Circadian Variations in Nicotine Sensitivity in Mice

小鼠尼古丁敏感性的昼夜节律变化

• 批准号: 7305834
• 负责人: JERRY A STITZEL
• 金额: $ 22.73万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7305834
• 关键词: Accounting; Acute; Address; Adult; Affect; Behavior; Biological Models; Body Temperature; Cessation of life; Cigarette; Circadian Rhythms; Consumption; Daily; Data; Development; Dissection; Exhibits; Future; Genes; Health Care Costs; Hormones; Inbred C3H Mice; Inbred Strain; Knowledge; Light; Melatonin; Melatonin Receptors; Metabolism; Methods; Modeling; Molecular; Motor Activity; Mouse Strains; Mus; Mutation; Neurobiology; Nicotine; Nicotine Dependence; Nicotinic Receptors; Oral; Pattern; Phase; Play; Property; Public Health; Purpose; Research; Rewards; Rodent; Rodent Model; Role; Seizures; Signal Transduction; Sleep; Sleep Wake Cycle; Smoke; Smoker; Smoking; Testing; Time; Tobacco use; United States; Variant; Withdrawal Symptom; circadian pacemaker; craving; day; drug of abuse; drug sensitivity; insight; nicotine craving; non-smoker; novel; preference; receptor expression; research study

DESCRIPTION (provided by applicant): In the United States, the use of tobacco products is responsible for over 450,000 premature deaths per year (about 20% of all premature deaths) and accounts for around $100 billion dollars per year in health care costs. Despite these facts, approximately 25% of adults in the United States continue to smoke. Typically, however, even heavy smokers can abstain from smoking during the normal sleep cycle and wake no more frequently during the night than do non-smokers. This observation suggests that there may be circadian patterns in which craving for nicotine is reduced at night. In support of this possibility, recent studies have demonstrated that sensitivity to drugs of abuse is generally reduced at night as well as altered by mutations in genes that regulate the circadian clock. In addition, melatonin, a hormone whose synthesis peaks at night, decreases craving in abstinent smokers and reduces sensitivity to the rewarding properties of some drugs of abuse in rodents. Despite this information, very little research has been done to assess circadian variations in sensitivity to nicotine. In the experiments outlined in this proposal, we will perform exploratory studies in mice in order to define the circadian pattern of sensitivity to the acute effects of nicotine. We also will examine whether any identified variation in sensitivity to nicotine is associated with circadian variations in melatonin synthesis, nicotinic receptor expression and/or nicotine metabolism. Finally, we will determine whether melatonin signaling through melatonin receptors is required for circadian variations in nicotine sensitivity, nicotinic receptor expression and nicotine metabolism. These studies will identify time points, mouse strains and potential mechanisms that will guide future studies to understand the mechanisms that regulate altered sensitivity to nicotine over the course of the circadian cycle. Such knowledge may provide novel insights into the neurobiology of nicotine addiction. to public health: Understanding the role of daily variations in nicotine sensitivity and the potential role of melatonin on regulating these daily variations in nicotine sensitivity may provide insight into why smokers typically can sleep through the night without the need for a cigarette. This knowledge would be extremely useful for the development of better methods to treat nicotine addiction.

描述(申请人提供)：在美国，烟草产品的使用每年导致超过45万人过早死亡(约占所有过早死亡人数的20%)，每年的医疗费用约为1000亿美元。尽管如此，美国仍有大约25%的成年人继续吸烟。然而，通常情况下，即使烟瘾很大的人也可以在正常的睡眠周期内戒烟，晚上醒来的频率也不会比不吸烟的人高。这一观察表明，可能存在昼夜节律模式，在这种模式下，对尼古丁的渴望在夜间减少。为了支持这种可能性，最近的研究表明，在夜间，对滥用药物的敏感性通常会降低，而且调节生物钟的基因突变也会改变这种敏感性。此外，褪黑激素是一种激素，其合成在夜间达到顶峰，它可以减少戒烟者的饥饿感，并降低对啮齿动物滥用药物的有益特性的敏感性。尽管有这些信息，但很少有研究评估尼古丁的昼夜变化。在这项提案中概述的实验中，我们将在小鼠身上进行探索性研究，以确定对尼古丁的急性影响敏感的昼夜模式。我们还将研究对尼古丁敏感性的任何已知变化是否与褪黑激素合成、尼古丁受体表达和/或尼古丁代谢的昼夜变化有关。最后，我们将确定通过褪黑激素受体传递的褪黑激素信号是否是尼古丁敏感性、尼古丁受体表达和尼古丁代谢昼夜变化所必需的。这些研究将确定时间点、小鼠品系和潜在的机制，这些机制将指导未来的研究，以了解在生理周期过程中调节尼古丁敏感性变化的机制。这些知识可能会为尼古丁成瘾的神经生物学提供新的见解。对公众健康：了解尼古丁敏感性每日变化的作用，以及褪黑素在调节尼古丁敏感性每日变化方面的潜在作用，可能有助于深入了解为什么吸烟者通常可以整夜睡眠而不需要吸烟。这些知识将对开发更好的治疗尼古丁成瘾的方法非常有用。