Genetic, Behavioral, & Neurobiological Substrates of Nicotine Withdrawal

遗传、行为、

• 批准号: 7689825
• 负责人: Thomas J Gould
• 金额: $ 34.1万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-19 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7689825
• 关键词: Abstinence; Affect; Affective; Affinity; Alanine; American; Animal Model; Behavioral; Behavioral Genetics; Binding; Brain region; Cessation of life; Chronic; Code; Cognition; Cognitive; Cognitive deficits; Development; Dose; Employee Strikes; Environment; Exposure to; Fibrinogen; Functional Magnetic Resonance Imaging; Genes; Genetic; Genetic Techniques; Genotype; Goals; Health; Hippocampus (Brain); Inbred Mouse; Inbred Strains Mice; Knowledge; Learning; Literature; Maintenance; Measures; Modification; Mus; Mutation; Nature; Neurobiology; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Pharmacodynamics; Pharmacology; Process; Property; Proteins; Relapse; Reporting; Severities; Signal Transduction; Sleeplessness; Smoker; Smoking; Surgeon; Symptoms; Testing; Threonine; Time; Tobacco; Tobacco use; United States; Variant; Withdrawal; Withdrawal Symptom; Withholding Treatment; behavioral pharmacology; conditioning; effective therapy; increased appetite; novel; receptor; receptor binding; receptor function; relating to nervous system; smoking cessation; statistics; treatment duration

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.

描述（由申请人提供）：在美国，烟草使用是一个严重的健康问题：每年超过435,000人死亡归因于吸烟，尽管每年有42％的吸烟者试图戒烟，但不到6％的成功。这些统计数据表明，目前的戒烟治疗不足。尼古丁戒断效应是尼古丁成瘾和复发的一种激励因素。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。实际上，禁欲期间的认知变化预测复发；表明了解这些变化的基础的神经和遗传底物可以促进更有效的治疗方法的发展。在理解尼古丁成瘾方面已经取得了巨大进步，但是我们对尼古丁戒断的知识存在很大的差距。例如，检查认知过程的尼古丁戒断破坏的神经生物学底物受到限制，并且对遗传影响的检查是不存在的。该建议的一个目的是确定尼古丁戒断缺陷的遗传和神经生物学底物在上下文调节（一种认知过程中）。该提案将使用传统的行为遗传技术和基因修饰的小鼠来实现这一目标。表征尼古丁戒断的动力学将进一步了解尼古丁成瘾，并有助于理解尼古丁的行为影响与受体功能变化与下游过程之间的关系。鉴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疗法，并在剪裁治疗方面产生最有效的结果。在对吸烟者的研究中，很明显，戒酒期间认知过程的变化是尼古丁戒断的重要组成部分。检查有关戒断动物模型的文献时，令人震惊的一件事是缺乏有关认知过程中尼古丁戒断缺陷的遗传和神经底物的信息。该提案将检查小鼠情境学习的尼古丁戒断破坏的药理学，神经生物学和遗传学。鉴定有助于尼古丁作用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由基因型量身定制以提供最有效治疗的新型治疗方法很重要。