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

描述(申请人提供)：尼古丁依赖仍然是美国可预防的死亡的主要原因，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。由于吸烟线索反应性与渴望密切相关，在试图戒烟的吸烟者中，发现降低吸烟线索反应性的治疗方法可能有助于促进持续的烟草戒断。！在临床前研究中，多巴胺(DA)D3受体拮抗剂有效地减少了尼古丁和其他药物条件反应，包括线索诱导的尼古丁恢复寻求。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。这项探索性的发展R21项目旨在确定吸烟者的D3受体是否升高，以及D3受体结合与功能磁共振成像(FMRI)对吸烟线索的反应性之间是否存在相关性，这与吸烟复发的易感性有关。在其他健康的尼古丁依赖吸烟者和年龄匹配的非吸烟者中，将使用3Tesla MRI扫描仪同时收集神经成像测量，该扫描仪配置为进行功能磁共振成像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来测量PET D3受体的结合，与其他标记D2/D3受体的放射性示踪剂相比，它对D3受体具有相对更高的亲和力。以前的研究报道，D3拮抗剂治疗降低了与奖赏学习有关的脑区的[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VPD3受体可能通过调节对药物线索的行为反应而在复发中发挥作用。由于临床前和临床证据表明，刺激剂暴露会增加D3受体水平，我们假设在SN中PET[11C]-(+)-PHNO结合，其中几乎只与D3受体结合，与非吸烟者相比，吸烟者的水平将升高。我们还假设，在吸烟者中，SN[11C]-(+)-PHNO结合将与先前显示高吸烟线索fMRI反应性的大脑区域的fMRI吸烟线索反应性正相关，包括前岛、杏仁核和背侧纹状体。验证这些假设可能有助于阐明复发易感性的潜在机制，并可能有助于识别将从D3拮抗剂治疗中特别受益的吸烟者，从而使个性化药物治疗成为可能。

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.