Imaging Nicotinic & GABAergic Markers in Smokers

烟草吸烟者的烟碱和GABA能标记物成像 吸烟和尼古丁成瘾的性质在男女之间是不同的。特别是，女性似乎对尼古丁的药理作用不太敏感，更耐受。妇女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）和亚综合征情绪障碍（抑郁和焦虑）。对动物和人类的研究表明，亚综合征焦虑和抑郁症状与慢性尼古丁暴露有关。在大脑中，尼古丁与烟碱乙酰胆碱受体（nAChR）结合，并启动大多数主要神经递质的释放，如主要的抑制性神经递质γ氨基丁酸（GABA）。高亲和力烟碱激动剂结合在长期治疗的动物中升高 以及吸烟者死后的大脑中也有这种现象。nAChR的调节变化对GABA能功能的影响目前尚不清楚。在本申请中，我们提出1）确定与含β 2的nAChR结合的高亲和力烟碱激动剂是否存在性别差异（β 2-nAChR）在男性和女性从不吸烟者和最近戒烟的吸烟者2）确定皮质GABA和GABAA-苯二氮卓类药物是否与从不吸烟者相比，主动依赖烟草吸烟者中的GABAA-BZR受体以性别特异性方式减少，和3）确定在戒烟的第一周内皮质GABA水平是否存在性别特异性升高。 尼古丁诱导的皮质β 2-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。了解吸烟和急性戒断对大脑中这些关键神经化学靶点的调节作用，可能会导致确定更好的药物治疗男性和女性吸烟者戒烟。

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.