Novel neuroendocrine mechanisms underlying nicotine seeking and withdrawal-induced hyperphagia

项目摘要 戒烟与美味食物的摄入量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，成功的个人 戒烟会增加7-22磅的体重，进而增加肥胖和糖尿病的风险 II型，高血压和其他合并症。此外，戒烟后的体重增加经常被认为是主要的 男性和女性持续吸烟和吸烟复发的原因。不幸的是，现有的治疗方法 对于戒烟后的体重增加是无效的。尽管戒烟后体重对公共健康具有重要意义 吸烟、食物摄入量和身体之间关系的神经生物学机制 体重控制的定义不够明确。因此，优化戒烟对健康的好处需要 更好地了解尼古丁戒断诱导的吞噬亢进的神经机制 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 自愿服用尼古丁后戒断诱导的吞噬功能亢进和体重增加模型。我们激动人心的 初步数据表明，全身应用胰高血糖素样肽-1(GLP-1)受体激动剂是 足以在戒烟期间减轻尼古丁自我给药后的尼古丁寻求行为。这些 结果首次强调了GLP-1受体在吸烟复发和吸烟动物模型中的新作用。 提示GLP-1信号的增加可能会减少其他戒断诱导的表型，包括 吞噬过多。我们将把我们的初步发现扩展到雌性老鼠，并在两性之间进行扩展，以 筛选两种不同的GLP-1受体激动剂减轻尼古丁寻求、吞噬亢进和 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受体减少药物幼稚啮齿动物对可口食物的摄入量 已知调节食物奖励和药物寻找行为，包括腹侧被盖区(VTA)和外侧 背被盖区(LDTg)由于神经回路和调节享乐性喂养和药物的机制 寻求重叠，这些结果在一定程度上支持了中枢GLP-1受体激活的假设 减轻尼古丁戒断引起的行为反应。因此，我们将注入GLP-1受体激动剂 在尼古丁戒断期间直接进入VTA和LDTg以确定是否激活离散的人群 中枢GLP-1受体足以减轻戒断期间的尼古丁寻求和过度吞噬(目标2)。 这些实验将首次深入了解尼古丁的神经内分泌机制。 在尼古丁戒断期间，寻求、吞噬过多和体重增加。这些研究的结果将会有一个 直接的翻译影响，因为它们将支持重新用途的GLP-1受体激动剂，这是FDA- 被批准用于治疗II型糖尿病和肥胖症，用于防止吸烟复发和戒烟后体重 收获。

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.