Electronic cigarettes, adolescents, and changes in neurobiology

项目概要/摘要 在了解电子尼古丁输送系统（ENDS）是如何... 青春期的大脑青少年是含尼古丁产品的高风险人群， 产前或早期接触会引发前额皮质的显著变化。随着越来越受欢迎的 在美国青少年中，迫切需要了解ENDS设备如何改变神经生物学。 引发尼古丁成瘾。考虑到ENDS与可燃雪茄不同，这一点尤其正确。 考虑到多种口味和不同的尼古丁配方，这些配方仅适用于ENDS电子烟液。 此外，基于Pod的ENDS（即，Juul）含有的尼古丁浓度明显高于 可燃香烟和坦克式ENDS。在这种知识差距被弥合之前，我们面临的风险增加了。 吸烟开始，减少戒烟，以及不断增长的终身吸烟人口的累积效应， 美国参考我们的总体目标是确定神经生物学的关键变化，具体到ENDS，在青少年 小鼠模型系统，调节尼古丁奖励和强化。为了解决这个问题，我们将利用一本小说 应急尼古丁自我管理分析系统，允许我们使用相同的电子液体罐和吊舱 在鼠标模型系统中，青少年ENDS用户很受欢迎。这将提供很高的翻译价值， 可以直接评估ENDS如何直接改变神经生物学和神经生理学。 我们假设，直接将自我给药行为与nAChR上调和 神经生理学将确定对尼古丁成瘾起关键作用的大脑区域和细胞类型 继续加强。这背后的理由来自申请人以前在正确的成功- 将尼古丁奖励与nAChR上调联系起来。我们将确定神经生物学中ENDS特异性的变化， 三个具体目标。首先，我们将在小鼠中利用e-Vape尼古丁自我给药试验来检查启动 和尼古丁强化ENDS，以检查尼古丁剂量，配方和口味对VAP的影响。 与行为有关的。第二，我们将使用第一个目标的大脑来检查nAChR的上调， 提供了自我管理行为和nAChR上调之间的直接联系。第三，我们将研究 通过电生理学和快速扫描循环伏安法的神经生理学变化。 在申请人看来，这种方法是创新的，因为它建立了一种直接的相关性， 与电子烟相关的自我给药和nAChR上调以及神经生理学变化之间的关系， 在体内模型，并利用完全相同的ENDS和电子液体流行与人类青少年vapers.这是 通过使用表达α4-mCherry和α6-GFP nAChR亚基的新型小鼠进行补充， 在不使用抗体的情况下分析上调。这项研究意义重大，因为它将 这极大地增加了我们对ENDS如何导致成瘾行为的了解。这将有助于... 对NIDA的一些优先事项和利益至关重要。

Project Summary/Abstract There is a fundamental gap in the understanding of how electronic nicotine delivery systems (ENDS) al- ter the adolescent brain. Adolescents are a high-risk population in regards to nicotine-containing products as prenatal or early exposure triggers significant changes in the prefrontal cortex. With the growing popularity of ENDS among American adolescents, there is a critical need to understand how ENDS devices alter neurobiol- ogy to trigger addiction to nicotine. This is especially true given that ENDS are unique from combustible ciga- rettes given the multitude of flavors and different nicotine formulations that are specific to only ENDS e-liquids. Additionally, pod-based ENDS (i.e., Juul) contain a significantly higher concentration of nicotine compared to combustible cigarettes and tank-based ENDS. Until this knowledge gap is closed, we face the risk of increased smoking initiation, decreased cessation, and a cumulative effect of a growing population of lifelong smokers in America. Our overall goal is to identify the key changes in neurobiology, specific to ENDS, in an adolescent mouse model system that regulates nicotine reward and reinforcement. To address this, we will utilize a novel contingent nicotine self-administration assay system that allows us to use the same e-liquid tanks and Pods popular with adolescent ENDS users in a mouse model system. This will provide high translational value as we can directly assess how ENDS directly alter neurobiology and neurophysiology. We hypothesize that directly linking self-administration behavior to nAChR upregulation and changes in neurophysiology will identify brain regions and cell-types that are critical for the initiation of nicotine addiction and continued reinforcement. The rationale behind this comes from the applicant’s previous success in corre- lating nicotine reward to nAChR upregulation. We will identify ENDS-specific changes in neurobiology with three specific aims. First, we will utilize e-Vape nicotine self-administration assays in mice to examine initiation and nicotine reinforcement of ENDS to examine the impact of nicotine dose, formulation, and flavors on vap- ing-related behavior. Second, we will use the brains from the first aim to examine nAChR upregulation and provide a direct link between self-administration behavior and nAChR upregulation. Third, we will examine changes in neurophysiology via electrophysiology and fast-scan cyclic voltammetry. This approach is innovative, in the applicant's opinion, because it establishes a direct correlation be- tween vaping-related self-administration and nAChR upregulation as well as changes in neurophysiology in an in vivo model and utilizes the exact same ENDS and e-liquids popular with human adolescent vapers. This is complemented by the use of a novel mouse expressing α4-mCherry and α6-GFP nAChR subunits that allow analysis of upregulation without the use of antibodies. The proposed research is significant, because it will dramatically increase our knowledge of how ENDS contribute to addictive behavior. This would contribute sig- nificantly to several of the priorities and interests of NIDA.