Genetic, Behavioral, & Neurobiological Substrates of Nicotine Withdrawal

烟草使用在美国是一个严重的健康问题：每年有超过435，000人死于吸烟，尽管每年有42%的吸烟者试图戒烟，但成功率不到6%。这些统计数据表明，目前的戒烟治疗还不够。尼古丁戒断效应是尼古丁成瘾维持和复发的一个诱因。吸烟者报告的戒断症状包括失眠、食欲增加、情感变化和认知缺陷。事实上，禁欲期间认知的变化可以预测复发;这表明了解这些变化背后的神经和遗传基质可以促进更有效的治疗方法的发展。在了解尼古丁成瘾方面已经取得了很大的进展，但我们对尼古丁戒断的认识存在严重差距。例如，尼古丁戒断中断认知过程的神经生物学底物的检查是有限的，遗传影响的检查是不存在的。本提案的一个目标是确定背景条件反射（一种认知过程）中尼古丁戒断缺陷的遗传和神经生物学底物。这项提议将使用传统的行为遗传技术和转基因小鼠来实现这一目标。描述尼古丁戒断的动力学将进一步了解尼古丁成瘾，并有助于了解尼古丁的行为效应与受体功能和下游过程变化之间的关系。确定尼古丁戒断的遗传和神经底物将有助于开发尼古丁戒断症状的新治疗方法，并有助于定制治疗方法以产生最有效的结果。在对吸烟者的研究中，很明显，戒烟期间认知过程的变化是尼古丁戒断的重要组成部分。在研究有关戒断动物模型的文献时，有一件事是引人注目的，那就是缺乏关于认知过程中尼古丁戒断缺陷的遗传和神经基质的信息。这项计划将研究药理学，神经生物学和遗传学的尼古丁戒断中断的上下文学习的小鼠。确定有助于尼古丁效应的神经生物学和遗传学因素对于理解尼古丁成瘾和开发可能根据基因型定制以提供最有效治疗的新型治疗方法非常重要。

DESCRIPTION (provided by applicant): Tobacco use is a serious health problem in the United States: over 435,000 deaths each year are attributed to smoking, and although 42% of smokers attempt to quit each year, less than 6% are successful. These statistics suggest that current smoking cessation treatments are not adequate. One motivating factor that may contribute to both the maintenance of nicotine addiction and relapse is nicotine withdrawal effects. Withdrawal symptoms reported by smokers include insomnia, increased appetite, affective changes, and cognitive deficits. In fact, changes in cognition during abstinence predict relapse; suggesting that understanding the neural and genetic substrates underlying these changes could facilitate development of more efficacious treatments. Great advances have been made in understanding nicotine addiction but there are serious gaps in our knowledge of nicotine withdrawal. For instance, examination of the neurobiological substrates of nicotine withdrawal disruption of cognitive processes is limited and examination of genetic influences is nonexistent. A goal of this proposal is to identify the genetic and neurobiological substrates of nicotine withdrawal deficits in contextual conditioning, a cognitive process. This proposal will use traditional behavioral genetic techniques and genetically modified mice to achieve this goal. Characterizing the dynamics of nicotine withdrawal will further understanding of nicotine addiction and aid in understanding the relationship between the behavioral effects of nicotine and changes in receptor function and downstream processes. Identification of the genetic and neural substrates of nicotine withdrawal will aid development of new treatments for nicotine withdrawal symptoms and in the tailoring of treatments to produce the most effective results. In studies of smokers, it is clear that changes in cognitive processes during abstinence are an important component of nicotine withdrawal. One thing that is striking when examining the literature on animal models of withdrawal is the dearth of information on the genetic and neural substrates of nicotine withdrawal deficits in cognitive processes. This proposal will examine the pharmacology, the neurobiology, and the genetics of nicotine withdrawal disruption of contextual learning in mice. Identifying neurobiological and genetics factors that contribute to the effects of nicotine is important for understanding nicotine addiction and for developing novel treatments that could potentially be tailored by genotype to provide the most effective treatment.