Nicotine and Food Intake

描述(申请人提供)：人体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，他们不愿戒烟，因为他们害怕增加体重，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自己的体重。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)中表达阿片黑素皮质素原(POMC)的烟碱型乙酰胆碱受体(NAChRs)，发出饱足感的信号，这是尼古丁减少小鼠摄食量所必需的。我们的初步分子遗传学和行为学研究已经确定了一个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，这些变化在很大一部分人中维持吸烟行为并降低戒烟动机。尼古丁对POMC神经元的影响在长期暴露后仍然存在，所涉及的nAChRs与那些介导药物最初奖赏效应的nAChRs不同。电生理研究表明，在ARC的POMC神经元和神经肽Y(NPY)表达的神经元上都有nAChRs，但POMC神经元的烟碱电流比NPY神经元的大。我们还发现，尼古丁给药调节突触前GABA输入到ARC的POMC神经元。因此，我们认为ARC胞体和终末上nAChR亚型的不同活动和脱敏可能有助于维持尼古丁依赖的摄食行为的减少，而通过这些改变的nAChR通路的乙酰胆碱(ACh)信号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归因于尼古丁激活和差异脱敏POMC和AGRP/NPY表达神经元及其突触前输入上不同nAChR亚型的能力，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，ARC中通过nAChRs的ACh信号的不平衡可能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学技术确定ARC中特定神经细胞类型上表达的nAChR亚单位；2)使用电生理和生化技术确定尼古丁注射期间和戒断后nAChR信号是否存在适应性，并使用细胞类型选择性shRNA传递来确定特定nAChR亚单位对神经元电流和摄食行为的贡献；3)使用光遗传学和行为技术确定胆碱能信号对基线、尼古丁注射期间和戒断后食物摄入量的影响。

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.