Glutamatergic mechanisms underlying nicotine addiction and relapse following nicotine reduction

项目总结/摘要 尼古丁滥用和成瘾是公共卫生的重大负担。尼古丁，一种活性生物碱 在烟草中，负责对含烟草产品如雪茄、香烟和 汽化的液体电子烟鉴于尼古丁成瘾对健康的巨大负面影响， 最近含尼古丁电子烟的流行激增，非常需要创新研究， 尼古丁成瘾和复发的神经生物学基础。2009年，联邦对尼古丁的监管 美国《家庭吸烟预防和烟草控制法》规定， 减少吸烟成瘾。具体而言，降低烟草产品中的尼古丁含量是一种 控制策略旨在减少吸烟依赖，随着时间的推移减少尼古丁含量（尽管 而不是零），从而逐步减少摄入量和依赖性。然而，尼古丁成瘾和复发 吸烟率仍然很高，尼古丁减少策略有效减少烟草和尼古丁的能力 上瘾是未知的。我们的初步结果说明了一个有效的和敏感的行为的效用 经济学（BE）的尼古丁需求和尼古丁动机的弹性检查方案。 重要的是，该模型采用了每日会话内尼古丁剂量减少方案与条件提示 与不同剂量的尼古丁有关。这些线索可以用来评估线索诱导的尼古丁 寻求不同剂量的尼古丁，以及尼古丁动机发生的神经生物学后遗症 行为尼古丁在与药物奖赏相关的大脑区域产生细胞适应性，例如 丘脑核然而，尼古丁复吸脆弱性背后的神经行为机制是 相对未知。尼古丁参与了丘脑核核心区（NAcore）的代谢能机制 复发，包括快速，短暂增加的突触强度（测量为AMPA电流从 中等多刺神经元）。在拟议的研究中，我们将确定尼古丁减少策略是否能抑制 线索诱导的尼古丁寻求以及异常的NAcore突触可塑性。在具体目标1中，我们将研究 使用简化BE方案的雄性和雌性大鼠中尼古丁需求弹性的个体差异， 并使用一种测定尼古丁突然减少抑制线索诱导的尼古丁寻求的能力的方法， 复原范式在具体目标2中，我们将确定尼古丁减少是否能抑制复吸- 相关的核可塑性。通过这些方式，拟议中的研究将揭示神经生物学基础， 降低尼古丁剂量的影响，并将确定谷氨酸信号传导中的潜在神经生物学靶点， 后期的操纵可能会增加对价格和剂量变化的敏感性， 监管目的。通过这些努力，我们将实现确定 减少尼古丁，促进尼古丁使用停止和减少复发的脆弱性。

PROJECT SUMMARY/ABSTRACT Nicotine abuse and addiction represent a substantial burden to public health. Nicotine, an active alkaloid in tobacco, is responsible for addiction to tobacco-containing products such as cigars, cigarettes, and vaporized liquid e-cigarettes. Given the immense negative health impact of nicotine addiction as well as the recent surge in popularity of nicotine-containing e-cigarettes, there is a great need for innovative research on the neurobiological underpinnings of nicotine addiction and relapse. In 2009, federal regulation of nicotine content was established by the Family Smoking Prevention and Tobacco Control Act in the United States to reduce addiction to cigarette smoking. Specifically, reduction of nicotine content in tobacco products is a control strategy intended to decrease smoking dependence that reduces nicotine content over time (although not to zero), resulting in gradual reduction of intake and dependence. However, nicotine addiction and relapse rates remain high, and the ability of nicotine reduction strategies to effectively reduce tobacco and nicotine addiction is unknown. Our preliminary results illustrate the utility of an efficient and sensitive behavioral economics (BE) protocol for the examination of elasticity of nicotine demand and nicotine motivation. Importantly, this model utilizes a daily within-session nicotine dose-reduction protocol with conditioned cues associated with different doses of nicotine. These cues can then be used to evaluate cue-induced nicotine seeking to different doses to nicotine, as well as the neurobiological sequelae that occur in nicotine-motivated behavior. Nicotine produces cellular adaptations in brain regions associated with drug reward, such as the nucleus accumbens. However, the neurobehavioral mechanisms underlying nicotine relapse vulnerability are relatively unknown. Nucleus accumbens core (NAcore) glutamatergic mechanisms are involved in nicotine relapse, including rapid, transient increased synaptic strength (measured as increased AMPA currents from medium spiny neurons). In the proposed studies, we will determine if nicotine reduction strategy can inhibit cue-induced nicotine seeking as well as aberrant NAcore synaptic plasticity. In Specific Aim 1, we will examine individual differences in nicotine demand elasticity in male and female rats using an abbreviated BE protocol, and determine the ability of abrupt nicotine reduction to inhibit cue-induced nicotine seeking using a reinstatement paradigm. In Specific Aim 2, we will determine if nicotine reduction can inhibit reinstatement- associated NAcore plasticity. In these ways, the proposed studies will uncover the neurobiological basis of the effects of decreasing nicotine dose, and will identify potential neurobiological targets in glutamate signaling for later manipulation that may increase sensitivity to changes in price and dose and could be beneficial for future regulatory purposes. Through these efforts, we will accomplish our overarching goal of determining efficacy of nicotine reduction to promote nicotine use cessation and reduced relapse vulnerability.