Menthol: An Accomplice of Nicotine in Tobacco Smoking

薄荷醇：吸烟中尼古丁的同谋

• 批准号: 8677048
• 负责人: XIU LIU
• 金额: $ 21.66万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677048
• 关键词: Accounting; Address; Adolescent; Adult; Area; Behavior; Behavioral; Brain region; Cigarette; Clinical Research; Cues; Dialysis procedure; Dopamine; Dose; Extinction (Psychology); Family Smoking Prevention and Tobacco Control Act; Flavoring; Hazardous Chemicals; Human; Intake; Intravenous; Left; Limb structure; Maintenance; Marketing; Measures; Mediating; Menthol; Microdialysis; Modeling; Neurotransmitters; Nicotine; Nicotine Dependence; Nicotinic Receptors; Nucleus Accumbens; Peripheral; Policies; Psychological reinforcement; Rattus; Relapse; Research; Research Priority; Rewards; Rodent; Self Administration; Sensory; Shapes; Smoker; Smoking; Testing; Tobacco; Tobacco Dependence; Tobacco smoking; Tobacco use; Ventral Tegmental Area; Vulnerable Populations; Work; World Health Organization; Youth; base; behavior test; experience; intraperitoneal; neurochemistry; neurotransmission; public health relevance; research study; response; skills

DESCRIPTION (provided by applicant): Menthol is a significant additive in tobacco products. Mentholated cigarettes account for approximately one- quarter of the total cigarette market. Approximately one-third of current smokers predominantly use mentholated cigarettes. Particularly concerning, young smokers are more likely to initiate smoking with mentholated cigarettes. A fundamental question regarding the mentholation of tobacco products is whether menthol directly enhances the reinforcing effects of nicotine and thus promotes tobacco addiction. Our preliminary studies showed that menthol increased nicotine self-administration at a low dose. This is consistent with other studies that showed that menthol, beyond its peripheral sensory effects, can interact with central nicotinic acetylcholine receptors and change dopamine neurotransmission. Based on these findings, we hypothesize that menthol directly enhances the reinforcing effects of nicotine. To test this hypothesis, this project proposes to systematically examine the effects of menthol on nicotine reinforcement using our established nicotine self-administration paradigm. Menthol will be administered intraperitoneally so the peripheral sensory effects of menthol are eliminated. In Specific Aim 1, we will test whether menthol promotes the initiation of nicotine self-administration in adolescent rats. In Specific Aim 2, the enhancing effect of menthol on nicotine reinforcement will be examined in adult rats after the establishment of stable self- administration of nicotine so we can assess whether menthol facilitates the maintenance and progression of nicotine self-administration. In Specific Aim 3, we will determine whether menthol reinstates nicotine-seeking behavior and promotes nicotine priming and/or nicotine-conditioned cue reinstatement of extinguished nicotine seeking. Finally, we will examine whether menthol changes nicotine-induced release of dopamine in the nucleus accumbens (a terminal region of the brain dopamine reward circuit that originates in the ventral tegmental area). The results of the proposed experiments will provide important information about the contribution of menthol to nicotine reinforcement and tobacco addiction. Thus, this project directly addresses the call of the FDA Center for Tobacco Products: "What are the factors, including menthol and other flavorings that influence the appeal of tobacco products to both users and non-users, including youth and other vulnerable populations? What is the impact of these factors on experimentation, initiation, cessation, switching tobacco products, and multiple uses?" The empirical evidence obtained from this project will support the Center to consider implementing new policies that regulate the addition of menthol in tobacco products, which is one of the Center's first actions mandated by the Family Smoking Prevention and Tobacco Control Act (2009).

说明（申请人提供）：薄荷脑是烟草制品中的重要添加剂。卷烟约占整个卷烟市场的四分之一.目前约有三分之一的吸烟者主要使用含薄荷醇的香烟。特别令人担忧的是，年轻吸烟者更有可能开始吸烟含薄荷的香烟。关于烟草产品的薄荷醇化的一个基本问题是薄荷醇是否直接增强尼古丁的增强作用，从而促进烟草成瘾。我们的初步研究表明，薄荷醇在低剂量下增加了尼古丁的自我给药。这与其他研究一致，这些研究表明，薄荷醇除了其外周感觉效应外，还可以与中枢烟碱乙酰胆碱受体相互作用并改变多巴胺神经传递。基于这些发现，我们假设薄荷醇直接增强尼古丁的增强作用。为了验证这一假设，本项目建议使用我们建立的尼古丁自我给药范式系统地检查薄荷醇对尼古丁强化的影响。将通过腹膜内给予薄荷醇，以消除薄荷醇的外周感觉效应。在具体目标1中，我们将测试薄荷醇是否促进青春期大鼠开始尼古丁自我给药。在具体目标2中，将在建立尼古丁稳定自我给药后，在成年大鼠中检查薄荷醇对尼古丁强化的增强作用，因此我们可以评估薄荷醇是否有助于尼古丁自我给药的维持和进展。在具体目标3中，我们将确定薄荷醇是否恢复尼古丁寻求行为，并促进尼古丁启动和/或尼古丁条件性线索恢复已熄灭的尼古丁寻求。最后，我们将研究薄荷醇是否会改变尼古丁诱导的多巴胺在脑桥核（起源于腹侧被盖区的大脑多巴胺奖赏回路的终端区域）中的释放。这些实验结果将为薄荷醇对尼古丁强化和烟草成瘾的作用提供重要信息。因此，该项目直接响应了FDA烟草产品中心的呼吁：“包括薄荷醇和其他调味剂在内，哪些因素影响了烟草产品对使用者和非使用者（包括青年和其他弱势群体）的吸引力？这些因素对实验、开始、戒烟、转换烟草产品和多次使用有什么影响？“从这个项目中获得的经验证据将支持该中心考虑实施新的政策，规范烟草产品中添加薄荷醇，这是该中心根据《家庭吸烟预防和烟草控制法》（2009年）授权的首批行动之一。