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

β-烟酪氨酸作为电子烟滥用倾向的潜在贡献者的评估

• 批准号: 10351947
• 负责人: John Richard Smethells
• 金额: $ 32.95万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10351947
• 关键词: Aerosols; Aging; Alkaloids; Animal Model; Behavior; Behavioral; Characteristics; Dependence; Development; Dose; Drug Kinetics; Electronic Nicotine Delivery Systems; Electronic cigarette; Evaluation; Half-Life; Knowledge; Liquid substance; Maintenance; Mediating; Metabolism; Methods; Minor; Nicotine; Nicotine Dependence; Nicotinic Receptors; Pharmaceutical Preparations; Policies; Property; Protocols documentation; Psychological reinforcement; Rattus; Regulation; Research; Saline; Science; Self Administration; Self Stimulation; Stimulus; Testing; Tobacco; Training; Update; Work; acetylcholine receptor agonist; addiction; aerosolized; drug discrimination; electronic liquid; experience; innovation; nicotine use; nornicotine; novel; pharmacokinetics and pharmacodynamics; reinforcer; response; tobacco products; vaping

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.

项目摘要/摘要 对末端产品的成瘾是尼古丁成瘾的新兴形式。了解产品 特征和有害和潜在的有害构成（HPHC），导致成瘾 对于有效的FDA CTP调节至关重要。然而，此HPHC列表最后一次更新于2012年，就在上升之前 在末端流行。由于五个与成瘾相关的HPHC中有两个是与烟草相关的小生物碱（例如， Nornicotine），然后建议对端特异性小生物碱进行研究。一个独特的普遍 末端生物碱是β-Nicotyrine，它是由衰老和/或雾化的电子液体形成的，可以到达 烟气中的尼古丁水平的25％。我们的飞行员工作发现，β-纽约汀大约翻了一番 尼古丁及其作为烟碱乙酰胆碱受体（NACHR）激动剂，具有功能效率 α4β2烟碱含量类似于诺糖苷。鉴于其a）在气溶胶中的末端抽象，b）与 norncotine和c）抑制尼古丁代谢的能力，β-纽约胺可能有助于与成瘾有关 末端的效果并代表一种新型的HPHC。如果我们发现β-NiCotyrine具有滥用责任或增加滥用 尼古丁的责任，这表明CTP应该认为这是HPHC，因为FDA认为其他人较少 普遍的小生物碱为HPHC。本项目最初将表征β-的药代动力学 烟碱及其与尼古丁代谢的相互作用，然后确定其在FDA- 推荐的虐待责任的动物模型，包括药物歧视，颅内自我刺激（ICS） 和药物自我管理。该项目具有创新性，因为：1）它扩展了对次要生物碱的研究， 包括既定虐待责任的HPHC的构成类别，2）这将是第一个检查 β-尼古丁的滥用责任及其改变尼古丁滥用责任的能力，包括在相关的情况下进行vap 浓度和3）将第一个表征β-尼古丁的PK及其如何改变尼古丁PK的浓度。 因此，该项目可以阐明介导的新机制，并测试提出的β- 烟碱假设。