Imaging Nicotinic & GABAergic Markers in Smokers

烟碱成像

• 批准号: 6864141
• 负责人: JULIE K STALEY
• 金额: $ 26.81万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6864141
• 关键词: GABA receptor; behavioral /social science research tag; benzodiazepine receptor; benzodiazepines; clinical research; drug addiction; gamma aminobutyrate; gender difference; human subject; neurochemistry; nicotine; nicotinic receptors; nuclear magnetic resonance spectroscopy; receptor binding; single photon emission computed tomography; smoking cessation; substance abuse related behavior; therapy compliance; tobacco abuse

Imaging Nicotinic & GABAergic Markers in Tobacco Smokers The nature of tobacco smoking and nicotine addiction is different between women and men. In particular, women appear to be less sensitive and more tolerant to the pharmacological effects of nicotine. Women also exhibit a poorer response to nicotine replacement therapies; are more vulnerable to smoking-related diseases (e.g. cancer and cardiovascular disease) and to subsyndromal mood disorders (depression and anxiety). Studies in animals and humans have linked subsyndromal anxiety and depressive symptoms to chronic nicotine exposure. In brain, nicotine binds to nicotinic acetylcholine receptors (nAChR) and initiates the release of most major neurotransmitters such as the major inhibitory neurotransmitter, gamma aminobutyric acid (GABA). High-affinity nicotinic agonist binding is elevated in animals chronically treated with nicotine and also in postmortem brain from tobacco smokers. The consequences of the regulatory changes in the nAChR, on GABAergic function are currently not well understood. In the present application, we propose 1) To determine if there are sex differences in high affinity nicotinic agonist binding to beta2-containing nAChR (beta2-nAChR) in men and women never smokers and recently abstinent smokers 2) To determine if cortical GABA and GABAA-benzodiazepine (GABAA-BZR) receptors are decreased in a sex-specific manner in actively dependent tobacco smokers compared to never smokers, and 3) To determine if there is a sex-specific elevation in cortical GABA levels over the first week of abstinence from smoking. Nicotine-induced adaptations in cortical beta2-nAChR, GABA and GABAA-BZR may underlie the anxiety and/or depressive symptoms often observed in women smokers. An understanding of the regulatory effects of smoking and acute abstinence on these key neurochemical targets in brain, may lead to the identification of better pharmacotherapies for smoking cessation in men and women smokers.

吸烟者体内烟碱能和GABA能标志物的成像 吸烟和尼古丁成瘾的性质在女性和男性之间是不同的。特别是，女性似乎对尼古丁的药理作用不那么敏感，更能耐受。女性对尼古丁替代疗法的反应也较差；更容易患上与吸烟有关的疾病(如癌症和心血管疾病)以及亚综合征情绪障碍(抑郁和焦虑)。对动物和人类的研究已经将亚综合征焦虑和抑郁症状与慢性尼古丁接触联系起来。在大脑中，尼古丁与烟碱型乙酰胆碱受体(NAChR)结合，并启动大多数主要神经递质的释放，如主要抑制性神经递质伽马氨基丁酸(GABA)。在长期治疗的动物中，高亲和力尼古丁激动剂结合增加 尼古丁和烟草吸烟者的死后大脑中。目前还不清楚nAChR调控变化对GABA能功能的影响。在目前的应用中，我们建议1)确定在从不吸烟和最近戒烟的男性和女性中，高亲和力尼古丁激动剂与含有β2的nAChR(β2-nAChR)结合是否存在性别差异；2)确定积极依赖烟草的吸烟者与从不吸烟者相比，皮质GABA和GABAA-苯二氮卓(GABAA-BZR)受体是否以性别特异性的方式减少；以及3)确定在戒烟的第一周，皮质GABA水平是否存在性别特异性的升高。 尼古丁诱导的皮质β2-nAChR、GABA和GABAA-BZR的适应可能是女性吸烟者经常观察到的焦虑和/或抑郁症状的基础。了解吸烟和急性戒烟对大脑中这些关键神经化学指标的调节作用，可能有助于确定对男性和女性吸烟者更好的戒烟药物疗法。