Circadian Variations in Nicotine Sensitivity in Mice

在美国，烟草产品的使用每年导致超过450，000例过早死亡（约占所有过早死亡的20%），每年的医疗保健费用约为1000亿美元。尽管如此，美国仍有约25%的成年人继续吸烟。然而，通常情况下，即使是重度吸烟者也可以在正常的睡眠周期内戒烟，并且在夜间醒来的频率也不会比不吸烟者高。这一观察结果表明，可能存在昼夜节律模式，其中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，对滥用药物的敏感性通常在夜间降低，并因调节生物钟的基因突变而改变。此外，褪黑激素（一种在夜间达到合成高峰的激素）可以减少戒烟者的烟瘾，并降低啮齿动物对某些滥用药物的奖励特性的敏感性。尽管有这些信息，但很少有研究评估尼古丁敏感性的昼夜变化。在本提案中概述的实验中，我们将在小鼠中进行探索性研究，以确定对尼古丁急性效应敏感性的昼夜节律模式。我们还将研究是否任何确定的变化，尼古丁的敏感性与昼夜变化的褪黑激素合成，烟碱受体表达和/或尼古丁代谢。最后，我们将确定是否褪黑激素信号通过褪黑激素受体所需的尼古丁敏感性，烟碱受体表达和尼古丁代谢的昼夜变化。这些研究将确定时间点、小鼠品系和潜在机制，这些机制将指导未来的研究，以了解在昼夜节律周期过程中调节尼古丁敏感性改变的机制。这些知识可能为尼古丁成瘾的神经生物学提供新的见解。公共卫生：了解尼古丁敏感性的日常变化的作用以及褪黑激素在调节尼古丁敏感性的这些日常变化中的潜在作用，可以深入了解为什么吸烟者通常可以在不需要吸烟的情况下整夜睡眠。这些知识对于开发更好的治疗尼古丁成瘾的方法非常有用。

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.