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: 9511762
• 负责人: Evan D Morris
• 金额: $ 72.5万
• 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/9511762
• 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 Differences; Smoke; Smoker; Smoking; Smoking Behavior; Smoking Cessation Intervention; 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 smoke; 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）：男性与女性的吸烟作用不同。男人会从尼古丁经历更大的增强和奖励，而女性则倾向于为压力吸烟并影响调节。研究报告说，尼古丁替代疗法（NRT）对男性的戒烟更有效。了解治疗功效和吸烟行为的神经化学机制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 Imaging，这是一个新的实验，包括在扫描仪中吸烟，并捕获时间信息以检测大脑多巴胺（DA）对吸烟的反应中的性别差异。迄今为止，吸烟的宠物成像研究受到了次优实验设计或数据模型不足的影响。我们通过高分辨率扫描和高频运动校正来填补设计中的知识空白。我们通过创新模型LP-NTPET填补了分析的空白，该模型专门解释了吸烟引起的短暂且随时间变化的DA激活。初步发现：由于我们的新方法，我们最近发现，在吸烟时，男性在右腹纹状体中激活DA传播，但女性却没有。我们还确定了背纹状体的不同区域，在吸烟时，女性激活DA的速度比男性快。这些初步数据提供了有关既定行为性别差异的潜在生物学基础的洞察力。方法：目的（1，2）：检查大量的男女吸烟，以确定由于吸烟而导致的位置，空间范围和DA释放的时机的性别差异。目的（3）：测量NRT对戒烟对DA系统的影响的性别差异。目的（4）：检查Chantix对DA时机的影响，以解释其独特的作用机理。进一步的目的旨在将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）和临床指标（例如依赖性）联系起来。通过这种方式，我们将发现药物作用机制，并建立基于图像的新时空生物标志物的成瘾关键元素。 PET将使用D2拮抗剂示踪剂，11C-杆菌杆进行。吸烟者将在配备高频头部运动检测的高分辨率脑扫描仪内抽烟。药物1周（NRT或Chantix）和安慰剂控制1周后，将扫描吸烟者。所有这些都将蒙蔽，秩序将是随机的。 LPNTPET是由研究人员开发的动态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，非常适合发现性别差异的神经化学基础，以应对吸烟和药物的戒烟。