Animal models to inform FDA tobacco regulation: Assessing the relative abuse liability of different classes of tobacco products

项目摘要/摘要 这项研究的目标是使用临床前模型来了解非尼古丁成分是否独特于 香烟烟雾(CS)导致传统卷烟和非卷烟之间滥用倾向的差异 燃烧的替代尼古丁输送系统(AND)，以告知FDA CTP烟草法规。 传统烟草香烟比电子烟(ECs)等传统烟草更容易滥用， 无烟烟草(ST)和尼古丁替代疗法(NRT)。与以下物质相关的非尼古丁成分 CS可能导致香烟的更大的滥用倾向，因为这些成分中的一些(例如， 单胺氧化酶(MAO)抑制剂、挥发性有机化合物(VOCs)可以模拟或增强这种效果 尼古丁，或者表现出自己的滥用责任。评估这一假说可能会导致识别新的 有害或潜在有害成分(HPHC)和与成瘾相关的产品标准的制定 这超出了FDA目前对尼古丁的关注范围。为此目的需要动物模型，因为它们 避免与人体研究相关的限制。涉及接触商业广告提取物的动物研究 烟草产品一直符合下列产品之间的不同滥用责任 人类。我们发现，ST提取物和EC再灌装液的相对滥用倾向与ST提取物和EC再灌装液相似 尼古丁本身，而其他人则发现CS提取物产生的成瘾相关效应比 在某些情况下只有尼古丁。这可能反映了与成瘾相关的非尼古丁水平较高。 壳聚糖提取物中的化学成分。拟议的研究将通过直接比较亲属 最新的CS、ST和EC气雾剂提取物和尼古丁(NRT类似物)的滥用风险，FDA- 评估滥用责任的推荐模型。一系列与行为相关的非尼古丁的水平 成分(例如，MAO抑制剂、乙醛)将被测量，并且单独的MAO抑制剂和 将对VOCs进行研究，以确定可能导致观察到的 滥用责任。在目标1中，对CS提取物的需求将与尼古丁剂量当量浓度进行比较 ST萃取物、EC萃取物和尼古丁单独可用时，或在新的并发选择下 确定制剂的相对增强效果和可替代性的程序。Aim 2将进行比较 配方之间的增强和厌恶效果。目标3将评估增援- 单独使用MAO抑制剂和挥发性有机化合物时的增强和厌恶效应 再加上尼古丁。据推测，CS提取物与成瘾相关的作用比 由于其行为活性非尼古丁成分水平较高的其他配方(例如，MAO抑制剂， VOCs)。这些研究将表征特定烟草产品特性的影响(即 非尼古丁成分)，并向FDA CTP通报潜在的化合物，以考虑 添加到HPHC名单中。因此，这些数据将有助于为FDA CTP的具体监管行动提供信息。

PROJECT SUMMARY/ABSTRACT The goal of this study is to use preclinical models to understand whether non-nicotine constituents unique to cigarette smoke (CS) contribute to differences in abuse liability between conventional cigarettes and non- combusted, alternative nicotine delivery systems (ANDs) in order to inform FDA CTP tobacco regulation. Conventional tobacco cigarettes have greater abuse liability than ANDs, such as electronic cigarettes (ECs), smokeless tobacco (ST), and nicotine replacement therapy (NRT). Non-nicotine constituents associated with CS may contribute to the greater abuse liability of cigarettes because some of these constituents (e.g., monoamine oxidase (MAO) inhibitors, volatile organic compounds (VOCs)) can mimic or enhance the effects of nicotine, or exhibit abuse liability themselves. Evaluating this hypothesis could lead to identification of new Harmful or Potentially Harmful Constituents (HPHCs) and development of addiction-related product standards that extend beyond the FDA's current focus on nicotine. Animal models are needed for this purpose, as they avoid limitations associated with human studies. Animal studies involving exposure to extracts of commercial tobacco products have been consistent with the differential abuse liability between products observed in humans. We have found that the relative abuse liability of ST extract and EC refill liquid is similar to that of nicotine alone, whereas others have found that CS extracts can produce greater addiction-related effects than nicotine alone under certain conditions. This may reflect the higher levels of addiction-relevant non-nicotine constituents in CS extracts. The proposed studies will evaluate this possibility by directly comparing the relative abuse liability of CS, ST, and EC aerosol extracts and nicotine alone (NRT analog) in state-of-the-art, FDA- recommended models for assessing abuse liability. Levels of a range of behaviorally relevant non-nicotine constituents (e.g., MAO inhibitors, acetaldehyde) will be measured and effects of isolated MAO inhibitors and VOCs will be studied to identify the specific constituents that may be responsible for observed differences in abuse liability. In Aim 1, demand for CS extract will be compared to nicotine dose-equivalent concentrations of ST extract, EC extract, and nicotine alone when each is available in isolation or under novel concurrent-choice procedures to determine relative reinforcing efficacy and substitutability of formulations. Aim 2 will compare reinforcement-enhancing and aversive effects between formulations. Aim 3 will evaluate the reinforcement- enhancing and aversive effects of isolated MAO inhibitors and VOCs when administered alone or in combination with nicotine. It is hypothesized that CS extract will have greater addiction-related effects than the other formulations due to its higher levels of behaviorally active non-nicotine constituents (e.g., MAO inhibitors, VOCs). These studies will characterize the impact of a specific tobacco product characteristic (i.e., profile of non-nicotine constituents) in tobacco abuse and inform the FDA CTP on potential compounds to consider for addition to the list of HPHCs. As such, the data will help inform specific regulatory actions of the FDA CTP.