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：
8303751
负责人：
Marc J Kaufman
金额：
$ 24.73万
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 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8303751
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. PUBLIC HEALTH RELEVANCE: Nicotine dependence remains the leading cause of preventable mortality in the United States. This Exploratory Developmental R21 program aims to determine whether smokers exhibit increased levels of dopamine D2/D3 receptors and whether there is an association between D2/D3 level, as measured with Positron Emission Tomography (PET), and smoking cue functional MRI reactivity, which when increased predicts heightened relapse vulnerability. PET and fMRI scans will be acquired simultaneously on an MRI scanner fit with a PET imaging insert. Program findings may lead to new smoking cessation and relapse prevention treatments.

描述（由申请人提供）：尼古丁的依赖仍然是美国可预防死亡率的主要原因，每年造成近450,000人死亡。烟草戒烟可带来明显的健康益处，并且存在部分有效的戒烟药物治疗。但是，最初戒烟者在12个月内复发65-80％。由于吸烟提示反应性与渴望密切相关，并且在试图戒烟的吸烟者中，发现降低吸烟提示反应性的治疗方法可能有助于促进持续的烟草禁欲。临床前研究，多巴胺（DA）D3受体拮抗剂有效地降低了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受体可能中度适中尼古丁和其他药物提示反应性，并可能在提示引起的复发中发挥作用。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）对吸烟线索的反应性之间是否存在相关性，这与吸烟复发脆弱性有关。神经影像措施将同时收集健康依赖性尼古丁依赖性吸烟者和年龄匹配的非吸烟者中，使用3 Tesla MRI扫描仪配置为进行fMRI和正电子发射断层扫描（PET）。我们建议使用放射性标记的[11C] - （+） - PHNO测量PET D3受体结合，该[11C] - （+） - 对D3受体的亲和力比其他放射性示意剂标记D2/D3受体的亲和力相对较高。先前的研究报告说，D3拮抗剂治疗降低了[11C] - （+） - 奖励学习中涉及的大脑区域的PHNO结合，包括Nigra（SN）（SN），Globus Pallidus（GP）和腹侧palliDum（VP）。因此，SN，GP和VP D3受体可能在复发中起作用，可能是通过调节对药物提示的行为反应。由于临床前和临床证据表明刺激性暴露会增加D3受体水平，因此我们假设PET [11C] - （+） - SN中的PHNO结合，其中与非烟民相比，吸烟者的结合几乎完全与D3受体的结合将升高。我们还假设在吸烟者中，SN [11C] - （+） - PHNO结合将与fMRI吸烟提示反应性呈正相关。先前显示出具有较高吸烟提示FMRI的反应性，包括前岛，包括前岛，杏仁核，amygdala和背纹状体。对这些假设的验证可能有助于阐明复发脆弱性的基础机制，并可能有助于识别那些尤其会从D3拮抗剂治疗中受益的吸烟者，从而实现个性化的医学方法。公共卫生相关性：尼古丁的依赖仍然是美国可预防死亡率的主要原因。该探索性发育R21计划旨在确定吸烟者是否表现出增加多巴胺D2/D3受体的水平，以及D2/D3水平之间是否存在与正电子发射断层扫描（PET）和吸烟提示功能性MRI反应性的相关性，当增加时，这会增加复发的脆弱性。 PET和FMRI扫描将与MRI扫描仪一起使用PET Imaging Insert同时获得。计划发现可能会导致新的戒烟和预防复发治疗。