Imaging Nicotinic & GABAergic Markers in Tobacco Smokers

烟碱成像

基本信息

批准号：
7681120
负责人：
JULIE K STALEY
金额：
$ 39.24万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7681120
关键词：
Abstinence Acute Affinity Age Agonist Aminobutyric Acid Aminobutyric Acids Animal Model Animals Anxiety Autopsy Behavior Benzodiazepine Receptor Benzodiazepines Binding Binding Sites Brain Cardiovascular Diseases Chronic Cigarette Data Dependence Disease Drug Delivery Systems Elevation Estradiol Exhibits Female Funding GABA Receptor Gonadal Steroid Hormones Hormones Human Image Laboratories Lead Learning Left Link Magnetic Resonance Spectroscopy Malignant Neoplasms Mediating Mental Depression Mood Disorders Nature Neurons Neurotransmitters Nicotine Nicotine Dependence Nicotinic Agonists Nicotinic Receptors Pharmaceutical Preparations Pharmacotherapy Phase I Clinical Trials Psychological reinforcement Reporting Residual state Scanning Sex Characteristics Smoke Smoker Smoking System Testing Time Tobacco Tobacco smoking Transdisciplinary Tobacco Research Center Week Withholding Treatment Woman center for epidemiological studies depression scale day depressive symptoms drug efficacy gabapentin gamma-Aminobutyric Acid improved iomazenil men neurochemistry nicotine replacement nicotinic receptor beta2 non-smoker proliferative phase Menstrual cycle pyridine radiotracer receptor receptor expression response sex single photon emission computed tomography smoking cessation trait uptake

项目摘要

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.

在烟草吸烟者中成像烟碱和GABA能标记男女之间吸烟和尼古丁成瘾的性质不同。特别是，妇女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较差。更容易患与吸烟相关的疾病（例如癌症和心血管疾病）和亚之症的情绪障碍（抑郁症和焦虑症）。对动物和人类的研究已将亚水产焦虑和抑郁症状与慢性尼古丁暴露联系起来。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，例如主要的抑制性神经递质，γ氨基丁酸（GABA）。高亲和力的烟碱激动剂结合在慢性治疗的动物中升高与烟草吸烟者的尼古丁以及死后大脑。目前尚不清楚NACHR的调节变化，对GABA能功能的后果。在本应用中，我们建议1）确定男性和女性从未吸烟的男性和女性与含BetA2的NACHR（Beta2-NACHR）结合的高亲和力激动剂的性别差异和最近戒烟者的性别差异。吸烟者与永不吸烟者相比，以及3）确定在禁欲的第一周，皮质GABA水平的性别特异性升高。尼古丁引起的皮质beta2-nachr，Gaba和Gabaa-BZR的适应性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。了解吸烟和急性戒酒对这些关键神经化学靶标的调节作用可能导致鉴定出更好的药物治疗，以减烟，以戒烟。