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

摘要 在美国使用电子尼古丁传递系统的1000多万人中， 绝大多数人正在使用非烟草口味的电子液体。迄今为止，水果口味是最受欢迎的 所有年龄段的成熟终端用户，估计有70%的年轻人和成年人使用水果口味的终端。 市场上大多数调味的电子液体使用相同的调味剂的组合，这是经过批准的 用于食物消费，但不能吸入。虽然很明显，味道增强了末端和 有助于启动、实验室和以人口为基础的研究之间尚未建立明确的联系 味道和结束成瘾的可能性，这对政策和预防很重要。这项研究的大部分内容都是 是在这样的前提下进行的，即香料可以通过其吸引力增强Ends的成瘾潜力 品尝一下。然而，在吸入过程中，电子液体中的风味化学物质从口腔转移到肺部，在那里 由于它们的低分子量和低分子量，它们可以进入血流并通过血脑屏障 亲油性。我们团队进行的严格的临床前研究表明，一些常见的风味化学物质可以 通过直接改变尼古丁来增强末端奖励和强化并提高使用频率 乙酰胆碱受体(NAChR)上调和化学计量学。这些nAChR改变增强了多巴胺 腹侧被盖区(VTA)的神经传递，这是成瘾形成的关键大脑区域。这些 这些发现挑战了我们目前的概念，即味道如何通过以下方式改变末端的成瘾潜力 指出了特定风味化学物质的明确神经行为机制。到目前为止，这些新颖而重要的 临床前的发现还没有转化到人类身上。拟议的两阶段研究将进行四个方面的研究 神经活性(乙酸己酯)与非神经活性(乙酸乙酯)的双盲随机对照试验 结束青苹果口味加和不加尼古丁，以确定对生物行为标记物的影响 成瘾潜力，包括VTA味道反应性，使用功能磁共振成像和验证 实验室任务，测量主观奖赏价值和风味末端的相对强化。这个 R61阶段(n=50)的具体目标是：1)建立Ends风味的累积效应与急性效应；以及 2)证实VTA的味道反应性与目标的主观奖励和强化有关。如果 达到里程碑，R33阶段(n=200)将包括全面试验，以：1)确定独立的 以及味道和尼古丁对成瘾潜能标志物的交互作用；2)确定VTA的反应性 调节末端风味和尼古丁对结果的影响；3)探索风味效应的调节因素， 包括性和尼古丁依赖。这项研究将是首次人工翻译的重要和严谨 临床前研究证实了香精增强末端功能的明确神经行为机制 可能会上瘾。这些结果有可能从根本上改变我们对 描述调味品的公共健康风险。

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.