Tobacco Smoking & Nicotinic Acetylcholine Receptors

描述（由申请人提供）：吸烟是高度成瘾性的，是众多社会、经济和医疗后果的来源。吸烟致死的美国人比事故、酗酒、火灾、非法毒品、艾滋病、谋杀和自杀加起来还要多，每年在美国导致大约40万人过早死亡。尽管有大量证据表明吸烟有医疗风险，但仍有大约20%的美国人继续吸烟。这些对社会造成的毁灭性损失强调了对吸烟成瘾形成和维持的神经化学机制进行研究的必要性。通过了解促进烟瘾的神经化学基质，可能会开发出更好的治疗这种破坏性和昂贵的脑部疾病的方法。尼古丁乙酰胆碱受体（nictinicacetylcholine receptor, nAChR）是烟草烟雾中主要致瘾化学物质尼古丁的初始作用位点。在目前的建议中，我们试图利用单光子发射计算机断层扫描（SPECT）和放射性示踪剂[12315 - 1a -85830 (5-1A)]在戒烟第一个月的吸烟者中成像β -烟碱乙酰胆碱受体（nAChR）上的激动剂结合位点。具体来说，我们建议1)确定最近戒烟的吸烟者与年龄、种族和性别匹配的非吸烟者相比，大脑中与nAChR结合的5-IA是否升高；2)确定吸烟者5-1A与nAChR的结合是否在使用应急管理维持戒烟四周后恢复正常；3)确定脑内5-1A与nAChR的结合是否与多形核淋巴细胞[3H]尼古丁结合相关。这些研究将描述戒烟第一个月吸烟者尼古丁受体上激动剂结合位点的调节状态，这将有助于指导有针对性的治疗策略的发展，以帮助这一严重成瘾人群。

DESCRIPTION (provided by applicant): Tobacco smoking is highly addictive and the source of a multitude of social, economic and medical consequences. Tobacco smoking kills more Americans than accidents, alcoholism, fires, illegal drugs, AIDS, murder and suicide combined and is responsible for approximately 400,000 premature deaths per year in the USA. Despite the overwhelming evidence of the medical risks associated with cigarette smoking, approximately 20% of the US population continues to smoke. These devastating costs to society underscore the need for research into the neurochemical mechanisms underlying the development and maintenance of the addiction to cigarette smoking. By understanding the neurochemical substrates promoting the addiction to cigarettes better treatments for this destructive and costly brain disorder may be developed. The nicotinic acetylcholine receptor (nAChR) is the initial site action of nicotine, the primary addictive chemical in tobacco smoke. In the present proposal, we seek to image the agonist binding site on beta2-nicotinic acetylcholine receptor (nAChR) using single photon emission computed tomography (SPECT) and the radiotracer [123115-1A-85830 (5-1A) in tobacco smokers over their first month of abstinence. Specifically, we propose 1) to determine if 5-IA binding to nAChR in brain is elevated in recently abstinent tobacco smokers as compared to age, race and sex-matched nonsmokers; 2) to determine if 5-1A binding to nAChR in smokers normalizes after four weeks of abstinence maintained using contingency management and 3) to determine if 5-1A binding to nAChR in brain correlates with [3H]nicotine binding in polymorphonuclear lymphocytes. These studies will characterize the regulatory state of the agonist binding site on the nicotinic receptor in smokers over the first month of smoking cessation, which will help guide the development of targeted treatment strategies to assist this severely addicted population.