Animal models for evaluating the relative abuse liability of electronic cigarettes

 描述（由申请人提供）：本提案将开发新型临床前方法，用于评估青少年中电子烟（EC）的相对滥用倾向，并检验非尼古丁成分导致该人群中EC滥用倾向的假设。美国食品和药物管理局（FDA）烟草产品中心（CTP）监管的新烟草产品在上市前必须进行滥用责任测试。FDA CTP已宣布打算对EC进行监管，EC已超过烟草卷烟，成为青少年使用的主要烟草产品，尽管其健康后果尚不清楚。迫切需要开发适当的方法来评估青少年中EC的相对滥用倾向，以告知FDA CTP关于这些产品的政策，并预测其对公众健康的影响。这一过程需要动物模型，因为它们允许检查难以或不可能在人类中进行实验研究的问题（例如，青少年开始吸烟）。目前的烟草滥用动物模型仅检查单独的尼古丁和/或其他分离的烟草成分，可能不足以评估烟草产品，如EC，因为a）烟草产品中的其他化合物可能有助于（积极或消极）烟草滥用，和B）是烟草产品中所有化合物的相互作用或总和决定了其实际的滥用倾向。因此，涉及暴露于尼古丁和直接来自EC的其他成分的混合物的新临床前模型对于准确评估这些产品的滥用倾向可能是必要的。为此，本项目将在青春期大鼠中比较单独尼古丁与尼古丁剂量当量浓度的EC气雾剂提取物的滥用相关效应。因为EC气雾剂中存在的一些非尼古丁成分（例如，虽然提取物（例如，少量生物碱）可以模拟或增强尼古丁的成瘾相关作用，但一般假设是，提取物将比单独使用同等剂量的尼古丁具有更大的滥用倾向。一致 根据这一假设，我们的初步数据表明，在EC补充液或气雾剂提取物中递送尼古丁减弱了其厌恶作用。由于尼古丁的厌恶作用限制了它的摄入量，这种作用可能会增加EC的消费。为了进一步检验我们的假设，目标1将比较单独尼古丁和提取物的增强作用，通过静脉自我给药来测量。还将使用行为经济学方法来比较这些制剂在尼古丁单位剂量逐渐减少期间的强化功效。目标2将比较制剂的厌恶作用，如使用条件性味觉厌恶所测量的。这些研究中建立的方法将有助于预测EC的相对滥用责任，以及模拟FDA CTP规定的EC中尼古丁或其他成分产品标准的变化。该项目还直接涉及几个FDA CTP感兴趣的领域，包括EC的启动、使用和依赖，以及烟草产品特性的影响（例如，在青少年中启动。

 DESCRIPTION (provided by applicant): This proposal will develop novel preclinical methodology for evaluating the relative abuse liability of electronic cigarettes (ECs) in adolescents, and test the hypothesis that non-nicotine constituents contribute to EC abuse liability in this population. New tobacco products regulated by the Food and Drug Administration (FDA) Center for Tobacco Products (CTP) must undergo abuse liability testing prior to marketing. The FDA CTP has announced its intention to regulate ECs, which have surpassed tobacco cigarettes as the primary tobacco product used by adolescents despite their unknown health consequences. Development of appropriate methodology for evaluating the relative abuse liability of ECs in adolescents is urgently needed for informing FDA CTP policy regarding these products and for anticipating their impact on public health. Animal models are needed for this process, as they allow for examination of issues that are difficult or impossible to study experimentally in humans (e.g., initiation of tobacco use in adolescents). Current animal models of tobacco abuse that only examine nicotine alone and/or other isolated tobacco constituents may not be sufficient for evaluating tobacco products such as ECs because a) other compounds in tobacco products may contribute (positively or negatively) to tobacco abuse, and b) it is the interaction or summation of all the compounds in a tobacco product that determines its actual abuse liability. Therefore, new preclinical models involving exposure to a mixture of nicotine and other constituents derived directly from ECs may be necessary for an accurate assessment of the abuse liability of these products. To this end, this project will compare the abuse-related effects of nicotine alone versus nicotine dose-equivalent concentrations of EC aerosol extracts in adolescent rats. Because some non-nicotine constituents present in EC aerosol (e.g., minor alkaloids) can mimic or enhance nicotine's addiction-related effects, the general hypothesis is that extracts will have greater abuse liability than equivalent doses of nicotine alone. Consistent with this hypothesis, our preliminary data indicate that delivery of nicotine in EC refill liquid o aerosol extract attenuates its aversive effects. Because nicotine's aversive effects limit its intake, this effect could increase EC consumption. To further test our hypothesis, Aim 1 will compare the reinforcing effects of nicotine alone and extracts as measured by acquisition of i.v. self-administration. A behavioral economic approach will also be used to compare the reinforcing efficacy of these formulations during a progressive reduction in nicotine unit dose. Aim 2 will compare formulations in terms of their aversive effects as measured using conditioned taste aversion. The methodology established in these studies will be useful for anticipating the relative abuse liability of ECs, as well as for modeling FDA CTP-mandated changes in product standards for nicotine or other constituents in ECs. This project also directly addresses several FDA CTP interest areas including EC initiation, use, and dependence, and the impact of tobacco product characteristics (e.g., constituents) on initiation in adolescents.