Novel neuroendocrine mechanisms underlying nicotine seeking and withdrawal-induced hyperphagia

尼古丁寻求和戒断引起的食欲亢进背后的新神经内分泌机制

• 批准号: 10017038
• 负责人: HEATH D SCHMIDT
• 金额: $ 24.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017038
• 关键词: Abstinence; Agonist; Animal Model; Area; Attenuated; Behavior; Behavioral; Body Weight; Brain; Brain region; Cell Nucleus; Chronic; Clinical; Clinical Research; Consumption; Data; Development; Dorsal; Dose; Drug Kinetics; Eating; FDA approved; Female; Food; Future; GLP-I receptor; Goals; Health Benefit; Human; Hyperphagia; Hypertension; Individual; Intake; Intervention; Lateral; Literature; Mediating; Methods; Mind; Modeling; Neurobiology; Neurons; Neuropeptides; Neurosecretory Systems; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Palate; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Physiology; Pilot Projects; Play; Population; Pre-Clinical Model; Property; Public Health; Rattus; Receptor Activation; Receptor Signaling; Regulation; Relapse; Rewards; Rodent; Rodent Model; Role; Satiation; Self Administration; Signal Transduction; Smoke; Smoker; Smoking; Testing; Time; Tobacco use; Ventral Tegmental Area; Weight; Weight Gain; Withdrawal; Woman; addiction; base; behavior influence; behavioral response; comorbidity; drug seeking behavior; energy balance; exenatide; experimental study; feeding; glucagon-like peptide 1; hedonic; improved; insight; liraglutide; men; neural circuit; neurobiological mechanism; neuromechanism; nicotine seeking behavior; novel; obesity risk; prevent; preventable death; sex; smoking abstinence; smoking cessation; smoking relapse; translational impact

Project Summary Smoking cessation is associated with significant increases in consumption of palatable food and body weight, which negate many of the health benefits conferred by smoking abstinence. Indeed, individuals who successfully quit smoking gain 7-22 pounds of body weight, which, in turn, contributes to increased risk of obesity, diabetes type II, hypertension and other comorbidities. Moreover, post-cessation weight gain is often cited as the primary reason for continued smoking and smoking relapse in both men and women. Unfortunately, existing treatments for post-cessation weight gain are ineffective. Despite the public health significance of post-cessation weight gain, the neurobiological mechanisms underlying the relationships between smoking, food intake, and body weight regulation are poorly defined. Therefore, optimizing the health benefits of smoking cessation requires greater understanding of the neural mechanisms mediating nicotine withdrawal-induced hyperphagia in order to prevent weight gain and relapse during smoking abstinence. With this in mind, we have developed a rodent model of withdrawal-induced hyperphagia and body weight gain following voluntary nicotine taking. Our exciting preliminary data indicate that systemic administration of a glucagon-like peptide-1 (GLP-1) receptor agonist is sufficient to attenuate nicotine-seeking behavior during abstinence following nicotine self-administration. These results highlight, for the first time, a novel role for GLP-1 receptors in an animal model of smoking relapse and suggest that increased GLP-1 signaling may reduce other withdrawal-induced phenotypes including hyperphagia. We will extend our preliminary findings to female rats and expand upon them in both sexes to screen the efficacy of two different GLP-1 receptor agonists in attenuating nicotine seeking, hyperphagia and weight gain during nicotine abstinence (Aim 1). Our previous studies have shown that GLP-1 receptor agonists reduce intake of palatable food in drug-naïve rodents by activating GLP-1 receptors expressed in brain regions known to regulate food reward and drug-seeking behavior, including the ventral tegmental area (VTA) and lateral dorsal tegmental area (LDTg). Since the neural circuits and mechanisms regulating hedonic feeding and drug seeking overlap, to a degree, these results support the hypothesis that activation of central GLP-1 receptors attenuates nicotine withdrawal-induced behavioral responses. Therefore, we will infuse GLP-1 receptor agonists directly into the VTA and LDTg during nicotine abstinence to determine if activation of discrete populations of central GLP-1 receptors is sufficient to attenuate nicotine seeking and hyperphagia during withdrawal (Aim 2). These experiments will provide the first insights into the neuroendocrine mechanisms underlying nicotine seeking, hyperphagia and weight gain during nicotine abstinence. Findings from these studies will have an immediate translational impact, as they will support re-purposing GLP-1 receptor agonists, which are FDA- approved for treating diabetes type II and obesity, for preventing smoking relapse and post-cessation weight gain.

项目摘要 戒烟与可口食物的消耗和体重的显著增加有关， 这否定了戒烟所带来的许多健康益处。事实上，那些成功地 戒烟会增加7-22磅的体重，这反过来又会增加肥胖、糖尿病的风险。 II型，高血压和其他合并症。此外，戒烟后体重增加通常被认为是主要的 男性和女性继续吸烟和吸烟复发的原因。不幸的是，现有的治疗方法 戒烟后体重增加是无效的。尽管戒烟后的体重对公众健康有重要意义， 增益，吸烟，食物摄入和身体之间的关系的神经生物学机制 体重控制不明确。因此，优化戒烟的健康益处需要 更好地了解介导尼古丁戒断诱导的食欲过盛的神经机制，以便 在戒烟期间防止体重增加和复发。考虑到这一点，我们开发了一种啮齿动物 自愿尼古丁摄入后戒断诱导的食欲亢进和体重增加模型。整理的丰厚 初步数据表明全身给予胰高血糖素样肽-1（GLP-1）受体激动剂 足以减弱尼古丁自我给药后戒断期间的尼古丁寻求行为。这些 研究结果首次强调了GLP-1受体在吸烟复吸动物模型中的新作用， 提示GLP-1信号传导增加可能减少其他戒断诱导的表型，包括 食欲过盛我们将把我们的初步发现扩展到雌性大鼠，并在两性大鼠中进行扩展， 筛选两种不同的GLP-1受体激动剂在减弱尼古丁寻求、食欲过盛和 尼古丁戒断期间体重增加（目标1）。我们之前的研究表明，GLP-1受体激动剂 通过激活脑区表达的GLP-1受体，减少未用药啮齿类动物的可口食物摄入 已知调节食物奖励和药物寻求行为，包括腹侧被盖区（VTA）和外侧 背侧被盖区（LDTg）。由于神经回路和机制调节享乐喂养和药物 寻求重叠，在一定程度上，这些结果支持中枢GLP-1受体激活的假设， 减弱尼古丁戒断诱导的行为反应。因此，我们将输注GLP-1受体激动剂 直接进入VTA和LDTg，以确定在尼古丁戒断期间， 中枢GLP-1受体足以减弱戒断过程中的尼古丁寻求和食欲亢进（目的2）。 这些实验将提供有关尼古丁神经内分泌机制的第一个见解 尼古丁戒断期间的寻求、暴食和体重增加。这些研究的结果将产生 直接的翻译影响，因为它们将支持GLP-1受体激动剂的再利用，这是FDA- 批准用于治疗II型糖尿病和肥胖症，用于预防吸烟复发和戒烟后体重 增益