Electronic cigarettes, adolescents, and changes in neurobiology

电子烟、青少年和神经生物学的变化

• 批准号: 10399991
• 负责人: Brandon Jarrod Henderson
• 金额: $ 37.53万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10399991
• 关键词: Addictive Behavior; Address; Adolescent; American; Americas; Antibodies; Ants; Basic Science; Behavior; Behavioral; Biological Assay; Biological Models; Brain; Brain region; Cells; Communities; Complement; Data; Devices; Disease; Dopamine; Dose; Drosophila acetylcholine receptor alpha-subunit; Electrochemistry; Electronic Nicotine Delivery Systems; Electronic cigarette; Electrophysiology (science); Exhibits; Face; Flavoring; Fluorescence Microscopy; Formulation; Generations; Goals; Human; JUUL; Knowledge; Lead; Link; Measures; Menthol; Methods; Modeling; Mus; National Institute of Drug Abuse; Neurobiology; Nicotine; Nicotine Dependence; Outcome; Pathway interactions; Periodicity; Policies; Population; Prefrontal Cortex; Psychological reinforcement; Public Health; Research; Rewards; Risk; Role; Salts; Scanning; Self Administration; Smoker; Sodium Chloride; System; Testing; Tweens; Up-Regulation; addiction; base; brain cell; cell type; combustible cigarette; dopaminergic neuron; electronic liquid; electronic vape; high risk population; in vivo Model; innovation; interest; mouse model; neuronal excitability; neurophysiology; neurotransmission; nicotine reward; nicotine use; novel; patch clamp; prenatal; preventable death; smoking initiation; success; tobacco products; vaper; vaping; vaping nicotine; vapor

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.

项目概要/摘要 对电子尼古丁传送系统（ENDS）如何运作的理解存在根本性差距。 青少年的大脑。青少年是含尼古丁产品的高危人群 产前或早期接触会引发前额皮质的显着变化。随着越来越受欢迎 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 ogy 引发尼古丁成瘾。鉴于 ENDS 不同于可燃香烟，这一点尤其正确。 雷特有多种口味和不同的尼古丁配方，仅适用于 ENDS 电子液体。 此外，与烟弹相比，基于烟弹的 ENDS（即 Juul）含有明显更高浓度的尼古丁。 可燃香烟和罐装电子尼古丁传送系统。在消除这一知识差距之前，我们面临着增加的风险 开始吸烟、戒烟减少以及终身吸烟者人数不断增加的累积效应 美国。我们的总体目标是确定青少年神经生物学的关键变化，特别是 ENDS 调节尼古丁奖励和强化的小鼠模型系统。为了解决这个问题，我们将利用一部小说 偶发性尼古丁自我管理检测系统，使我们能够使用相同的电子烟油罐和 Pods 在小鼠模型系统中深受青少年 ENDS 用户的欢迎。这将提供很高的转化价值，因为我们 可以直接评估 ENDS 如何直接改变神经生物学和神经生理学。 我们假设自我给药行为与 nAChR 上调和变化直接相关 神经生理学将识别对引发尼古丁成瘾至关重要的大脑区域和细胞类型 并持续加固。其背后的理由来自于申请人之前在相关方面的成功 将尼古丁奖励与 nAChR 上调联系起来。我们将通过以下方法确定神经生物学中 ENDS 特定的变化： 三个具体目标。首先，我们将利用小鼠电子烟尼古丁自我给药测定来检查启动情况 ENDS 的尼古丁强化，以检查尼古丁剂量、配方和口味对电子烟的影响 ing相关的行为。其次，我们将使用第一个目标的大脑来检查 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，我们将检查 通过电生理学和快速扫描循环伏安法改变神经生理学。 申请人认为，这种方法是创新的，因为它建立了直接相关性： 电子烟相关的自我管理和 nAChR 上调以及神经生理学的变化 体内模型，并利用与青少年电子烟玩家所流行的完全相同的 ENDS 和电子液体。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，使得 不使用抗体的上调分析。拟议的研究意义重大，因为它将 极大地增加了我们对电子尼古丁传送系统如何导致成瘾行为的了解。这将有助于信号 对 NIDA 的一些优先事项和利益有重大影响。