innovation; insight; men; mesolimbic system; neurochemistry; nicotine patch; nicotine replacement; novel; public health relevance; response; satisfaction; sex; smoking cessation; spatiotemporal; success; therapy development; tool; transmission process; treatment response; varenicline

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.

描述（由申请人提供）：吸烟对男性和女性的影响不同。男性从尼古丁中获得更大的强化和奖励，而女性则倾向于因压力和影响调节而吸烟。研究表明，尼古丁替代疗法（NRT）对男性戒烟更有效。了解性别-治疗效果和吸烟行为背后的神经化学机制的差异将有助于推动性别敏感的治疗发展。创新：我们将使用PET成像，这是一种新的实验，包括在扫描仪中吸烟，以及捕获时间信息的分析，以检测大脑对吸烟的多巴胺（DA）反应的性别差异。迄今为止，吸烟的PET成像研究受到次优实验设计或数据模型不足的阻碍。我们通过高分辨率扫描和高频运动校正填补了设计中的知识空白。我们填补了差距分析与我们的创新模型，lp- ntPET，特别是占短暂的和随时间变化的DA激活吸烟引起的。初步调查结果：多亏了我们的新方法，我们最近发现男性在吸烟时激活了右腹侧纹状体的DA传输，而女性则没有。我们还确定了背侧纹状体的不同区域，女性在吸烟时比男性更快地激活DA。这些初步的数据提供了深入了解潜在的生物学基础，建立行为的性别差异。方法：目标（1、2）：研究男性和女性吸烟的大队列，以确定吸烟导致的DA释放的位置、空间范围和时间的性别差异。目的（3）：测量NRT戒烟对DA系统影响的性别差异。目的（4）：研究Chantix对DA时间的影响，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）与吸烟期间的个体行为（例如，渴望）和临床措施（例如，依赖）。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的时空生物标志物。将使用D2拮抗剂示踪剂11 C-雷氯必利进行PET。吸烟者将在一台配备了高频头部运动检测的高分辨率大脑扫描仪内吸烟。吸烟者将在用药（NRT或Chantix）1周后和安慰剂对照1周后接受扫描。所有受试者均将设盲，顺序将随机化。lpntPET是由研究人员开发的用于动态PET数据的新型模型，用于在体素水平上捕获DA动力学。这些方法是新颖的，但经过验证，独特地适合于发现对吸烟和戒烟药物反应的性别差异的神经化学基础。