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

项目摘要/摘要 终端产品成瘾是尼古丁成瘾的一种新形式。了解产品 特征和导致毒瘾的有害和潜在有害成分(HPHCs) 对于FDA有效的CTP监管至关重要。然而，这份HPHC榜单上一次更新是在2012年，就在上升之前 在人气方面。由于五个与成瘾有关的HPHC中有两个是与烟草有关的次要生物碱(例如， 降尼古丁)，那么它就表明有必要对末端特异的次要生物碱进行研究。一个独一无二的流行 末端的次要生物碱是β-尼古丁，它是通过老化和/或雾化电子液体形成的，可以达到 蒸发时尼古丁含量的25%。我们的试点工作发现，β-尼古丁大约使 尼古丁，其功能是烟碱型乙酰胆碱受体(NAChR)激动剂，在 α4β2尼古丁-AChRs类似于去甲尼古丁。鉴于其a)末端气溶胶丰富，b)与 C)抑制尼古丁代谢的能力，β-尼古丁可能与成瘾有关 末端效应，代表了一种新颖的HPHC。如果我们发现β-尼古丁有滥用责任或增加了滥用 尼古丁的责任，它建议CTP应该将其视为HPHC，因为FDA考虑了其他较低的 普遍存在的少量生物碱，如HPHCs。本项目将初步表征β的药代动力学-- 尼古丁及其与尼古丁代谢的相互作用，然后随后确定其在FDA的作用- 滥用倾向的推荐动物模型，包括药物歧视、颅内自我刺激(ICSS) 和药物自我管理。这个项目的创新之处在于：1)它扩展了对次要生物碱的研究， 包括已确定滥用责任的HPHC的构成类别，2)它将首先审查 β-尼古丁的滥用责任及其改变尼古丁滥用责任的能力，包括在与蒸发有关的情况下 3)它将首次表征β-尼古丁的PK及其如何改变尼古丁PK。在……里面 这样，该项目可以阐明介导末端成瘾的新机制，并测试拟议的β- 尼古丁假说。

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.