Concurrent PET D2/D3 receptor imaging and fMRI smoking cue reactivity in smokers

吸烟者的同步 PET D2/D3 受体成像和 fMRI 吸烟提示反应

基本信息

批准号：
8453354
负责人：
Marc J Kaufman
金额：
$ 18.53万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-15 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8453354
关键词：
Accounting Affinity Age Amygdaloid structure Anterior Area Behavioral Binding Brain Brain region Cessation of life Clinical Clinical Trials Corpus striatum structure Cues Data Development Dopamine Dopamine D2 Receptor Dorsal Emotional Exhibits Exploratory/Developmental Grant Functional Magnetic Resonance Imaging Future General Hospitals Globus Pallidus Health Benefit Image Insula of Reil Label Lead Learning MRI Scans Magnetic Resonance Magnetic Resonance Imaging Maintenance Massachusetts Measures Medicine Methods Nicotine Nicotine Dependence Pharmaceutical Preparations Pharmacotherapy Play Positron-Emission Tomography Publishing Radiolabeled Relapse Reporting Research Project Grants Rewards Role Smoker Smoking Smoking Status Stimulus Substantia nigra structure Time Tobacco smoking United States Validation Withholding Treatment base craving cue reactivity dependence relapse disorder later incidence prevention dopamine D3 receptor drug of abuse mortality neuroimaging nicotine replacement non-smoker pre-clinical preclinical study programs public health priorities radiotracer receptor receptor binding response reward circuitry smoking cessation smoking relapse tobacco abstinence

项目摘要

DESCRIPTION (provided by applicant): Nicotine dependence remains the leading cause of preventable mortality in the United States, accounting for nearly 450,000 deaths annually. Tobacco smoking cessation offers clear health benefits and partially effective cessation pharmacotherapies exist. However, 65-80 percent of initially abstinent smokers relapse within 12 months. Since smoking cue reactivity is strongly associated with craving and, in smokers trying to quit, with relapse, discovering treatments that reduce smoking cue reactivity may help promote sustained tobacco abstinence. !n preclinical studies, dopamine (DA) D3 receptor antagonists effectively reduced nicotine and other drug- conditioned responses including cue-induced reinstatement of nicotine seeking. Therefore, D3 receptors may moderate nicotine and other drug cue-reactivity and may play a role in cue-induced relapse. This Exploratory Developmental R21 project aims to determine whether D3 receptors are elevated in smokers and whether correlations exist between D3 receptor binding and functional MRI (fMRI) reactivity to smoking cues, which has been associated with smoking relapse vulnerability. Neuroimaging measures will be collected concurrently in otherwise healthy nicotine-dependent smokers and age-matched nonsmokers using a 3 Tesla MRI scanner configured to conduct fMRI and Positron Emission Tomography (PET). We propose to measure PET D3 receptor binding using radiolabeled [11C]-(+)-PHNO, which has a relatively higher affinity for D3 receptors over other radiotracers labeling D2/D3 receptors. Prior studies reported that D3 antagonist treatment decreased [11C]-(+)-PHNO binding in brain regions involved in reward learning including the substantia nigra (SN), globus pallidus (GP), and ventral pallidum (VP). Thus, SN, GP, and VP D3 receptors may play a role in relapse, possibly by moderating behavioral responses to drug cues. Because preclinical and clinical evidence suggest that stimulant exposures increase D3 receptor levels, we hypothesize that PET [11C]-(+)-PHNO binding in SN, in which binding is almost exclusively to D3 receptors, will be elevated in smokers when compared to nonsmokers. We also hypothesize that within smokers, SN [11C]-(+)-PHNO binding will be positively correlated with fMRI smoking cue reactivity in brain areas previously shown to exhibit high smoking cue fMRI reactivity, including anterior insula, amygdala, and dorsal striatum. Validation of these hypotheses may help clarify mechanisms underlying relapse vulnerability and may help identify smokers who would particularly benefit from D3 antagonist treatment, thereby enabling a personalized medicine approach.

描述（由申请人提供）：尼古丁依赖仍然是美国可预防死亡的主要原因，每年导致近 45 万人死亡。戒烟对健康有明显的好处，并且存在部分有效的戒烟药物疗法。然而，65-80% 最初戒烟的人会在 12 个月内复吸。由于吸烟提示反应性与渴望密切相关，并且对于试图戒烟的吸烟者来说，如果复吸，发现减少吸烟提示反应性的治疗方法可能有助于促进持续戒烟。在临床前研究中，多巴胺 (DA) D3 受体拮抗剂有效减少尼古丁和其他药物条件反应，包括提示诱导的尼古丁寻求恢复。因此，D3 受体可能会调节尼古丁和其他药物的提示反应性，并可能在提示诱导的复发中发挥作用。该探索性发育 R21 项目旨在确定吸烟者的 D3 受体是否升高，以及 D3 受体结合与功能性 MRI (fMRI) 对吸烟线索的反应之间是否存在相关性，而功能性 MRI (fMRI) 与吸烟复发易感性相关。将使用配置为进行 fMRI 和正电子发射断层扫描 (PET) 的 3 特斯拉 MRI 扫描仪，同时收集其他健康的尼古丁依赖吸烟者和年龄匹配的非吸烟者的神经影像测量。我们建议使用放射性标记的[11C]-(+)-PHNO 来测量 PET D3 受体结合，与其他标记 D2/D3 受体的放射性示踪剂相比，它对 D3 受体的亲和力相对较高。先前的研究报道，D3 拮抗剂治疗减少了参与奖赏学习的大脑区域的 [11C]-(+)-PHNO 结合，包括黑质 (SN)、苍白球 (GP) 和腹侧苍白球 (VP)。因此，SN、GP 和 VP D3 受体可能在复发中发挥作用，可能是通过调节对药物提示的行为反应来实现的。由于临床前和临床证据表明，兴奋剂暴露会增加 D3 受体水平，因此我们假设与非吸烟者相比，吸烟者中 SN 中的 PET [11C]-(+)-PHNO 结合（其中几乎完全与 D3 受体结合）会升高。。我们还假设，在吸烟者中，SN [11C]-(+)-PHNO 结合将与先前显示出高吸烟提示 fMRI 反应性的大脑区域（包括前岛叶、杏仁核和背侧纹状体）的 fMRI 吸烟提示反应性呈正相关。这些假设的验证可能有助于阐明复发易感性的潜在机制，并可能有助于确定哪些吸烟者会特别受益于 D3 拮抗剂治疗，从而实现个性化医疗方法。