Comparative neurobehavioral pharmacology of combusted and non-combusted tobacco products

燃烧和未燃烧烟草产品的神经行为药理学比较

• 批准号: 10206086
• 负责人: ANDREW Charles HARRIS
• 金额: $ 70.22万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10206086
• 关键词: Address; Affinity; Animals; Area; Attenuated; Behavioral; Behavioral Model; Binding; Biological Assay; Brain; Chemicals; Cigarette; Development; Dopamine; Dose; Drug Kinetics; Elasticity; Electronic cigarette; Exhibits; Exposure to; FOS gene; Formulation; Gases; Human; In Vitro; Lead; Liquid substance; Measures; Mediating; Methods; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neurobiology; Nicotine; Nicotinic Receptors; Nucleus Accumbens; Outcome; Particulate; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Prevention; Procedures; Psychological reinforcement; Research; Self Administration; Self Stimulation; Serotonin; Smokeless Tobacco; Tobacco; Tobacco Dependence; Tobacco use; Water; Work; addiction; analog; animal data; cigarette smoke; comparative; e-cigarette aerosols; in vivo; monoamine; neurobehavioral; neurobiological mechanism; nicotine replacement; novel; pre-clinical; receptor; relating to nervous system; tobacco products; volatile organic compound

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.

概括 该项目的目的是确定介导燃烧的差异滥用责任的机制 香烟与未燃烧的烟草产品。传统的烟草香烟滥用更多 责任比非燃烧产品（例如电子烟（EC），无烟烟草和尼古丁） 替代疗法（NRT）。迄今为止，来自动物研究的数据暴露于商业烟草提取物 含有尼古丁和一系列非新氧化烟草成分的产品似乎与 在人类中观察到的燃烧产品的更大滥用责任。介导更大的机制 燃烧产品的滥用责任尚不清楚，但可能反映了独特或更高水平的成瘾 - 香烟烟雾（CS）中相关的非纽约胺成分。其中一些成分（例如，有机挥发性 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，或者可以表现出来 虐待责任本身。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气溶胶提取物和尼古丁的影响（NRT类似物）。重要的是，CS提取物将包含 从CS的颗粒和气相都有水和非水溶性成分，从而 提供临床前成瘾研究中使用的最全面的CS提取物。范围 将测量提取物中与行为相关的非脱糖苷成分，以识别特定成分 这可能导致观察到的虐待责任差异。我们的总体假设是CS提取 由于其，与其他制剂有关 较高的行为活性非核生素成分。 AIM 1将比较与成瘾有关的 CS提取物，EC提取物和尼古丁的神经生物学和药代动力学作用，包括结合 在体外与成瘾相关的受体的亲和力和功能活性，上调的能力 烟碱乙酰胆碱受体，产生MAO抑制作用，并在成瘾中诱导C-FOS表达 大脑区域离体，体内伏隔核中多巴胺和5-羟色胺释放的能力，并且 尼古丁药代动力学。 AIM 2将比较增强的增强作用和厌恶的影响 使用颅内自我刺激的制剂，以及它们对这些下体内神经措施的影响 给药条件。 AIM 3将比较（增强）配方效力的相对弹性 当每个公式都可以孤立并在新颖的选择下使用时，请使用自我管理方法 每种提取物与尼古丁同时可用以检查替代性的过程。这个项目 将提供与成瘾相关的行为和神经生物学效应的首次直接比较 不同类别的烟草产品，并将大大提高我们对基本的理解 神经生物学机制是它们之间差异滥用责任的基础。因此，这项工作可能 通过将其定制为不同的产品类别，为烟草成瘾的更好的药物开发。