Animal Models for Assessing the Relative Abuse Liability of Tobacco Products

评估烟草制品相对滥用责任的动物模型

• 批准号: 8310407
• 负责人: MARK G LESAGE
• 金额: $ 28.53万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8310407
• 关键词: Address; Adolescent; Adult; Animal Model; Animals; Behavioral; Camels; Chemicals; Chronic; Clinical Trials; Data; Dependence; Development; Dose; Drug Formulations; Economics; Evaluation; Exposure to; Future; Goals; Health; Human; Infusion procedures; Institute of Medicine (U.S.); Instruction; Intake; Intravenous; Marketing; Measures; Methodology; Methods; Modeling; Nicotine; Nicotine Dependence; Performance; Pharmaceutical Preparations; Policies; Population; Pre-Clinical Model; Process; Psychological reinforcement; Public Health; Rattus; Recording of previous events; Relative (related person); Risk; Role; Screening procedure; Self Administration; Self Stimulation; Self-Administered; Severities; Smell Perception; Specific qualifier value; Stimulus; Taste Perception; Tobacco; Tobacco Dependence; Tobacco Industry; Tobacco use; Toxin; Training; United States Food and Drug Administration; Validation; Withdrawal; Work; addiction; age difference; aqueous; base; clinically relevant; design; exposed human population; meetings; novel; pre-clinical; programs; public policy on tobacco; snus; tobacco abuse; tool

The goal of this component of the POI application is to develop methods to evaluate the relative abuse liability of tobacco products in animals. The tobacco industry is introducing several "modified risk" tobacco products (MRTPs) promoted to be safer or less addictive than conventional products. The Food and Drug Administration (FDA) is now required to evaluate the abuse liability of current and future MRTPs. Animal models are urgently needed for this process because they allow a) examination of critical phenomena that cannot be studied experimentally in humans (e.g., initiation of tobacco use in adolescents), b) isolation of the role of nicotine and other tobacco constituents from other factors, and c) screening of novel tobacco formulations prior to human exposure. Current animal models that only examine nicotine or other isolated constituents may not accurately assess the abuse liability of tobacco products because a) as yet unidentified compounds may contribute (positively or negatively) to tobacco abuse and b) it is the interaction of these compounds that determines the actual abuse liability of a product. The current project will address this issue by using well-established animal models to examine the abuse liability of aqueous tobacco extracts from four different MRTPs and a conventional product. These extracts provide an extensive range of nicotine and other tobacco constituents to more closely model actual product exposure in humans. Aim la will compare the reinforcing efficacy of tobacco extracts and nicofine with intravenous self-administration (SA) models using behavioral economic methods Aim lb will compare acquisifion of extract and nicofine SA in adolescent and adult rats. Aim 1c will compare extracts and nicotine in terms of their reinforcement-enhancing and aversive effects measured as changes in intracranial self-stimulation (ICSS) thresholds. Aim 2 will compare the ability of chronic infusion of extracts and nicofine to induce dependence as measured by withdrawal-induced elevafions in ICSS thresholds. Because some non-nicotine constituents are known to enhance nicotine's dependence-related effects, the general working hypothesis is that tobacco extracts will have greater abuse liability than equivalent doses of pure nicotine. We also hypothesize that the proposed methods will be sufficiently sensifive to disfinguish between extracts of different products. The proposed studies were specifically designed to parallel the human studies in this POI by a) employing behavioral economic methods to assess reinforcing efficacy, b) measuring withdrawal severity, and c) examining some of the same products. As such, this POI will allow validation of behavioral economics as a framework for integrating findings across species and predicting populafion-level abuse of different products. Examining abuse liability in adolescents will provide a critical extension of the human projects. By studying several more products than the human studies, findings in animals may help prioritize other products that need to be evaluated in humans. This study will provide the basis for standardized animal models of abuse liability to evaluate tobacco products and inform FDA regulafion of performance standards.

POI应用程序的该组成部分的目的是开发评估相对虐待责任的方法 动物中的烟草产品。烟草业推出了几种“改良风险”烟草产品 （MRTPS）晋升为比常规产品更安全或更少。食品药物管理局 （FDA）现在需要评估当前和将来的MRTP的滥用责任。动物模型紧急 此过程所需 在人类中实验（例如，在青少年中使用烟草使用），b）尼古丁和 来自其他因素的其他烟草成分，c）在人类之前筛选新型烟草制剂 接触。当前仅检查尼古丁或其他孤立成分的动物模型可能无法准确 评估烟草产品的滥用责任，因为a）尚未确定的化合物可能会贡献 （积极或负面的）滥用烟草和b）这些化合物的相互作用决定了 产品的实际滥用责任。当前项目将通过使用良好的动物来解决这个问题 模型检查来自四个不同的MRTP和A的水性烟草提取物的滥用责任 传统产品。这些提取物为尼古丁和其他烟草成分提供了广泛的范围 更紧密地模拟了人类实际产品的影响。 AIM LA将比较烟草的增强功效 使用行为经济方法的提取物和带有静脉自我管理（SA）模型的矿物 AIM LB将比较青少年和成年大鼠中提取物和尼古丁SA的获取。 AIM 1C将比较 提取物和尼古丁在增强增强的增强和厌恶效果方面被衡量 颅内自刺激（ICS）阈值。 AIM 2将比较提取物的慢性输注能力和 通过ICSS阈值中撤回诱导的高升高来诱导依赖性。因为 已知某些非纽约胺成分可以增强尼古丁的依赖性作用，即一般 工作假设是，烟草提取物将具有比等效剂量纯的滥用责任 尼古丁。我们还假设所提出的方法将足够敏感 不同产品的提取物。拟议的研究是专门设计的，是为了使人类研究与 通过a）采用行为经济方法来评估增强功效的POI，b）测量戒断 严重性，c）检查一些相同的产品。因此，此POI将允许验证行为 经济学是整合跨物种发现并预测人口级滥用的框架 不同的产品。检查青少年的虐待责任将为人类提供关键的扩展 项目。通过研究比人类研究多的几种产品，动物的发现可能有助于确定优先级 需要在人类中评估的其他产品。这项研究将为标准动物提供基础 滥用责任的模型，以评估烟草产品并为FDA调节性能标准提供信息。