Project 3: Adolescent Nicotine

项目 3：青少年尼古丁

• 批准号: 9151765
• 负责人: M. Imad Damaj
• 金额: $ 17.34万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9151765
• 关键词: Acute; Address; Adolescence; Adolescent; Adult; Affect; Age; Alcohols; Animals; Architecture; Behavior; Behavioral; Behavioral Paradigm; Biological; Candidate Disease Gene; Chromosome Mapping; Circadian Rhythms; Cocaine; Corpus striatum structure; Data; Dopamine; Dose; Drug Addiction; Drug abuse; Drug usage; Electronic cigarette; Exhibits; Exposure to; Gene Expression; Genes; Genetic; Genetic Variation; Genotype; Goals; Health; Human; Impulsivity; Inbreeding; Individual; Individual Differences; Intervention; Intravenous; Laboratories; Life; Link; Maps; Measurement; Measures; Mediating; Methods; Molecular Genetics; Mus; Nicotine; Pharmaceutical Preparations; Phenotype; Population; Population Genetics; Predisposition; Quantitative Trait Loci; Rewards; Risk; Risk Factors; Rodent; Saline; Self Administration; Severities; Signal Transduction; Substance Use Disorder; Sushi Domain; System; Technology; Testing; Time; Tobacco; Tobacco use; addiction; adolescent drug use; base; behavioral response; biobank; cigarette smoking; cohort; drug of abuse; early adolescence; follow-up; genetic analysis; genome editing; high risk; illicit drug use; mouse model; neurobiological mechanism; neurogenetics; novel; preference; response; trait; validation studies

PROJECT SUMMARY PROJECT 3 – ADOLESCENT NICOTINE Nicotine is one of the most commonly used drugs among adolescents. Several studies link tobacco and nicotine use in human adolescence and subsequent problems in adulthood, including later tobacco, alcohol, cocaine and other illicit drug use. Individuals who smoke cigarettes before the age of 15 are estimated to be eighty times more likely to use illegal drugs such as cocaine than those who do not. In addition, studies in animals have shown that adolescent nicotine exposure affects nicotine and cocaine reward and sensitivity in rodents; we have shown that repeated exposure to low doses of nicotine in adolescence clearly induces age- specific enhancement of the rewarding effects of nicotine and other drugs of abuse that persisted long after the termination of nicotine exposure. However, the molecular and genetic mechanisms underlining nicotine- induced enhancements to the reward effects are still unclear. This project will identify risk associated genes and gene networks using highly diverse mouse genetic populations. We will use inbred Collaborative Cross (CC)/ Diversity Outcross (DO) founder and CC strains to measure nicotine reward using the conditioned place preference (CPP) test after exposure to nicotine in early adolescence. These data will be used to conduct genetic correlations across behaviors including impulsivity, cocaine self-administration (IVSA), acute and sensitized cocaine induced locomotor activation and circadian rhythms to determine common genetic architecture shared among traits. We will also study changes in striatal dopamine (DA) signaling in CC strains that exhibit extreme behavioral responses to nicotine. Secondly, we will correlate nicotine CPP behaviors with gene expression changes in the striatum of CC mice to further identify potential candidate genes, gene networks and biological mechanisms that may mediate the effects of adolescent nicotine exposure. Finally, we will map nicotine reward in the CPP test in a large DO cohort after exposure to nicotine during early adolescence. Genotype data will be used to reveal QTLs specific to nicotine in adolescence as well as identify common QTLs shared between impulsivity, cocaine self-administration, cocaine sensitization and circadian rhythms phenotypes generated by the various projects and cores within the Center for Systems Neurogenetics of Addiction. Genetic mapping data along with expression studies will be used to identify candidate genes for validation studies in novel mouse models made through genome editing technologies. If successful, this application promises to have a significant positive impact on human health through the identification of genetically high-risk individuals who would benefit from proactive interventions following nicotine exposure in adolescence.

项目摘要项目3--青少年尼古丁 尼古丁是青少年最常用的药物之一。几项研究将烟草和 尼古丁在人类青春期的使用和成年后的问题，包括后来的烟草，酒精， 可卡因和其他非法药物的使用。据估计，15岁之前吸烟的人 使用可卡因等非法药物的可能性是不使用可卡因的人的80倍。此外，在中国的研究 动物已经表明，青少年接触尼古丁会影响尼古丁和可卡因的奖赏和敏感度 啮齿动物；我们已经表明，在青春期反复接触低剂量尼古丁显然会诱导衰老- 具体加强尼古丁和其他滥用药物的奖励效应，这些药物在 终止尼古丁接触。然而，尼古丁的分子和遗传机制- 对奖励效应的诱导增强仍不清楚。该项目将识别风险相关基因 以及使用高度多样化的小鼠遗传群体的基因网络。我们将使用近交系合作杂交 (CC)/多样性异交(DO)创始人和CC菌株使用条件化位置测量尼古丁奖励 青春期早期尼古丁暴露后的喜好(CPP)试验。这些数据将用于进行 行为的遗传相关性，包括冲动、可卡因自我给药(IVSA)、急性和 致敏可卡因诱导运动激活和昼夜节律以确定共同基因 建筑在不同的特征中是相同的。我们还将研究CC菌株纹状体多巴胺(DA)信号的变化 对尼古丁表现出极端的行为反应。其次，我们将尼古丁CPP行为与 CC小鼠纹状体内基因表达的变化以进一步寻找潜在的候选基因 可能调节青少年尼古丁暴露影响的网络和生物机制。最后，我们 在早期接触尼古丁后，将在CPP测试中将尼古丁奖赏映射到大量DO队列中 青春期。基因数据将被用来揭示青春期尼古丁特有的QTL，以及识别 冲动、可卡因自我给药、可卡因敏化和昼夜节律之间共有的共同QTL 系统神经遗传学中心内各种项目和核心所产生的节律表型 上瘾的人。基因图谱数据和表达研究将用于确定候选基因 通过基因组编辑技术对新的小鼠模型进行验证研究。如果成功，这将是 应用程序有望通过识别 因接触尼古丁而受益的基因高危人群 青春期。