Glutamatergic mechanisms underlying nicotine addiction and relapse following nicotine reduction

项目摘要/摘要 尼古丁滥用和上瘾是公共卫生的重大负担。尼古丁，一种活性生物碱 在烟草方面，负责对含烟草产品，如雪茄、香烟和 蒸发液体电子烟。鉴于尼古丁成瘾对健康的巨大负面影响，以及 近年来，含尼古丁电子烟的流行激增，迫切需要对其进行创新研究 尼古丁成瘾和复发的神经生物学基础。2009年，联邦政府对尼古丁的监管 内容由美国《家庭吸烟预防和烟草控制法案》确定，以 减少吸烟成瘾。具体地说，减少烟草产品中的尼古丁含量是一种 旨在减少吸烟依赖的控制策略，随着时间的推移减少尼古丁含量(尽管 不是零)，导致摄入量和依赖性逐渐减少。然而，尼古丁成瘾和复发 烟草率居高不下，而尼古丁减少战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种有效和敏感的行为 研究尼古丁需求弹性和尼古丁动机的经济学(BE)方案。 重要的是，这个模型利用了每日一次的尼古丁减量方案和条件性提示 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，以及尼古丁引发的神经生物学后遗症 行为。尼古丁在与药物奖励相关的大脑区域产生细胞适应，例如 伏隔核。然而，尼古丁复发易感性的神经行为机制是 相对不为人所知。伏核核心(NAcore)谷氨酸能机制与尼古丁有关 复发，包括突触强度的快速、一过性增加(以AMPA电流从 中等刺状神经元)。在拟议的研究中，我们将确定尼古丁减少策略是否可以抑制 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尼古丁需求弹性的个体差异， 并确定尼古丁突然减少的能力，以抑制线索诱导的尼古丁寻求 复职范式。在具体目标2中，我们将确定减少尼古丁是否会抑制尼古丁的恢复- 相关的NAcore可塑性。通过这些方式，拟议的研究将揭示高血压的神经生物学基础 减少尼古丁剂量的影响，并将确定谷氨酸信号转导的潜在神经生物学靶点 以后的操作可能会增加对价格和剂量变化的敏感度，并可能对未来有利 监管目的。通过这些努力，我们将实现我们的首要目标，即确定 减少尼古丁，以促进尼古丁的戒断和降低复发的脆弱性。

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.