Brain Nicotine Receptor Density & Response to Nicotine Patch

脑尼古丁受体密度

• 批准号: 8105537
• 负责人: Arthur Brody
• 金额: $ 19.7万
• 依托单位: BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105537
• 关键词: Abstinence; Adult; Advertisements; Affect; Aftercare; American; Binding; Bolus Infusion; Brain; Brain Stem; Brain imaging; Bupropion HCl; Carbon Monoxide; Cerebellum; Chantix; Cigarette; Cigarette Smoker; Clinical; Clinical Data; Continuous Infusion; Cotinine; Data; Exhalation; Goals; Group Psychotherapy; Health; Human; Image; Inhalators; Internet; Lead; Link; Magnetic Resonance Imaging; Measures; Mental Depression; Methods; Newspapers; Nicotine; Nicotine Dependence; Nicotinic Receptors; Nose; Outcome; Participant; Patient Preferences; Patients; Persons; Pharmaceutical Preparations; Placebos; Positron-Emission Tomography; Procedures; Publishing; Randomized; Receptor Up-Regulation; Recruitment Activity; Reporting; Research; Risk; Satiation; Scanning; Screening procedure; Self Efficacy; Severities; Smoke; Smoker; Smoking; Smoking Status; Telephone; Thalamic structure; Time; TimeLine; Tobacco; Tobacco Dependence; Treatment outcome; Up-Regulation; Visit; Withholding Treatment; Zyban; base; brain tissue; cigarette smoking; cost; craving; density; effective therapy; follow-up; imaging modality; improved; interest; neuropsychiatry; nicotine patch; nicotine replacement; non-smoker; non-smoking; pyridine; radiotracer; receptor; receptor density; response; smoking cessation; smoking prevalence; standard of care; urinary; varenicline

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. PUBLIC HEALTH RELEVANCE: Cigarette smokers have elevated levels of nicotine receptors in the brain compared to non-smokers. Recently, we developed a relatively precise brain imaging method to examine levels of brain nicotine receptors in human smokers. The study proposed here will use this method to determine if pre-treatment brain nicotine receptor levels can be used to predict which smokers are more or less likely to quit smoking with nicotine patch treatment. It is hypothesized that smokers with less elevation of nicotine receptors will have better responses to treatment than smokers with more severe elevation of these receptors.

描述（由申请人提供）：尽管吸烟的健康风险和社会成本是众所周知的，但大约19.8%的美国成年人继续吸烟。虽然大多数吸烟者都有戒烟的愿望，但很少（< 5%）的人会在没有治疗的情况下在给定的一年内真正戒烟，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，改善寻求治疗的吸烟者的结果仍然是至关重要的。目前治疗烟草依赖的一线药物包括尼古丁替代疗法（如贴片、口香糖、含片、鼻喷雾剂和吸入器）、盐酸伐尼克兰（Chantix）和盐酸安非他酮（Zyban），目前在大多数治疗环境中的护理标准是主要根据可获得性、易用性和患者偏好来选择特定药物。拟议研究的目的是通过确定吸烟者治疗前1422*尼古丁乙酰胆碱受体（nAChR）密度是否与标准尼古丁贴片逐渐减少的戒烟结果相关，从而改善戒烟治疗的提供。我们正在对吸烟者进行的正电子发射断层扫描（PET）和放射性示踪剂2-[18F]氟-3-（2(S)偶氮基甲氧基）吡啶（简称2- fa）的初步研究数据表明，1422* nAChRs上调的严重程度预示着谁或多或少可能对尼古丁贴片治疗有反应。1422* nAChR上调与治疗结果之间的关系在尼古丁贴片治疗中比其他与1422* nAChR占用没有明显联系的戒烟治疗（例如盐酸安非他酮和团体心理治疗）更为特异性。这项拟议的研究建立在几项正在进行的研究基础上。首先，这里使用的2-FA PET方法是最近由我们的团队和密切的合作者开发和改进的，这些改进可以提高测定吸烟者大脑1422* nAChR密度的精度。其次，人类脑功能成像研究和人类脑组织的尸检研究都表明，与不吸烟的对照组相比，吸烟人群中1422* nachr表达上调，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，尼古丁贴片锥形继续被广泛使用。第四，临床特征和脑功能的一般测量（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* nAChRs）的密度与影响该受体的药物的治疗结果联系起来。在拟议的研究中，将通过报纸和互联网广告招募烟草依赖吸烟者（n = 148，每天10至30支香烟）。参与者将接受电话和现场筛查，然后在一周内进行2-FA PET扫描。对于这个PET疗程，将在1分钟内注射2-FA，并在剩余的时间内注射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），参与者将进行1小时的PET扫描。然后，他们将被带出扫描仪，吸到饱（2到3支烟）。然后，参与者将被额外扫描3.5小时，以便在感兴趣的区域（例如，丘脑、脑干和小脑）中确定特异性和不可置换的2-FA结合。将在PET治疗后一周内获得大脑的结构磁共振图像，以帮助定位PET上的roi。然后，参与者将被随机分配到一个为期10周的疗程中，要么服用活性尼古丁，要么服用相应的安慰剂贴片。吸烟状况将在每周治疗访问和治疗结束时使用参与者报告、呼出一氧化碳水平和尿可替宁水平进行评估。治疗前roi中的1422* nAChR密度将分别与治疗组（尼古丁和安慰剂贴片）的治疗结果（例如戒烟状态）和其他变量相关联，并与整个组相关联。此外，我们将探索PET图像和评分量表的信息组合是否可以用于更有效地识别谁将通过尼古丁贴片治疗戒烟。