Comparative neurobehavioral pharmacology of combusted and non-combusted tobacco products

总结 本项目的目的是确定调解燃烧的不同滥用责任的机制， 香烟与非燃烧的烟草产品。传统烟草的滥用 电子烟（EC），无烟烟草和尼古丁等非燃烧产品的责任 替代疗法（NRT）。迄今为止，来自暴露于商业烟草提取物的动物研究的数据 含有尼古丁和一系列非尼古丁烟草成分的产品似乎与 在人类中观察到的燃烧产品的滥用倾向更大。调解更大规模冲突的机制 燃烧产品的滥用责任仍不清楚，但可能反映了独特或更高的成瘾水平- 香烟烟雾（CS）中的相关非尼古丁成分。这些成分中的一些（例如，挥发性有机 化合物、单胺氧化酶（MAO）抑制剂）可以模拟或增强尼古丁的作用，或者可以表现出 自己承担责任。本项目将比较成瘾相关的行为和神经生物学 CS浸提液、EC气雾剂浸提液和单独尼古丁（NRT类似物）的影响。重要的是，CS浸提液将含有 来自CS的颗粒和气相的水溶性和非水溶性成分， 提供临床前成瘾研究中使用的最全面的CS提取物。一系列的水平 将测量提取物中与行为相关的非尼古丁成分， 这可能是造成滥用责任差异的原因。我们的一般假设是，CS提取物 将比其他制剂具有更大的成瘾相关行为和神经生物学效应， 更高水平的行为活性非尼古丁成分。目标1将比较与成瘾相关的 CS浸提液、EC浸提液和尼古丁单独的神经生物学和药代动力学效应，包括结合 体外对多种成瘾相关受体的亲和力和功能活性，上调 烟碱乙酰胆碱受体，产生单胺氧化酶抑制，并诱导c-fos表达成瘾相关 离体脑区，在体内引起丘脑核中多巴胺和5-羟色胺释放的能力，以及 尼古丁药代动力学目标2将比较以下因素的增强和抑制作用： 使用颅内自刺激的制剂，以及它们在这些条件下对离体神经测量的影响。 给药条件。目标3将比较制剂（增强效力）需求的相对弹性 当每种制剂可单独获得并在新的选择下使用自我给药方法 每种提取物与尼古丁同时使用以检查替代性的程序。这个项目 将提供第一个直接比较与成瘾相关的行为和神经生物学影响， 不同类别的烟草产品，并将大大提高我们的基本认识， 神经生物学机制之间的差异滥用责任。因此，这项工作可能 通过针对不同的产品类别，为更好的烟草成瘾药物的开发提供信息。

SUMMARY The purpose of this project is to identify mechanisms mediating the differential abuse liability of combusted cigarettes versus non-combusted tobacco products. Conventional tobacco cigarettes have greater abuse liability than non-combusted products such as electronic cigarettes (ECs), smokeless tobacco, and nicotine replacement therapy (NRT). To date, data from animal studies of exposure to extracts of commercial tobacco products that contain nicotine and a range of non-nicotine tobacco constituents appear to be consistent with the greater abuse liability of combusted products observed in humans. The mechanisms mediating the greater abuse liability of combusted products remain unclear, but may reflect the unique or higher levels of addiction- relevant non-nicotine constituents in cigarette smoke (CS). Some of these constituents (e.g., volatile organic compounds, monoamine oxidase (MAO) inhibitors) can mimic or enhance the effects of nicotine, or can exhibit abuse liability themselves. This project will compare the addiction-related behavioral and neurobiological effects of CS extract, EC aerosol extract, and nicotine alone (NRT analog). Importantly, CS extract will contain both water- and non-water-soluble constituents from both the particulate and gas phase of CS, thereby providing the most comprehensive CS extract ever used in preclinical addiction studies. Levels of a range of behaviorally relevant non-nicotine constituents in the extracts will be measured to identify specific constituents that may be responsible for observed differences in abuse liability. Our general hypothesis is that CS extract will have greater addiction-related behavioral and neurobiological effects than the other formulations due to its higher levels of behaviorally active non-nicotine constituents. Aim 1 will compare the addiction-related neurobiological and pharmacokinetic effects of CS extract, EC extract and nicotine alone, including binding affinity and functional activity at a wide range of addiction-related receptors in vitro, ability to up-regulate nicotinic acetylcholine receptors, produce MAO inhibition, and induce c-fos expression in addiction-related brain areas ex vivo, ability to elicit dopamine and serotonin release in the nucleus accumbens in vivo, and nicotine pharmacokinetics. Aim 2 will compare the reinforcement-enhancing and aversive effects of formulations using intracranial self-stimulation, as well as their effects on ex vivo neural measures under these dosing conditions. Aim 3 will compare the relative elasticity of demand for (reinforcing efficacy of) formulations using self-administration methods when each formulation is available in isolation and under novel choice procedures where each extract is available concurrently with nicotine to examine substitutability. This project will provide the first direct comparison of both the addiction-related behavioral and neurobiological effects of different classes of tobacco products, and will significantly advance our understanding of the basic neurobiological mechanisms underlying the differential abuse liability between them. As such, this work may inform development of better medications for tobacco addiction by tailoring them to different product classes.