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

尼古丁依赖仍然是美国可预防死亡的主要原因，每年造成近45万人死亡。戒烟提供了明确的健康益处，并且存在部分有效的戒烟药物疗法。然而，65- 80%的最初戒烟者在12个月内复发。由于吸烟提示反应与渴望密切相关，并且在试图戒烟的吸烟者中，与复发密切相关，因此发现降低吸烟提示反应的治疗方法可能有助于促进持续的戒烟。!在临床前研究中，多巴胺（DA）D3受体拮抗剂有效地减少尼古丁和其他药物条件反应，包括线索诱导的尼古丁寻求恢复。因此，D3受体可能调节尼古丁和其他药物的线索反应性，并可能在线索诱导的复发中发挥作用。这个探索性发展R21项目旨在确定D3受体是否在吸烟者中升高，以及D3受体结合和功能性MRI（fMRI）对吸烟线索的反应性之间是否存在相关性，这与吸烟复发的脆弱性有关。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，同时收集其他健康尼古丁依赖吸烟者和年龄匹配的非吸烟者的神经影像学指标。我们建议使用放射性标记的[11 C]-（+）-PHNO来测量PET D3受体结合，与标记D2/D3受体的其他放射性示踪剂相比，[11 C]-（+）-PHNO对D3受体具有相对较高的亲和力。先前的研究报道，D3拮抗剂治疗降低了参与奖励学习的脑区（包括黑质（SN）、苍白球（GP）和腹侧苍白球（VP））中的[11 C]-（+）-PHNO结合。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线索的行为反应。由于临床前和临床证据表明，兴奋剂暴露增加D3受体水平，我们假设，与非吸烟者相比，吸烟者的SN中PET [11 C]-（+）-PHNO结合（几乎仅与D3受体结合）将升高。我们还假设，在吸烟者中，SN [11 C]-（+）-PHNO结合将与先前显示出高吸烟线索fMRI反应性的脑区（包括前额叶、杏仁核和背侧纹状体）的fMRI吸烟线索反应性呈正相关。这些假设的验证可能有助于阐明复发脆弱性的潜在机制，并可能有助于识别特别受益于D3拮抗剂治疗的吸烟者，从而实现个性化的医学方法。 公共卫生相关性：尼古丁依赖仍然是美国可预防死亡的主要原因。这项探索性发展R21计划旨在确定吸烟者是否表现出多巴胺D2/D3受体水平的增加，以及D2/D3水平（用正电子发射断层扫描（PET）测量）与吸烟提示功能性MRI反应性之间是否存在关联，当增加时预测复发脆弱性增加。将在配有PET成像插件的MRI扫描仪上同时采集PET和fMRI扫描。该计划的发现可能会导致新的戒烟和预防复发的治疗方法。

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.