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: 10413953
• 负责人: ANDREW Charles HARRIS
• 金额: $ 68.31万
• 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/10413953
• 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; abuse liability; 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.

总结