An evaluation of Beta-nicotyrine as a potential contributor to the abuse liability of e-cigarettes

项目总结/摘要 ENDS产品成瘾是尼古丁成瘾的一种新形式。了解产品 特征以及导致ENDS成瘾的有害和潜在有害成分（HPHC） 对于有效的FDA CTP监管至关重要。然而，这份HPHC名单最后一次更新是在2012年，就在上升之前。 在ENDS的流行中。由于五种成瘾相关的HPHC中有两种是烟草相关的次要生物碱（例如， 去甲烟碱），那么它表明对ENDS特异性次要生物碱的研究是必要的。一个独特的流行 ENDS中的次要生物碱是β-二烯烟碱，它是通过老化和/或雾化电子液体形成的，可以达到 25%的尼古丁水平时vaped。我们的试点工作发现，β-二烯烟碱的半衰期约为 尼古丁，并且其作为烟碱乙酰胆碱受体（nAChR）激动剂发挥作用， α4β2烟碱-AChR类似于去甲烟碱。鉴于其a）在ENDS气溶胶中的丰度，B）与 去甲烟碱，和c）抑制烟碱代谢的能力，β-二烯烟碱可能有助于成瘾相关的 ENDS的影响，并代表了一种新的HPHC。如果我们发现β-二烯烟碱有滥用倾向或增加了滥用 尼古丁的责任，它建议CTP应该考虑它的HPHC考虑到FDA认为其他较少 常见的次要生物碱如HPHC。本项目将初步表征β- 二烯烟碱及其与尼古丁代谢的相互作用，然后确定其在FDA- 推荐的滥用倾向动物模型，包括药物辨别、颅内自我刺激（ICSS） 和药物自我给药。这个项目是创新的，因为：1）它扩展了对次要生物碱的研究， 包括具有既定滥用责任的HPHC在内的一类成员，2）它将是第一个审查 β-二烯烟碱的滥用倾向及其改变尼古丁滥用倾向的能力，包括与电子烟相关的 3）它将首次表征β-二烯烟碱的PK及其如何改变尼古丁PK。在 因此，该项目可以阐明介导ENDS成瘾的新机制，并测试所提出的β- 烟碱假说

Project Summary/Abstract Addiction to ENDS products is a newly emerging form of nicotine addiction. Understanding the product characteristics and the harmful and potentially harmful constituents (HPHCs) that contribute to ENDS addiction is vital for effective FDA CTP regulation. This HPHC list, however, was last updated in 2012, just prior to the rise in ENDS popularity. Since two of the five addiction-related HPHCs are tobacco-related minor alkaloids (e.g., nornicotine), then it suggests research on ENDS-specific minor alkaloids is warranted. One uniquely prevalent minor alkaloid in ENDS is β-nicotyrine, which is formed by aging and/or aerosolizing e-liquids and can reach 25% of nicotine levels when vaped. Our pilot work found that β-nicotyrine approximately doubles the half-life of nicotine and that it functions as a nicotinic acetylcholine receptor (nAChR) agonist with functional efficacy at α4β2 nicotinic-AChRs similar to nornicotine. Given its a) abundance in ENDS aerosols, b) similarities to nornicotine, and c) ability to inhibit nicotine metabolism, β-nicotyrine may contribute to the addiction-relevant effects of ENDS and represent a novel HPHC. If we find β-nicotyrine has abuse liability or increases the abuse liability of nicotine, it suggests the CTP should consider it a HPHC given that the FDA considers other less prevalent minor alkaloids as HPHCs. The present project will initially characterize the pharmacokinetics of β- nicotyrine and its interaction with nicotine metabolism, and then subsequently determine its effects in FDA- recommended animal models of abuse liability, including drug discrimination, intracranial self-stimulation (ICSS) and drug self-administration. This project is innovative because: 1) it extends research on minor alkaloids, a class of constituents that includes HPHCs with established abuse liability, 2) it will be the first to examine the abuse liability of β-nicotyrine and its ability to alter the abuse liability of nicotine, including at vaping relevant concentrations, and 3) it will be the first to characterize the PK of β-nicotyrine and how it alters nicotine PK. In so doing, this project could elucidate novel mechanisms mediating ENDS addiction and test the proposed β- nicotyrine hypothesis.