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，因为他们害怕体重增加，而部分吸烟者，特别是十几岁的女孩，报告说他们开始吸烟是为了控制体重。尼古丁是烟草中的主要精神活性物质，它刺激下丘脑（ARC）弓状核（ARC）表达阿片黑皮质素原（POMC）的神经元上的烟碱乙酰胆碱受体（nAChR），从而发出饱腹感，这是尼古丁发挥作用所必需的。以减少小鼠的食物摄入量。我们的初步分子遗传学和行为研究已经确定了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维持吸烟行为并降低大部分个体戒烟动机的食欲变化的影响。长期暴露后，尼古丁对 POMC 神经元的影响持续存在，并且所涉及的 nAChR 与介导药物最初奖励作用的 nAChR 不同。电生理学研究表明，ARC 中的 POMC 神经元以及表达神经肽 Y (NPY) 的神经元上都存在 nAChR，这些神经元可驱动食物摄入；然而，POMC 神经元中的烟碱电流大于 NPY 神经元中的烟碱电流。我们还发现尼古丁的施用会调节 ARC 中 POMC 神经元的突触前 GABA 输入。因此，我们认为 ARC 细胞体和末端上 nAChR 亚型的差异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，并且通过这些改变的 nAChR 途径的乙酰胆碱 (ACh) 信号传导可能有助于戒断后的体重增加。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 亚型并使其不同程度脱敏的能力，这可能也会导致这些受体上内源性乙酰胆碱信号传导的改变。长期接触尼古丁后，ARC 中 nAChR 的乙酰胆碱信号传导失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）使用分子生物学和解剖学技术来识别 ARC 中特定神经元细胞类型表达的 nAChR 亚基； 2）使用电生理学和生化技术来确定尼古丁给药期间和戒断后nAChR信号传导是否存在适应性，并使用细胞类型选择性shRNA递送来确定特定nAChR亚基对神经元电流和进食行为的贡献； 3）并使用光遗传学和行为技术来确定胆碱能信号对基线、尼古丁给药期间和戒断后食物摄入的影响。