Brain Nicotine Receptor Density & Response to Nicotine Patch

描述（由申请人提供）：尽管吸烟的健康风险和社会成本众所周知，但大约19.8%的美国成年人继续吸烟。虽然大多数吸烟者支持戒烟的愿望，但很少有（< 5%）会在没有治疗的情况下在给定的一年内戒烟，只有大约20-25%的人在6个月或更长时间的有效治疗后实现戒烟。因此，仍然迫切需要改善寻求治疗的吸烟者的结果。目前烟草依赖的一线药物包括尼古丁替代疗法（如贴剂、口香糖、锭剂、鼻喷雾剂和吸入器）、盐酸伐尼克兰（Chantix）和盐酸安非他酮（Zyban），大多数治疗环境中的当前护理标准主要是根据可用性、易用性和患者偏好选择特定药物。拟议研究的目的是通过确定吸烟者治疗前1422* 烟碱乙酰胆碱受体（nAChR）密度是否与标准尼古丁贴片减量的戒烟结果相关，来改善戒烟治疗的效果。我们正在进行的使用正电子发射断层扫描（PET）和放射性示踪剂2-[18 F]氟-3-（2（S）氮杂环丁烷甲氧基）吡啶的研究的初步数据（缩写为2-FA）表明，1422* nAChR上调的严重程度可预测哪些人或多或少可能对尼古丁贴片治疗有反应，并且1422* nAChR上调和治疗结果之间的这种关系对于尼古丁贴片治疗比对于与1422* nAChR占用率没有明显联系的其他戒烟治疗更特异（例如，盐酸安非他酮和团体心理治疗）。拟议的研究建立在几个正在进行的研究基础上。首先，本文使用的2-FA PET方法是由我们的团队和密切合作者最近开发和改进的，这些改进可以提高确定吸烟者大脑1422* nAChR密度的精度。其次，人类的功能性脑成像研究和人类脑组织的尸检研究都表明，与非吸烟对照组相比，吸烟者的1422* nAChR上调，本研究的初步数据表明，这种上调的严重程度与尼古丁替代疗法的反应有关。第三，尼古丁贴片锥度继续广泛使用。第四，临床特征和大脑功能的一般测量（例如，脑活动）已被用于预测烟草依赖和其他神经精神疾病的治疗结果;然而，据我们所知，没有发表的报告将特定脑受体（1422* nAChR）的密度与影响该受体的药物的治疗结果联系起来。对于拟定的研究，将通过报纸和互联网广告招募烟草依赖性吸烟者（n = 148;每天10至30支香烟）。参与者将接受电话和亲自筛查，然后在一周内进行2-FA PET扫描。对于该PET疗程，将在1分钟内注射2-FA推注，并在疗程的剩余时间内输注2-FA。3小时后（放射性示踪剂在大脑中达到近似稳定状态所需的时间），受试者将接受1小时的PET扫描。然后，他们将被带出扫描仪，并将吸烟到饱（2至3支香烟）。然后将对参与者进行额外的3.5小时扫描，以便可以在感兴趣的区域（ROI）（例如，丘脑、脑干和小脑）。将在PET会话的一周内获得大脑的结构磁共振图像，以帮助在PET上定位ROI。然后将受试者随机分配至活性尼古丁或匹配安慰剂贴片减量的10周疗程。将在每次每周治疗访视和治疗结束时使用受试者报告、呼出的一氧化碳水平和尿可替宁水平评估吸烟状态。ROI中的治疗前1422* nAChR密度将与治疗结果（例如，戒烟状态）和其他变量（尼古丁和安慰剂贴剂）。此外，我们将探索PET图像和评级量表的信息组合是否可用于更有力地识别尼古丁贴片治疗戒烟者。

DESCRIPTION (provided by applicant): Even though the health risks and societal costs of cigarette smoking are well-known, roughly 19.8% of American adults continue to smoke. While most smokers endorse a desire to quit, very few (< 5%) will actually quit in a given year without treatment, and only about 20-25% achieve abstinence after 6 months or more of effective treatment. Therefore, there continues to be a vital need to improve outcomes for cigarette smokers seeking treatment. Current first-line medications for Tobacco Dependence include nicotine replacement therapies (such as the patch, gum, lozenge, nasal spray, and inhaler), varenicline HCl (Chantix), and bupropion HCl (Zyban), with the current standard of care in most treatment settings being to choose specific medications based primarily on availability, ease of use, and patient preference. The goal of the proposed research is to improve the delivery of smoking cessation treatment by determining if pre-treatment 1422* nicotinic acetylcholine receptor (nAChR) density in cigarette smokers is associated with smoking cessation outcome with the standard nicotine patch taper. Pilot data from our ongoing studies using positron emission tomography (PET) and the radiotracer 2-[18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (abbreviated as 2-FA) in cigarette smokers indicate that the severity of up-regulation of 1422* nAChRs predicts who will be more or less likely to respond to treatment with the nicotine patch, and that this relationship between 1422* nAChR up-regulation and treatment outcome is more specific for nicotine patch treatment than for other smoking cessation treatments which are not linked as clearly with 1422* nAChR occupancy (e.g., bupropion HCl and group psychotherapy). The proposed study builds upon several ongoing lines of research. First, the 2-FA PET method to be used here was recently developed and refined by our group and close collaborators, and these refinements allow for improved precision in determining brain 1422* nAChR density in smokers than was previously possible. Second, both functional brain imaging studies of humans and post-mortem studies of human brain tissue demonstrate up-regulation of 1422* nAChRs in cigarette smokers compared to non-smoking controls, and the pilot data for this study indicates that the severity of this up-regulation is associated with response to nicotine replacement therapy. Third, the nicotine patch taper continues to be widely used. And fourth, clinical features and general measures of brain function (e.g., brain activity) have been used to predict treatment outcomes in Tobacco Dependence and other neuropsychiatric conditions; however, to our knowledge, there are no published reports linking the density of a specific brain receptor (1422* nAChRs) with treatment outcome for a medication that affects that receptor. For the proposed study, tobacco dependent cigarette smokers (n = 148; 10 to 30 cigarettes per day) will be recruited through newspaper and internet advertisements. Participants will undergo telephone and in-person screening, followed within one week by a 2-FA PET scanning session. For this PET session, a bolus of 2-FA will be injected over 1 minute and 2-FA will be infused for the remainder of the session. After 3 h (the amount of time needed for the radiotracer to reach an approximate steady state in the brain), participants will undergo 1 h of PET scanning. They will then be taken out of the scanner and will smoke to satiety (2 to 3 cigarettes). Participants will then be scanned an additional 3.5 h, so that both specific and non-displaceable 2-FA binding can be determined in regions of interest (ROIs) (e.g., thalamus, brainstem, and cerebellum). A structural magnetic resonance image of the brain will be obtained within one week of the PET session to aid in localization of ROIs on PET. Participants will then be randomly assigned to a 10-week course of treatment with either an active nicotine or matching placebo patch taper. Smoking status will be assessed at each weekly treatment visit and at the end of treatment using participant reports, exhaled carbon monoxide levels, and urinary cotinine levels. Pre-treatment 1422* nAChR density in the ROIs will be linked with treatment outcome (e.g., quit status) and other variables for the treatment groups (nicotine and placebo patch) separately and for the total group. Additionally, we will explore whether the combination of information from the PET images and rating scales can be used to identify even more robustly who will quit smoking with nicotine patch treatment.