Determinants of Nicotine Reinforcement Thresholds and Demand Elasticity in Rats

大鼠尼古丁强化阈值和需求弹性的决定因素

• 批准号: 8311755
• 负责人: MARK G LESAGE
• 金额: $ 32.45万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311755
• 关键词: Address; Adolescent; Adult; Adverse effects; Affect; Animal Experimentation; Animal Model; Animals; Behavioral; Biological; Cigarette; Clinical; Complement; Data; Development; Dose; Drug Kinetics; Drug abuse; Economics; Elasticity; Evaluation; Extinction (Psychology); Financial compensation; Goals; Half-Life; Health; Health Policy; Human; Immunization; Individual; Individual Differences; Industry; Infusion procedures; Intake; Intervention; Maintenance; Marketing; Measures; Metabolism; Methods; Modeling; Nicotine; Nicotine Dependence; Pharmaceutical Preparations; Pharmacotherapy; Policies; Population; Price; Psychological reinforcement; Public Health; Public Policy; Rattus; Regulation; Risk; Role; Safety; Self Administration; Self-Administered; Smoker; Smoking; Source; Testing; Tobacco; Training; addiction; adverse outcome; base; behavior measurement; cigarette smoking; drug of abuse; drug reinforcement; experimental analysis; indexing; insight; nicotine replacement; novel; policy implication; prevent; public health relevance; response; smoking cessation; tool; treatment strategy; varenicline

DESCRIPTION (provided by applicant): The overall goal of this study is to examine determinants of nicotine reinforcement thresholds in rats in order to provide a scientific basis for evaluation of low-nicotine tobacco products. Such products are being introduced by industry as alternatives to higher nicotine products or examined clinically as aids to smoking cessation. In addition, gradual reduction of the levels of nicotine in cigarettes to render them non-addictive has been proposed as a population-wide regulatory approach to promoting smoking cessation and preventing initiation of smoking in adolescents. However, the feasibility and consequences of reducing nicotine in tobacco products is largely unknown. Key questions include: a) What is the threshold level of nicotine needed to maintain smoking in adults, and would reducing nicotine delivery below this threshold be sufficient to also prevent development of nicotine addiction in adolescents? b) To what extent would compensatory smoking, an adverse side effect, occur in response to progressively reduced nicotine cigarettes? c) What behavioral and pharmacological factors contribute to individual variability in nicotine reinforcement thresholds and compensation that represent potential sources of individual variability in addiction and health risk across different populations? d) Would smoking cessation medications facilitate or impede smoking cessation in the context of nicotine regulation? Because experimental analysis of initiation of smoking in adolescents, and control of nicotine exposure in general, is difficult to accomplish in human studies, animal research is needed to examine comprehensively these issues. Behavioral economic (i.e., demand curve) analysis is uniquely suited to the present studies and will be used to provide information on determinants of the reinforcing efficacy of nicotine that will complement analysis of nicotine reinforcement thresholds. The primary hypothesis to be tested is that the nicotine reinforcement threshold and elasticity of demand (an index of reinforcing efficacy) for maintenance of nicotine self-administration (NSA) in adult rats during reductions in unit dose is lower than that for acquisition of NSA in adolescents. Specific Aim 1 will characterize nicotine reinforcement thresholds, elasticity of demand, and degree of compensation during maintenance of NSA in adult rats, and examine whether these variables are correlated with individual differences in baseline intake, measures of extinction, and nicotine metabolism. Specific Aim 2 will characterize and compare nicotine reinforcement thresholds and elasticity of demand for acquisition of NSA in adolescent and adult rats, and examine whether these variables are correlated with individual differences in nicotine metabolism. Specific Aim 3 will test the hypothesis that currently-approved (nicotine replacement, varenicline) and novel (immunization) medications for cessation will increase the nicotine reinforcement threshold and elasticity of demand for nicotine, and reduce compensation. This project will provide an extensive assessment of the effects of nicotine unit dose manipulation on NSA and could have important clinical, public health, and policy implications for nicotine reduction products and strategies. PUBLIC HEALTH RELEVANCE: Tobacco products with reduced nicotine content are being marketed by industry and also being considered as a population-wide regulatory approach to promote cessation and prevent initiation of smoking in adolescents. However, the feasibility, efficacy, and safety of this approach has not been firmly established due to a lack of scientific data. Findings from the present project will provide scientific data on the effects of nicotine dose reduction in an animal model of smoking, identify potential biological or pharmacologic contributors to individual differences that might influence the applicability of nicotine dose reduction, identify potential adverse consequences, and clarify the role of smoking cessation medications in this context. As such, the present study could contribute to the scientific basis for evaluation of reduced nicotine tobacco products and their clinical and public health consequences.

描述（由申请人提供）：这项研究的总体目标是检查大鼠尼古丁增强阈值的决定因素，以便为评估低烟碱烟草产品的科学依据。行业将这些产品作为较高尼古丁产品的替代品或临床检查作为戒烟的帮助。此外，已经提出，逐渐降低了香烟中尼古丁的水平，以使其不依赖，以促进促进戒烟并防止青少年吸烟开始的监管方法。但是，在烟草产品中减少尼古丁的可行性和后果在很大程度上尚不清楚。关键问题包括：a）在成年人中维持吸烟所需的尼古丁的阈值水平是多少，将尼古丁的递送降低到此阈值以下是否足以防止青少年的尼古丁成瘾发展？ b）响应逐渐减少尼古丁香烟，补偿性吸烟会在多大程度上发生不利的副作用？ c）哪些行为和药理因素导致尼古丁增强阈值和补偿的个体变异性，这些阈值代表了不同人群中成瘾和健康风险中个人变异性的潜在来源？ d）在尼古丁调节的背景下，戒烟药物会促进或阻碍戒烟？由于对青少年吸烟的起始和对尼古丁暴露的控制的实验分析很难在人类研究中完成，因此需要进行动物研究来全面研究这些问题。行为经济（即需求曲线）分析非常适合当前研究，并将用于提供有关尼古丁增强功效的确定因素的信息，这些信息将补充尼古丁增强阈值的分析。要测试的主要假设是，尼古丁的增强阈值和需求的弹性（增强功效指数）维持尼古丁自我给药（NSA）在成年大鼠减少期间单位剂量减少期间的尼古丁自我给药（NSA）低于青少年中NSA的收购。具体目标1将表征尼古丁增强阈值，需求的弹性以及成年大鼠NSA的维持期间的补偿程度，并检查这些变量是否与基线摄入量的个体差异，灭绝量和尼古丁代谢相关。具体目标2将表征和比较尼古丁增强阈值以及青少年和成年大鼠中NSA的需求的弹性，并检查这些变量是否与尼古丁代谢的个体差异相关。具体目标3将检验以下假设：当前批准的（尼古丁替代，varenicline）和新型（免疫）用于戒烟将增加尼古丁的增强阈值和对尼古丁的需求弹性，并减少补偿。该项目将对尼古丁单位剂量操纵对NSA的影响提供广泛的评估，并可能对尼古丁还原产品和策略产生重要的临床，公共卫生和政策影响。 公共卫生相关性：烟碱含量减少的烟草产品正在用行业销售，也被视为一种范围内的监管方法，以促进戒烟并防止青少年吸烟。但是，由于缺乏科学数据，这种方法的可行性，功效和安全性尚未牢固确定。本项目的发现将提供有关尼古丁剂量减少在吸烟动物模型中的影响的科学数据，确定可能影响尼古丁剂量降低，识别潜在不良后果的个体差异的潜在生物学或药理学贡献者，并阐明在这种情况下吸烟药物的作用。因此，本研究可能有助于评估减少尼古丁烟草产品及其临床和公共卫生后果的科学基础。