Genetic, Behavioral, & Neurobiological Substrates of Nicotine Withdrawal

遗传、行为、

• 批准号: 7803692
• 负责人: Thomas J Gould
• 金额: $ 37.18万
• 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/7803692
• 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：每年有超过 435,000 人死于吸烟，尽管每年有 42% 的吸烟者尝试戒烟，但成功的人不到 6%。这些统计数据表明，目前的戒烟治疗还不够。可能导致尼古丁成瘾维持和复发的一个激励因素是尼古丁戒断效应。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，戒烟期间认知的变化预示着旧病复发。这表明了解这些变化背后的神经和遗传底物可以促进更有效治疗方法的开发。在了解尼古丁成瘾方面已经取得了巨大进展，但我们对尼古丁戒断的了解还存在严重差距。例如，对尼古丁戒断对认知过程破坏的神经生物学基础的检查是有限的，并且对遗传影响的检查也不存在。该提案的目标是确定情境调节（认知过程）中尼古丁戒断缺陷的遗传和神经生物学基础。该提案将利用传统的行为遗传技术和转基因小鼠来实现这一目标。表征尼古丁戒断的动态将进一步了解尼古丁成瘾，并有助于理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。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，并有助于调整治疗方案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。在审查关于戒断动物模型的文献时，引人注目的一件事是缺乏关于认知过程中尼古丁戒断缺陷的遗传和神经基础的信息。该提案将研究尼古丁戒断对小鼠情境学习破坏的药理学、神经生物学和遗传学。识别导致尼古丁影响的神经生物学和遗传学因素对于了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。