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 在美国使用电子尼古丁输送系统（END）的1000万人中， 绝大多数人都使用具有非烟熏口味的电子液体。水果口味是迄今为止最受欢迎的 所有年龄段的用户建立的用户，估计有70％的青年和成人使用水果味的末端。 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，这些化学品已批准 食物消费，但没有吸入。虽然很明显，风味增强了末端的外观和 有助于倡议，实验室和基于人群的研究尚未建立明确的联系 口味和末端成瘾潜力，这对于政策和预防很重要。这项研究的大部分 是在风味可以通过外观增强末端成瘾潜力的前提下进行的 品尝。然而，在吸入期间，电子液体中的化学物质从口腔越来越多，到达肺部 由于其低分子量和 亲脂性。我们团队严格的临床前研究表明，某些常见的风味化学品可以 通过直接改变烟素来增强最终奖励和增强并增加使用频率 乙酰胆碱受体（NACHR）上调和化学计量法。这些NACHR改变增强了多巴胺 腹侧盖区域（VTA）的神经传递，这是成瘾发展中的关键大脑区域。这些 调查结果挑战了我们目前关于风味如何改变目的的概念的概念 指出特定风味化学物质的明确神经行为机制。迄今为止，这些小说和重要 临床前发现尚未转化为人类。拟议的两阶段研究将进行四臂 神经活性（乙酸己酯）与神经活性（乙酸乙酯）的双盲随机对照试验 结束有和没有尼古丁的绿色苹果风味，以确定对生物行为标记的影响 成瘾电位，包括使用功能磁共振成像的VTA风味反应性并经过验证 衡量主题奖励价值和相对强化的实验室任务。这 R61期的具体目的（n = 50）是：1）建立累积量与急性效果的风味；和 2）确认VTA风味反应性与主观奖励和增强有关。如果 达到里程碑，R33阶段（n = 200）将包括一个完全动力的试验：1）确定独立 风味和尼古丁对成瘾潜力标记的交互作用； 2）确定VTA反应性是否 介导末端风味和尼古丁对结局的影响； 3）探索风味效应的主持人， 包括性别和尼古丁依赖性。这项研究将是重要和严格的人类翻译 临床前研究证明了一种明确的神经行为机制，可增强末端的能力 成瘾潜力。结果有可能从根本上改变我们对的理解和能力 表征了风味末端的公共卫生风险。