Nicotine and Food Intake

性状（由申请方提供）：人类吸烟和动物给予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。尼古丁是烟草中的主要精神活性物质，其刺激下丘脑弓状核（ARC）中表达前阿黑皮素（POMC）的神经元上的烟碱乙酰胆碱受体（nAChR），所述神经元发出饱腹感信号，并且这是尼古丁减少小鼠食物摄入的能力所必需的。我们的初步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，这些食欲变化维持了吸烟行为并降低了大量个体的戒烟动机。尼古丁对POMC神经元的影响在慢性暴露后持续存在，并且所涉及的nAChRs与介导药物初始奖励效应的nAChRs不同。电生理学研究表明，在ARC中的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神经元中的烟碱电流大于NPY神经元中的烟碱电流。我们还发现，尼古丁管理调制突触前GABA输入POMC神经元在ARC。因此，我们建议，差异活动和脱敏的nAChR亚型的细胞体和终端在ARC可能有助于抑制尼古丁依赖性减少摄食行为和乙酰胆碱（ACh）信号通过这些改变nAChR途径可能有助于体重增加后撤退。我们的假设是，吸烟对食欲的影响是由于，至少部分，尼古丁激活的能力，并差异脱敏，不同的nAChR亚型POMC和AGRP/NPY表达的神经元和突触前输入，这也可能导致改变信号的内源性乙酰胆碱在这些受体。慢性尼古丁暴露后，ARC中通过nAChRs的ACh信号失衡可能导致戒断期食物摄入量增加。在这些研究中，我们将：1）使用分子生物学和解剖学技术鉴定ARC中特定神经元细胞类型上表达的nAChR亚基; 2）使用电生理学和生物化学技术确定尼古丁施用期间和戒断后nAChR信号是否存在适应，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摄食行为的贡献; 3）并使用光遗传学和行为技术来确定胆碱能信号传导在基线、尼古丁施用期间和戒断后对食物摄入的影响。

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.