Nicotine dependence and central adiposity signaling

说明（申请人提供）：吸烟是为了控制食物摄入和体重增加。相反，戒烟与食物摄入增加和体重增加加速有关。有证据表明，吸烟有助于通过提高调节神经行为过程的肥胖信号（如胰岛素和瘦素）来控制食物摄入。我们假设，长期服用尼古丁会导致大脑中涉及食物动机的脂肪信号的适应。在停止使用尼古丁后，这些适应仍然不受反对，从而导致食物摄入量增加。第一个具体目的是研究慢性尼古丁给药对涉及食物动机的两个大脑区域（下丘脑弓状核和腹侧被盖区）胰岛素和瘦素信号的影响。颅内自我刺激程序（ICSS）将用于评估尼古丁对肥胖信号的影响，因为它提供了中枢性肥胖信号变化的动机效应的定量测量。胰岛素和瘦素的使用提高了大脑的奖励阈值，这表明对电刺激的敏感性降低。预计胰岛素和瘦素的阈值升高作用在长期暴露于尼古丁期间和之后会降低。此外，预计血浆胰岛素和瘦素水平在尼古丁给药期间升高，并在尼古丁给药停止后恢复到基线水平。这种模式的结果表明，对胰岛素或瘦素的中枢反应的降低介导了与戒烟相关的食物动机的增加。超重的青少年比不超重的青少年更有可能开始吸烟并形成尼古丁依赖。我们假设，与饮食引起的肥胖相关的激素变化和神经适应增强了尼古丁的有益作用，从而加速了从吸烟实验到习惯性吸烟的转变。具体目标2使用大鼠ICSS范式检查饮食诱导的肥胖对尼古丁奖励效应的影响。综上所述，这些拟议的研究将开始探索肥胖信号和尼古丁奖励效应之间的相互作用。戒烟会增加食物摄入量和体重增加。本资助申请中描述的研究调查了为什么戒烟会导致食物摄入量增加和体重增加。更好地了解戒烟后体重增加的大脑机制可能有助于戒烟后体重增加的新治疗方法，从而提高戒烟率。

DESCRIPTION (provided by applicant): Tobacco smoking is used to control food intake and body weight gain. Conversely, tobacco smoking cessation has been associated with increased food intake and accelerated body weight gain. Evidence indicates that smoking helps to control food intake by elevating adiposity signals (e.g., insulin and leptin) that modulate neurobehavioral processes. We hypothesize that chronic administration of nicotine results in adaptations in adiposty signaling in brain areas involved in food motivation. Upon cessation of nicotine administration these adaptations remain unopposed which leads to increased food intake. The first specific aim examines the effects of chronic nicotine administration on insulin and leptin signaling in two brain areas involved in food motivation, the arcuate hypothalamic nucleus and the ventral tegmental area. The intracranial self-stimulation procedure (ICSS) will be used to assess the effects of nicotine on adiposity signaling as it provides a quantitative measure of the motivational effects of changes in central adiposity signaling. Administration of insulin and leptin elevates brain reward thresholds, which is indicative of a decreased sensitivity to the electrical stimuli. It is expected that the threshold elevating effects of insulin and leptin are reduced during and after chronic exposure to nicotine. In addition, it is expected that plasma insulin and leptin levels are elevated during nicotine administration and return to baseline levels after cessation of nicotine administration. This pattern of results would suggest that that a decreased central responsivity to insulin or leptin mediates the increased food motivation associated with smoking cessation. Overweight adolescents are more likely to initiate tobacco smoking and develop a nicotine dependency than non-overweight adolescents. We hypothesize that the hormonal changes and neuroadaptations associated with diet-induced obesity potentiate the rewarding effects of nicotine and thereby accelerate the transition from experimenting with cigarettes to habitual smoking. Specific aim 2 examines the effects of diet-induced obesity on the rewarding effects of nicotine using the rat ICSS paradigm. Taken together, these proposed studies will start exploring the interplay between adiposity signaling and the rewarding effects of nicotine. Quitting smoking increases food intake and body weight gain. The studies described in this grant application investigate why quitting smoking leads to increased food intake and body weight gain. A better understanding of the brain mechanisms underlying post-cessation weight gain may contribute to new treatments for post-cessation weight gain and thereby improve smoking cessation rates.