Nicotinic Acetylcholine Receptor Density and Veteran Cigarette Smokers

烟碱乙酰胆碱受体密度和老烟民

• 批准号: 8244305
• 负责人: Arthur Brody
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244305
• 关键词: Abstinence; Adult; Affect; Affinity; Aftercare; Applications Grants; Behavioral; Binding; Biological Markers; Bolus Infusion; Brain; Brain imaging; Brain region; Carbon Monoxide; Cigarette; Cigarette Smoker; Clinical; Cognitive; Continuous Infusion; Cotinine; Data; Data Analyses; Dose; Exhalation; Funding; Future; Group Psychotherapy; Human; Literature; Los Angeles; Magnetic Resonance Imaging; Marketing; Measures; Mediating; Mental Depression; Menthol; Metabolism; Methods; Military Personnel; Morbidity - disease rate; Nicotine; Nicotine Dependence; Nicotinic Receptors; Outcome; Participant; Persons; Pilot Projects; Plasma; Population; Positron-Emission Tomography; Predictive Value; Prevalence; Procedures; Protocols documentation; Receptor Up-Regulation; Recruitment Activity; Relative (related person); Reporting; Research; Satiation; Serum; Severities; Smoke; Smoker; Smoking; Smoking Status; Specificity; Symptoms; Telephone; Testing; Thalamic structure; Time; Tobacco Dependence; Treatment outcome; Up-Regulation; Urine; Veterans; Withholding Treatment; addiction; age group; base; cigarette smoking; contingency management; craving; density; follow-up; hydroxycotinine; improved; interest; member; mortality; nicotine patch; nicotinic receptor alpha4beta2; non-smoker; non-smoking; programs; public health relevance; pyridine; radiotracer; receptor density; response; screening; smoking cessation; standard care; tobacco control; treatment duration; treatment program

DESCRIPTION (provided by applicant): Despite improvements in tobacco control, the prevalence of cigarette smoking remains high at 27% among Veterans and 21% among the general U.S. population (~46 million U.S. adults). Of these smokers, approximately 33% smoke menthols, meaning that roughly 9% of all Veterans smoke menthol cigarettes. In addition to menthol cigarette usage being prevalent among Veterans, this problem is likely to worsen over time, because recent military deployments increase the chances of smoking initiation and marketing of menthol cigarettes is aimed at roughly the age group that comprises the active military. A central difficulty with menthol cigarettes is that smokers who use them have lower cessation rates in standardized treatment programs than smokers who use non-menthol cigarettes. Though many factors have been implicated in the initiation and continued usage of menthol cigarettes, studies of biological markers of smoking demonstrate that menthol itself inhibits nicotine metabolism, and that menthol cigarette smoking leads to elevated serum levels of nicotine and cotinine, and greater exhaled carbon monoxide levels. These elevated levels would be expected to up-regulate the density of brain 1422* nicotinic acetylcholine receptors (nAChRs), which could mediate the greater severity of Tobacco Dependence found in menthol cigarette smokers; however, these points have not yet been demonstrated in human smokers. Based on prior literature and pilot data collected for this grant application, the primary hypothesis for the proposed research are that: 1) pre-treatment 1422* nAChR densities in the thalami (and other brain regions of interest) will be higher in menthol than non-menthol cigarette smokers, 2) menthol cigarette smokers will have greater reductions in 1422* nAChR density in the thalami (and other brain regions of interest) from before to after quitting smoking (with combination treatment with the nicotine patch, cognitive behavioral group psychotherapy, and contingency management) than non-menthol cigarette smokers, 3) menthol cigarette smokers who quit smoking with treatment (compared to those who receive treatment but do not quit) will have greater reductions in 1422* nAChR density in the regions of interest than non-menthol cigarette smokers who quit (compared to those who do not quit), and 4) lesser severity of 1422* nAChR up-regulation at baseline (along with clinical factors such as lesser severity of nicotine dependence) will be associated with better treatment outcomes, including an improved likelihood of quitting and/or decreasing smoking. To test these hypotheses, menthol and non-menthol cigarette smokers will be recruited through flyers distributed at the VA Greater Los Angeles Smoking Cessation Programs. Participants will undergo the following sequence of procedures: (1) telephone/in-person screening, (2) a bolus-plus-continuous-infusion 2- FA positron emission tomography (PET) scanning session, (3) a structural magnetic resonance imaging scan within one week of the initial PET session, (4) ten weeks of standard treatment with a nicotine patch taper plus cognitive-behavioral group psychotherapy (CBT), (5) four weeks of treatment with continued CBT plus contingency management (CM), and (6) a follow-up 2-FA PET session with the same protocol as the initial PET session at the end of the 14-week treatment period. Rating scales for the determination of smoking- related symptoms will be collected before, during, and at the end of treatment. Smoking status and measures of nicotine exposure and metabolism will be collected throughout the study using participant reports, exhaled carbon monoxide (CO) levels, urine cotinine levels, and plasma nicotine, cotinine, and 3'-hydroxycotinine levels. PET data will be analyzed to determine the total volume of distribution (VT) in primary brain regions of interest (a measure directly proportional to 4 2* nAChR density). For the central study analyses, differences in pre-treatment VT levels between menthol and non-menthol smokers will be determined, followed by a comparison of changes in VT levels between menthol and non-menthol smokers who quit with treatment. A comparison of VT level change in menthol and non-menthol smokers will also be performed including quit status as a factor. And, the predictive value of pre-treatment VT levels (and other smoking-related variables) in determining who will quit with treatment will also be determined. If the central hypotheses hold true, this study will identify a potential mediating factor for the relative severity of addiction to menthol cigarettes, which results in these smokers having more difficulty quitting than non-menthol cigarette smokers. Thus, the proposed study may contribute to our understanding of the relationships between brain 1422* nAChR densities, menthol cigarette smoking, subjective symptoms of Nicotine Dependence, nicotine metabolism, and treatment outcomes, and may (in the future) have implications for the treatment of menthol cigarette smokers.

描述（由申请人提供）： 尽管烟草控制有所改善，但吸烟的流行率仍然很高，退伍军人中为27%，美国普通人口中为21%（约4600万美国成年人）。在这些吸烟者中，大约33%的人吸烟薄荷，这意味着大约9%的退伍军人吸烟薄荷香烟。除了薄荷醇香烟的使用在退伍军人中很普遍之外，这个问题可能会随着时间的推移而恶化，因为最近的军事部署增加了吸烟的机会，并且薄荷醇香烟的营销目标大致是包括现役军人的年龄组。 薄荷醇香烟的一个主要困难是，使用薄荷醇香烟的吸烟者在标准化治疗计划中的戒烟率低于使用非薄荷醇香烟的吸烟者。虽然许多因素与薄荷醇香烟的开始和持续使用有关，但对吸烟生物标志物的研究表明，薄荷醇本身抑制尼古丁代谢，并且薄荷醇香烟吸烟导致尼古丁和可替宁的血清水平升高，以及呼出的一氧化碳水平升高。预期这些升高的水平将上调脑1422* 烟碱乙酰胆碱受体（nAChR）的密度，这可能介导在薄荷醇香烟吸烟者中发现的更严重的烟草依赖;然而，这些点尚未在人类吸烟者中得到证实。 根据先前的文献和为这项拨款申请收集的试点数据，拟议研究的主要假设是：1）处理前丘脑中的1422* nAChR密度（和其他感兴趣的大脑区域）的薄荷醇含量将高于非薄荷醇香烟吸烟者，2）薄荷醇香烟吸烟者丘脑中1422* nAChR密度将有更大的降低（和其他感兴趣的大脑区域）从戒烟前到戒烟后（与尼古丁贴片，认知行为团体心理治疗和应急管理联合治疗）比非薄荷醇香烟吸烟者，3）薄荷香烟吸烟者通过治疗戒烟（与接受治疗但不戒烟的人相比）在感兴趣区域中的1422* nAChR密度将比戒烟的非薄荷醇香烟吸烟者有更大的降低（与不放弃的人相比），和4）基线时1422* nAChR上调的严重程度较低（沿着临床因素，如尼古丁依赖的严重程度较低）将与更好的治疗结果相关，包括提高戒烟和/或减少吸烟的可能性。 为了检验这些假设，将通过在VA大洛杉矶戒烟计划分发的传单招募薄荷醇和非薄荷醇卷烟吸烟者。参与者将接受以下程序：（1）电话/现场筛查，（2）推注加连续输注2- FA正电子发射断层扫描（PET）扫描，（3）在初始PET扫描后一周内进行结构磁共振成像扫描，（4）尼古丁贴片减量加认知行为团体心理治疗（CBT）的10周标准治疗，（5）持续CBT+应急管理（CM）治疗4周，以及（6）在14周治疗期结束时，采用与初始PET治疗相同的方案进行随访2-FA PET治疗。将在治疗前、治疗期间和治疗结束时收集用于确定吸烟相关症状的评定量表。将在整个研究期间使用受试者报告、呼出一氧化碳（CO）水平、尿可替宁水平和血浆尼古丁、可替宁和3 '-羟基可替宁水平收集吸烟状态和尼古丁暴露和代谢指标。 PET数据将 分析以确定主要感兴趣脑区域中的总分布容积（VT （与42 * nAChR密度成正比的量度）。对于中心研究分析，将确定薄荷醇和非薄荷醇吸烟者之间治疗前VT水平的差异，然后比较治疗后戒烟的薄荷醇和非薄荷醇吸烟者之间VT水平的变化。还将比较薄荷醇和非薄荷醇吸烟者的VT水平变化，包括戒烟状态作为一个因素。而且，还将确定治疗前VT水平（和其他吸烟相关变量）在确定谁将通过治疗戒烟方面的预测价值。 如果中心假设成立，这项研究将确定一个潜在的中介因素的相对严重程度上瘾的薄荷醇香烟， 这导致这些吸烟者比非薄荷醇香烟吸烟者更难戒烟。因此，拟议的研究可能有助于我们理解大脑1422* nAChR密度，薄荷醇香烟吸烟，尼古丁依赖的主观症状，尼古丁代谢和治疗结果之间的关系，并可能（在未来）对薄荷醇香烟吸烟者的治疗产生影响。