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）：人类吸烟和动物服用尼古丁会降低食欲和体重。许多吸烟者报告说，他们不愿意戒烟是因为他们害怕体重增加，而一部分吸烟者，特别是少女，报告说他们开始吸烟是为了控制体重。尼古丁是烟草中主要的精神活性物质，它刺激下丘脑弓状核（ARC）中表达鸦片黑素皮质素（POMC）的神经元上的尼古丁乙酰胆碱受体（nAChRs），该受体发出饱腹感信号，这是尼古丁减少小鼠食物摄入量的能力所必需的。我们初步的分子遗传和行为研究已经确定了一种特定的细胞类型和回路，我们可以进一步研究，以评估尼古丁和尼古丁戒断对食欲变化的影响，这些变化维持了吸烟行为，降低了很大一部分人戒烟的动机。尼古丁对POMC神经元的影响在长期暴露后持续存在，所涉及的nachr与那些介导药物初始奖励效应的nachr不同。电生理研究表明，在ARC的POMC-神经元以及驱动食物摄入的神经肽Y （NPY）表达神经元上都存在nachr；然而，POMC神经元中的尼古丁电流大于NPY神经元。我们还发现尼古丁可以调节ARC中POMC神经元的突触前GABA输入。因此，我们提出，ARC细胞体和终末nAChR亚型的不同活性和脱敏可能有助于维持尼古丁依赖性摄食行为的减少，并且乙酰胆碱（ACh）信号通过这些改变的nAChR途径可能有助于戒断后体重增加。我们的假设是，吸烟对食欲的影响至少部分是由于尼古丁能够激活POMC-和AGRP/ npy表达神经元及其突触前输入上不同的nAChR亚型，并使其差异脱敏，这也可能导致这些受体上内源性ACh信号的改变。在慢性尼古丁暴露后，通过ARC中nachr的乙酰胆碱信号不平衡可能导致戒断期间食物摄入量增加。在这些研究中，我们将：1)利用分子生物学和解剖学技术鉴定在ARC中特定神经元细胞类型上表达的nAChR亚基；2)利用电生理和生化技术确定尼古丁给药期间和戒断后nAChR信号是否存在适应性，并利用细胞型选择性shRNA递送确定特定nAChR亚基对神经元电流和摄食行为的贡献；3)利用光遗传学和行为学技术确定基线、给药期间和停药后胆碱能信号对食物摄入的影响。