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: 10671683
• 负责人: Andrea Hobkirk
• 金额: $ 38.95万
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671683
• 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; Learning; Light; Link; Lung; Marketing; 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; Receptor Up-Regulation; 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.

抽象的 美国有超过 1000 万人使用电子尼古丁传送系统 (ENDS)，其中 绝大多数人使用非烟草口味的电子烟油，水果口味是迄今为止最受欢迎的。 所有年龄段的电子尼古丁传送系统用户均已建立，估计 70% 的青少年和成人使用果味电子尼古丁传送系统。 市场上大多数调味电子烟液都使用相同调味化学品的组合，这些化学品已获得批准 用于食品消费，但不用于吸入，但很明显，味道增强了电子尼古丁传送系统和电子烟的吸引力。 有助于启动、实验室和基于人群的研究之间尚未建立明确的联系 口味和电子烟成瘾潜力，这对于政策和预防非常重要。 进行的前提是口味可以通过其吸引力增强电子烟成瘾潜力 然而，在吸入过程中，电子液体中的风味化学物质会从口腔转移到肺部。 由于分子量低，它们可以进入血流并穿过血脑屏障 我们团队的严格临床前研究表明，一些常见的香料化学物质可以 通过直接改变烟碱来增强 ENDS 奖励和强化并增加使用频率 乙酰胆碱受体 (nAChR) 上调和化学计量这些 nAChR 改变增强多巴胺。 腹侧被盖区（VTA）的神经传递，这是成瘾发展的关键大脑区域。 研究结果挑战了我们目前关于风味如何改变 ENDS 成瘾潜力的概念： 迄今为止，这些新颖且重要的化学物质揭示了特定风味化学物质的明确神经行为机制。 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四臂研究。 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 ENDS 含有和不含尼古丁的青苹果口味，以确定对生物行为标志物的影响 成瘾潜力，包括使用功能磁共振成像验证的 VTA 风味反应性 测量调味电子烟的主观奖励值和相对强化的实验室任务。 R61 阶段（n=50）的具体目标是： 1) 确定 ENDS 风味的累积效应与急性效应；以及 2) 确认 VTA 风味反应与 ENDS 主观奖励和强化相关。 达到里程碑后，R33 阶段（n=200）将包括一次全功率试验，以： 1) 确定独立的 以及风味和尼古丁对成瘾潜力标志物的相互作用影响 2) 确定 VTA 反应性； 调节 ENDS 风味和尼古丁对结果的影响；以及 3) 探索风味影响的调节因素， 这项研究将是第一个重要且严格的人类翻译。 临床前研究表明风味增强 ENDS 能力的明确神经行为机制 研究结果有可能从根本上改变我们对成瘾的理解和能力。 描述调味电子尼古丁传送系统的公共健康风险。