A human translation of research on the neurobehavioral reward and reinforcement of flavored electronic nicotine delivery systems (ENDS)

神经行为奖励和调味电子尼古丁输送系统 (ENDS) 强化研究的人类翻译

• 批准号: 10506990
• 负责人: Andrea Hobkirk
• 金额: $ 39.61万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10506990
• 关键词: Acetates; Acute; Adult; Age; Apple; Automobile Driving; Blood; Blood - brain barrier anatomy; Brain; Brain region; Bypass; Chemicals; Development; Dopamine; Double-Blind Method; Electronic Nicotine Delivery Systems; Flavoring; Frequencies; Fruit; Functional Magnetic Resonance Imaging; Human; Inhalation; Laboratories; Laboratory Research; Learning; Light; Link; Lung; Measures; Mediating; Molecular Weight; Nicotine; Nicotine Dependence; Nicotinic Receptors; Oral cavity; Outcome; Pathway interactions; Persons; Phase; Policies; Population Research; Prevention; Prevention strategy; Process; Psychological reinforcement; Public Health; Randomized; Randomized Controlled Trials; Regulation; Research; Rewards; Risk; Role; Smoker; Stream; Taste Perception; Translating; Translational Research; Translations; United States; Ventral Tegmental Area; Youth; addiction; addiction liability; arm; biobehavior; carcinogenicity; electronic liquid; ethyl acetate; food consumption; lipophilicity; neurobehavioral; neurobiological mechanism; neurotransmission; novel; pre-clinical; pre-clinical research; receptor upregulation; sex; stoichiometry; translational study

Abstract Of the more than 10 million people in the United States using electronic nicotine delivery systems (ENDS), the vast majority are using e-liquids with non-tobacco flavors. Fruit flavors are by far the most popular among established ENDS users of all ages, with an estimated 70% of youth and adults using fruit-flavored ENDS. Most flavored e-liquids on the market use a combination of the same flavoring chemicals, which are approved for food consumption, but not inhalation. While it is clear that flavors enhance the appeal of ENDS and contribute to initiation, laboratory and population-based research has not established a clear link between flavors and ENDS addiction potential, which is important for policy and prevention. Much of this research has been conducted under the premise that flavors can enhance ENDS addiction potential through their appealing taste. However, during inhalation, flavor chemicals in e-liquids move beyond the mouth to the lungs, where they can enter the blood stream and pass through the blood-brain-barrier due to their low molecular weight and lipophilicity. Rigorous preclinical research by our team demonstrates that some common flavor chemicals can enhance ENDS reward and reinforcement and increase use frequency by directly altering nicotinic acetylcholine receptor (nAChR) upregulation and stoichiometry. These nAChR alterations enhance dopamine neurotransmission in the ventral tegmental area (VTA), a key brain region in addiction development. These findings challenge our current conceptualization of how flavor can alter the addiction potential of ENDS by pointing to a clear neurobehavioral mechanism of specific flavor chemicals. To date, these novel and important preclinical findings have not been translated to humans. The proposed two-phase study will conduct a four-arm double-blind randomized controlled trial of a neuro-active (hexyl acetate) vs. neuro-inactive (ethyl acetate) ENDS green apple flavors with and without nicotine to determine the effects on biobehavioral markers of addiction potential, including VTA flavor reactivity using functional magnetic resonance imaging and validated laboratory tasks measuring the subjective reward value and relative reinforcement of flavored ENDS. The specific aims of the R61 phase (n=50) are to: 1) Establish the cumulative vs. acute effects of ENDS flavor; and 2) Confirm that VTA flavor-reactivity is associated with ENDS subjective reward and reinforcement. If milestones are met, the R33 phase (n=200) will include a fully-powered trial to: 1) Determine the independent and interactive effects of flavor and nicotine on markers of addiction potential; 2) Determine if VTA reactivity mediates the effects of ENDS flavor and nicotine on outcomes; and 3) Explore moderators of the flavor effects, including sex and nicotine dependence. This study will be the first human translation of important and rigorous preclinical research demonstrating a clear neurobehavioral mechanism for flavor’s ability to enhance ENDS addiction potential. The results have the potential to fundamentally shift our understanding of and ability to characterize the public health risks of flavored ENDS.

摘要 在美国使用电子尼古丁输送系统（ENDS）的1000多万人中， 绝大多数使用非烟草口味的电子液体。水果口味是迄今为止最受欢迎的 所有年龄段的ENDS使用者，估计70%的青少年和成年人使用水果口味的ENDS。 市场上大多数调味的电子液体使用相同的调味化学品的组合，这些化学品是经过批准的。 但不能吸入虽然很明显，风味增强了ENDS的吸引力， 有助于启动，实验室和人口为基础的研究还没有建立一个明确的联系之间 口味和ENDS成瘾潜力，这对政策和预防很重要。大部分的研究 进行的前提下，口味可以提高ENDS成瘾的潜力，通过他们的吸引力 味道然而，在吸入过程中，电子液体中的风味化学物质从口腔移动到肺部， 由于它们的低分子量， 亲脂性我们团队的严格临床前研究表明，一些常见的风味化学品可以 增强ENDS的奖励和强化，并通过直接改变尼古丁 乙酰胆碱受体（nAChR）上调和化学计量。这些nAChR的改变增强了多巴胺 腹侧被盖区（VTA）的神经传递，这是成瘾发展的关键大脑区域。这些 这些发现挑战了我们目前关于味道如何改变ENDS成瘾潜力的概念， 指出了特定风味化学物质的明确神经行为机制。迄今为止，这些新颖而重要的 临床前研究结果尚未转化为人类。拟议的两阶段研究将进行一项四组研究， 神经活性（乙酸己酯）与神经非活性（乙酸乙酯）的双盲随机对照试验 结束绿色苹果口味与尼古丁和不含尼古丁，以确定对生物行为标志物的影响， 成瘾潜力，包括使用功能性磁共振成像和验证的VTA风味反应性 实验室任务测量主观奖励值和相对强化风味ENDS。的 R61阶段（n=50）的具体目标是：1）建立ENDS风味剂的累积效应与急性效应;以及 2)确认VTA味觉反应与ENDS主观奖励和强化相关。如果 达到里程碑后，R33阶段（n=200）将包括一项完全把握度试验，以：1）确定 以及香料和尼古丁对成瘾潜力标志物的相互作用; 2）确定VTA反应性是否 介导ENDS风味和尼古丁对结果的影响;和3）探索风味影响的调节剂， 包括性和尼古丁依赖。这一研究将是人类翻译史上第一次重要而严谨的研究 临床前研究证明了风味增强ENDS能力的明确神经行为机制 成瘾的可能性这些结果有可能从根本上改变我们对以下问题的理解和能力： 描述调味ENDS的公共卫生风险。