Electronic cigarettes, adolescents, and changes in neurobiology

项目摘要/摘要 对于电子尼古丁递送系统(END)是如何实现的，在理解上存在着根本性的差距。 称为青春期大脑。青少年是尼古丁产品的高危人群，如 产前或早期接触会触发前额叶皮质的显著变化。随着……越来越受欢迎 在美国青少年中，迫切需要了解终端设备是如何改变神经生物的-- 可能会引发尼古丁成瘾。这一点尤其正确，因为末端是不同于可燃CIGA的- 给出了多种口味和不同的尼古丁配方，只针对END电子液体。 此外，豆荚端(即JUUL)含有的尼古丁浓度明显高于 可燃香烟和基于坦克的烟头。在这一知识鸿沟被弥合之前，我们面临的风险是 吸烟开始、戒烟减少和终身吸烟者人数增加的累积影响 美国。我们的总体目标是确定神经生物学中的关键变化，具体到青少年的末端 调节尼古丁奖赏和强化的小鼠模型系统。为了解决这个问题，我们将利用一本小说 临时尼古丁自我给药检测系统，允许我们使用相同的e-Liquid罐和Pods 在青少年终端用户中流行的鼠标模型系统。这将提供很高的翻译价值，因为我们 可以直接评估最终结果如何直接改变神经生物学和神经生理学。 我们假设，自我管理行为直接与nAChR上调和 神经生理学将确定对尼古丁成瘾的启动至关重要的大脑区域和细胞类型 并继续增援。这背后的理由来自于申请者以前在Corre- 延迟尼古丁奖励上调nAChR。我们将通过以下方式确定神经生物学中特定于末端的变化 三个具体目标。首先，我们将利用e-Vape尼古丁在小鼠体内的自我给药试验来检查启动 和尼古丁强化末端，以检查尼古丁剂量、配方和口味对VAP的影响。 与ING相关的行为。第二，我们将使用第一个目标中的大脑来检查nAChR上调和 提供自我管理行为和nAChR上调之间的直接联系。第三，我们将审查 电生理学和快速扫描循环伏安法对神经生理学的影响。 申请人认为，这种方法是创新的，因为它建立了一种直接关系，即： 蒸发相关自我给药与nAChR上调及神经生理学改变之间的关系 体内模型，并使用与人类青少年尿布流行的完全相同的末端和电子液体。这是 此外，还使用了一种表达α4-mCherry和α6-GFP nAChR亚单位的新型小鼠 不使用抗体的上调分析。这项拟议的研究意义重大，因为它将 极大地增加我们对最终结果如何导致上瘾行为的了解。这将有助于签名- 对NIDA的几个优先事项和利益具有重大意义。

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.