Comparative neurobehavioral pharmacology of combusted and non-combusted tobacco products

摘要 本项目的目的是确定调解燃烧的不同滥用责任的机制 卷烟与非燃烧烟草产品。传统的烟草香烟有更大的滥用 比电子烟(ECS)、无烟烟草和尼古丁等非燃烧产品更容易受到伤害 替代疗法(NRT)。到目前为止，接触商业烟草提取物的动物研究数据 含有尼古丁和一系列非尼古丁烟草成分的产品似乎与 在人类身上观察到的燃烧产品的更大的滥用倾向。调解大局的机制 焚烧产品的滥用责任仍不清楚，但可能反映了独特的或更高水平的成瘾- 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)可以模仿或增强尼古丁的作用，或者可以表现出 滥用责任本身。该项目将比较与成瘾相关的行为和神经生物学 CS提取物、EC气雾剂提取物和尼古丁单独作用(NRT类似物)。重要的是，CS摘录将包含 来自CS颗粒和气相的水和非水可溶成分，从而 提供有史以来用于临床前成瘾研究的最全面的CS提取物。一系列级别的 将对提取物中与行为相关的非尼古丁成分进行测量，以确定特定的成分 这可能是观察到的滥用责任差异的原因。我们的一般假设是CS提取 将有比其他配方更大的成瘾相关的行为和神经生物学影响，因为它的 更高水平的行为活性非尼古丁成分。目标1将比较与上瘾有关的 CS提取物、EC提取物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，上调能力 烟碱型乙酰胆碱受体产生MAO抑制并诱导成瘾相关的c-fos表达 体外脑区，在体内诱发伏隔核多巴胺和5-羟色胺释放的能力，以及 尼古丁的药代动力学。目标2将比较增强增强和厌恶的效果 使用颅内自我刺激的配方，以及它们对体外神经测量的影响 给药条件。目标3将比较配方需求(增强疗效)的相对弹性 使用自我给药方法，当每种配方单独可用并在新的选择下 每种提取物与尼古丁同时可用的程序，以检查替代性。这个项目 将提供与成瘾相关的行为和神经生物学影响的第一次直接比较 不同类别的烟草产品，并将大大促进我们对基本 他们之间不同的滥用责任背后的神经生物学机制。因此，这项工作可能会 通过为不同的产品类别量身定做更好的治疗烟草成瘾的药物来通知开发。

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.