Nicotinic Acetylcholine Receptor Density and Veteran Cigarette Smokers

描述(由申请人提供)： 尽管烟草控制有所改善，但在退伍军人中吸烟的流行率仍然很高，为27%，在美国总人口(约4600万美国成年人)中为21%。在这些吸烟者中，大约33%吸薄荷醇，这意味着大约9%的退伍军人吸薄荷醇香烟。除了薄荷醇香烟在退伍军人中的普遍使用外，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，薄荷醇香烟的开始和营销主要针对组成现役军人的年龄段。薄荷醇香烟的一个核心困难是，在标准化治疗计划中，使用薄荷醇香烟的吸烟者戒烟率低于使用非薄荷醇香烟的吸烟者。尽管薄荷醇香烟的开始和持续使用涉及许多因素，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，而且薄荷醇香烟吸烟会导致血清尼古丁和可替宁水平升高，呼出的一氧化碳水平更高。这些升高的水平有望上调大脑1422*烟碱型乙酰胆碱受体(NAChRs)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。基于为这项拨款申请收集的先前文献和试点数据，提议的研究的主要假设是：1)治疗前，薄荷醇吸烟者丘脑(和其他感兴趣的大脑区域)中的1422*nAChR密度将高于非薄荷醇吸烟者，2)从戒烟前到戒烟后(结合尼古丁贴片治疗、认知行为团体心理治疗和应急管理)，吸薄荷醇香烟的吸烟者丘脑(和其他感兴趣的大脑区域)的1422*nAChR密度将比非薄荷醇吸烟者降低得更多，3)接受治疗戒烟的薄荷醇香烟吸烟者(与接受治疗但没有戒烟的人相比)在感兴趣区域的1422*nAChR密度将比不戒烟的非薄荷醇香烟吸烟者降低更多；4)1422*nAChR在基线水平上调的严重程度(以及临床因素，如尼古丁依赖程度较低)将与更好的治疗结果相关，包括戒烟和/或减少吸烟的可能性增加。为了验证这些假设，薄荷醇和非薄荷醇香烟吸烟者将通过在退伍军人管理局大洛杉矶戒烟计划分发的传单招募。参与者将接受以下顺序的程序：(1)电话/面对面筛查，(2)推注+持续输注2-FA正电子发射断层扫描(PET)扫描，(3)在首次PET治疗后一周内进行结构磁共振成像扫描，(4)采用尼古丁贴片逐渐减少加认知行为团体心理治疗(CBT)的标准治疗10周，(5)持续CBT加应急处理(CM)治疗4周，以及(6)在14周治疗周期结束时，采用与初始PET疗程相同的方案进行后续的2-FA PET疗程。将在治疗前、治疗中和治疗结束时收集确定吸烟相关症状的评分表。在整个研究过程中，将使用参与者报告、呼出的一氧化碳(CO)水平、尿可替宁水平以及血浆尼古丁、可替宁和3‘-羟基可替宁水平来收集吸烟状况以及尼古丁暴露和代谢的测量结果。宠物数据将 被分析以确定主要大脑感兴趣区域的总分布体积(VT) (与4 2*nAChR密度成正比)。对于中心研究分析，将确定薄荷醇吸烟者和非薄荷醇吸烟者之间治疗前VT水平的差异，然后比较薄荷醇吸烟者和非薄荷醇吸烟者在戒烟治疗后VT水平的变化。还将对薄荷醇吸烟者和非薄荷醇吸烟者的VT水平变化进行比较，包括戒烟状态作为一个因素。此外，还将确定治疗前VT水平(和其他与吸烟有关的变量)在决定谁将通过治疗戒烟方面的预测价值。如果中心假设成立，这项研究将确定对薄荷醇香烟成瘾相对严重的潜在中介因素， 这导致这些吸烟者比不吸薄荷醇香烟的人更难戒烟。因此，这项拟议的研究可能有助于我们理解大脑1422*nAChR密度、薄荷醇吸烟、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)对薄荷醇吸烟者的治疗产生影响。

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.