Nicotine and Food Intake

尼古丁和食物摄入量

• 批准号: 8828369
• 负责人: Marina R Picciotto
• 金额: $ 41.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828369
• 关键词: ART protein; Acetylcholine; Acute; Adolescence; Animals; Behavior; Behavioral; Biochemical; Biological; Body Weight; Brain; Cells; Chronic; Data; Desire for food; Development; Drosophila acetylcholine receptor alpha-subunit; Eating; Equilibrium; Feeding behaviors; Female; Fluorescent in Situ Hybridization; Health; Human; Hypothalamic structure; Individual; Lasers; Lead; Mediating; Metabolic Pathway; Methods; Microscopy; Molecular; Molecular Genetics; Motivation; Mus; Neurons; Nicotine; Nicotine Withdrawal; Nicotinic Receptors; Pathway interactions; Pharmaceutical Preparations; Population; Pro-Opiomelanocortin; Publications; Reporting; Rewards; Satiation; Signal Transduction; Site; Slice; Smoke; Smoker; Smoking; Smoking Behavior; Structure of nucleus infundibularis hypothalami; Synapses; Techniques; Tobacco; Tobacco smoking; Transgenic Mice; Weight; Weight Gain; Withdrawal; cell type; cholinergic; desensitization; gamma-Aminobutyric Acid; girls; in vivo; knock-down; male; neurobiological mechanism; neuronal cell body; neuropeptide Y; novel; optogenetics; presynaptic; protein expression; receptor; research study; small hairpin RNA; smoking cessation

DESCRIPTION (provided by applicant): Tobacco smoking in humans and nicotine administration in animals decrease appetite and body weight. Many smokers report that they are reluctant to quit because they are afraid to gain weight, and subsets of smokers, including teenage girls in particular, report that they initiate smoking to control their weight. Nicotine, te primary psychoactive substance in tobacco, stimulates nicotinic acetylcholine receptors (nAChRs) on the pro- opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) that signal satiety, and this is required for the ability of nicotine to decrease food intake in mice. Our preliminary molecular genetic and behavioral studies have identified a specific cell type and circuit, that we can investigate further to evaluate the effect of nicotine and nicotine withdrawal on the changes in appetite that maintain smoking behavior and decrease motivation to quit in a large subset of individuals. The effects of nicotine on POMC neurons persist after chronic exposure, and the nAChRs involved are distinct from those that mediate the initial rewarding effects of the drug. Electrophysiological studies have shown that there are nAChRs on both POMC- neurons in the ARC, as well as neuropeptide Y (NPY)-expressing neurons that drive food intake; however, nicotinic currents in POMC neurons are larger than in NPY neurons. We have also found that nicotine administration modulates presynaptic GABA inputs to POMC neurons in ARC. Thus, we propose that differential activity and desensitization of nAChR subtypes on cell bodies and terminals in ARC may contribute to maintainenance of nicotine-dependent decreases in feeding behavior and that acetylcholine (ACh) signaling through these altered nAChR pathways could contribute to weight gain following withdrawal. Our hypothesis is that the effects of smoking on appetite are due, at least in part, to the ability of nicotine to activate, and differentially desensitize, distinct nAChR subtypes on POMC- and AGRP/NPY-expressing neurons and their presynaptic inputs, which could also lead to altered signaling of endogenous ACh at these receptors. Following chronic nicotine exposure, an imbalance of ACh signaling through nAChRs in the ARC could then lead to increases in food intake during the withdrawal period. In these studies we will: 1) use molecular biological and anatomical techniques to identify the nAChR subunits expressed on specific neuronal cell types in the ARC; 2) use electrophysiological and biochemical techniques to determine whether there are adaptations in nAChR signaling during nicotine administration and after withdrawal and use cell-type selective shRNA delivery to determine the contribution of specific nAChR subunits to neuronal currents and feeding behavior; 3) and use optogenetic and behavioral techniques to determine the effects of cholinergic signaling on food intake at baseline, during nicotine administration and after withdrawal.

描述（由申请人提供）：人类吸烟和动物的尼古丁给药可减少食欲和体重。许多吸烟者报告说，他们不愿退出，因为他们害怕体重增加，尤其是少女在内的吸烟者的子集报告说，他们会发起吸烟以控制体重。烟草中的主要心理活性物质在烟草中刺激烟碱乙酰胆碱受体（NACHRS），这些苯基苯甲酸酯（POMC）表达神经元的神经元在假设的阳离子核（ARC）（ARC）中，该假设的假设核（ARC）信号是含糊不清的，这是对烟气的信号和烟气的能力。我们的初步分子遗传和行为研究已经确定了特定的细胞类型和电路，我们可以进一步研究，以评估尼古丁和尼古丁戒断对维持吸烟行为的食欲变化的影响，并减少了大量个体中戒烟的动机。尼古丁对慢性暴露后POMC神经元的影响以及所涉及的NACHR的影响与介导该药物初始奖励作用的nachr不同。电生理学研究表明，弧线中的POMC-神经元上都有NACHR，以及表达食物摄入量的神经肽Y（NPY）表达神经元。但是，POMC神经元中的烟碱电流大于NPY神经元中的烟碱电流。我们还发现，尼古丁给药会调节ARC中POMC神经元的突触前GABA输入。因此，我们提出，NACHR亚型对细胞体和ARC中末端的差异活性和脱敏可能有助于维持喂养行为的尼古丁依赖性降低，而该乙酰胆碱（ACH）信号通过这些改变的NACHR途径可能导致体重增加后的体重增加。我们的假设是，至少部分是由于尼古丁激活和差异脱敏的，不同的NACHR亚型对POMC和AGRP/NPY表达神经元的脱敏的能力及其脱敏性脱敏的能力，这也可能导致这些受体的信号变化。慢性尼古丁暴露后，通过ARC中NACHR的ACH信号失衡可能会导致戒断期间食物摄入量的增加。在这些研究中，我们将：1）使用分子生物学和解剖技术来识别ARC中特定神经元细胞类型表达的NACHR亚基； 2）使用电生理和生化技术来确定尼古丁给药期间NACHR信号的适应性以及戒断后是否存在适应性，并使用细胞型选择性SHRNA递送来确定特定NACHR亚基对神经元电流的贡献； 3）并使用光遗传学和行为技术来确定胆碱能信号传导对基线，尼古丁给药期间和退出后食物摄入的影响。