Adolescent brains, nicotine and endogenous prototoxins

青少年大脑、尼古丁和内源性原毒素

• 批准号: 7933994
• 负责人: Rae Nishi
• 金额: $ 49.83万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933994
• 关键词: Address; Adolescence; Adolescent; Adolescent Behavior; Adult; Affect; Agonist; Alcohols; Alleles; Animal Behavior; Animals; Anxiety; Area; Behavior; Behavioral; Behavioral inhibition; Binding; Blood specimen; Brain; Candidate Disease Gene; Cellular biology; Cessation of life; Childhood; Chromosomes, Human, Pair 8; Cognition; Cognitive; Consumption; DNA; Dendrites; Development; Disease; Drug abuse; Epidemic; Esthesia; Exhibits; Exposure to; Genes; Genetic Polymorphism; Genotype; Grant; Haplotypes; Health; Hippocampus (Brain); Human; Impulsivity; Individual; Label; Lead; Measures; Methamphetamine; Modeling; Molecular; Mus; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Nucleus Accumbens; Opiates; Outcome; Outcome Measure; Pathway interactions; Pattern; Performance; Physiological; Plastics; Preventive; Reporting; Research Personnel; Rewards; Smoke; Smoker; Smoking; Structure; System; Testing; Tobacco Dependence; Transgenic Organisms; Translational Research; Vertebral column; adolescent smoking; basal forebrain; base; cholinergic; density; drug of abuse; genetic epidemiology; high risk behavior; interdisciplinary approach; nerve supply; neurochemistry; novel strategies; preference; prevent; public health relevance; response

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15- DA-110: Determining if and how Adolescent Behaviors Affect Connections in the Developing Brain. The adverse impact of smoking on health is a world-wide epidemic that contributes to four million deaths a year, with an expected increase to 10 million per year world-wide by 2030. Tobacco dependence is viewed as a "pediatric disease" because most people begin smoking during adolescence. Adolescents display a greater sensitivity to the addictive effects of nicotine, becoming dependent upon smoking more rapidly than adults. Studies also show that smokers who began as adolescents smoke more frequently with a lower rate of quitting. Despite the many reports establishing a greater sensitivity of adolescent brains to nicotine, the fundamental basis of this greater sensitivity together with the long-term consequences of nicotine exposure on the wiring and neurochemistry of the brain is unknown. Most animal studies on adolescents have limited outcome measures of nicotine exposure to a single aspect such as behavior, agonist binding, or electrophysiological outcomes. Furthermore, none of the studies have examined plastic changes at the level of individual neurons with respect to the normal endogenous cholinergic system of the basal forebrain, and we know of no studies that integrate information from animal systems with human behavior. Thus, this Challenge Grant is a multidisciplinary approach that involves investigators from the fields of animal behavior, human cognition, genetic epidemiology, and molecular cell biology to test the validity of the following model: that the enhanced sensitivity of adolescents to nicotine is due to an imbalance between the endogenous cholinergic system and the function of nicotinic acetylcholine receptors (nAChRs). We predict that the cholinergic pathway from the basal forebrain to the cortex and hippocampus is not yet functionally mature in adolescents, yet an overabundance of terminals with nAChRs combined with a reduced level of prototoxin modulators of nAChRs allows exogenously administered nicotine to lead to long term changes that enhance reward pathways, while preventing full cholinergic maturation, leading to a beneficial effect of nicotine in cognitive performance that reinforces the use of nicotine. The specific aims of this application are: 1) to use adolescent and adult transgenic Thy-1-eYFP mice that demonstrate nicotine-induced conditioned place to determine whether changes in arborization of eYFP- labeled dendrites in layer 5 as well as changes in eYFP-terminals in nucleus accumbens occur; to determine if correlative changes in cholinergic innervation or dopaminergic interaction with eYFP-containing structures occur; 2) to determine whether mice that lack or carry only one copy of the prototoxin gene psca exhibit a greater physiological and behavioral response to nicotine and to determine whether this correlates with parameters examined in Aim 1; 3) to genotype human adolescent subjects that have been screened and tested for impulsivity, nicotine exposure, and drug abuse to determine whether specific alleles of prototoxin genes are correlated with increased impulsivity or nicotine dependence. PUBLIC HEALTH RELEVANCE: The adverse impact of smoking on health is a world-wide epidemic that contributes to four million deaths a year. Studies show that smokers who began as adolescents smoke more frequently with a lower rate of quitting. Despite the many reports establishing a greater sensitivity of adolescent brains to nicotine, the fundamental basis of this greater sensitivity together with the long-term consequences of nicotine exposure on the wiring and neurochemistry of the brain is unknown. A greater understanding of these will lead to possible preventive measures and therapies, having a significant long-term impact on human health.

描述（由申请人提供）：此申请应解决广泛的挑战领域（15）转化科学和特定挑战主题，15- da-1110：确定青少年行为是否以及如何影响发展中心的联系。吸烟对健康的不利影响是一种全球流行病，每年有400万人死亡，预计到2030年，全球每年每年增加1000万。烟草依赖被视为“儿科疾病”，因为大多数人在青春期开始吸烟。青少年对尼古丁的成瘾作用具有更大的敏感性，比成年人更快地依赖吸烟。研究还表明，从青少年开始抽烟的吸烟者以较低的戒烟率更频繁地吸烟。尽管许多报道表明，青少年对尼古丁的敏感性更高，但这种更大的敏感性的基本基础以及尼古丁暴露对大脑接线和神经化学的长期后果尚不清楚。大多数对青少年的动物研究的结果有限，尼古丁暴露于行为，激动剂结合或电生理结局等单一方面。此外，与基础前脑的正常内源性胆碱能系统相对于单个神经元水平上的塑性变化，我们没有知道将动物系统中的信息与人类行为相结合的研究。 Thus, this Challenge Grant is a multidisciplinary approach that involves investigators from the fields of animal behavior, human cognition, genetic epidemiology, and molecular cell biology to test the validity of the following model: that the enhanced sensitivity of adolescents to nicotine is due to an imbalance between the endogenous cholinergic system and the function of nicotinic acetylcholine receptors (nAChRs).我们预测，从基础前脑到皮质和海马的胆碱能途径在青少年中尚未功能成熟，但是，具有NACHR的末端过多，结合了NACHR的结合，与nACHR的原始毒素调节剂的水平降低，可以使尼古丁的良好良好的变化，从而使尼古丁的良好变化，从而使尼古丁的良好变化，从而使尼古丁的良好变化，从而使尼古丁的变化良好，从而使尼古丁的变化又一次奖励。尼古丁在认知性能中的影响，从而增强了尼古丁的使用。该应用的具体目的是：1）使用青少年和成人转基因THY-1-EYFP小鼠，这些小鼠证明了尼古丁诱导的条件位置，以确定第5层中EYFP标记的树突的变化以及EYFP-terminals Accumbens中的EYFP末端的变化是否发生了；确定胆碱能神经支配或多巴胺能与含EYFP的结构的相关性是否发生； 2）确定缺乏或携带一份原始毒素基因PSCA的小鼠是否表现出对尼古丁的生理和行为反应更大，并确定这是否与AIM 1中检查的参数相关； 3）对于已经筛查和测试的脉冲，尼古丁暴露和药物滥用的基因型人类青少年受试者，以确定原始毒素基因的特定等位基因是否与脉冲性增加或尼古丁依赖性相关。 公共卫生相关性：吸烟对健康的不利影响是一种全球流行病，每年造成400万人死亡。研究表明，从青少年开始抽烟的吸烟者以较低的戒烟率更频繁地吸烟。尽管许多报道表明，青少年对尼古丁的敏感性更高，但这种更大的敏感性的基本基础以及尼古丁暴露对大脑接线和神经化学的长期后果尚不清楚。对这些的更多了解将导致可能的预防措施和疗法，对人类健康产生重大影响。