NICOTINE EFFECTS ON THE ADRENAL MEDULLA AND BRAIN

尼古丁对肾上腺髓质和大脑的影响

• 批准号: 6197375
• 负责人: ARNOLD WILLIAM Tank
• 金额: $ 27.38万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-05-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6197375
• 关键词: PC12 cells; adrenal medulla; biological signal transduction; catecholamines; cholinergic receptors; chromaffin cells; endocrine pharmacology; enzyme activity; enzyme induction /repression; gene induction /repression; genetic regulatory element; genetic transcription; laboratory rat; locus coeruleus; neuropharmacology; neurotransmitter transport; nicotine; nicotinic receptors; tyrosine 3 monooxygenase

DESCRIPTION(Adapted from applicant's abstract): This is the first revision of a competing renewal that received a score of 189 (29.8) from an associate professor at the University of Rochester, who has been studying tyrosine hydroxylase for many years. His research has principally concentrated on stress interactions, but he is now interested in investigating the complexities of nicotine effects on expression of this regulatory enzyme in catecholamine synthesis. Nicotine increases catecholamine release and biosynthesis in the adrenal medulla and in the brain. The effects on the adrenal medulla likely mediate nicotine's peripheral actions, e.g. on the cardiovascular system. However, brain effects on catecholaminergic systems might mediate some of nicotine's addictive properties. Tyrosine hydroxylase (TH) gene expression is enhanced in both the adrenal medulla and the locus coeruleus (LC) after twice daily injections of nicotine for 14 days; a single injection does not induce TH. Repeated nicotine injections result in repeated activation of several signaling pathways in catecholaminergic cells. Nicotinic antagonists do not completely block induction of TH by nicotine, suggesting that the induction may involve transsynaptic signaling pathways. Further, the induction of TH gene expression is hypothesized to involve both transcriptional and post-transcriptional mechanisms. The investigator will use two animal models (rat and transgenic mouse) and a tissue culture system (PC12 cells, a rat pheochromocytoma)to 1)Test whether the enhanced induction of TH gene expression observed after repeated nicotine treatment is mediated by transcriptional and/or post-transcriptional mechanisms; 2) Test which adrenal chromaffin cell receptors participate in the enhanced induction of TH gene expression which occurs after repeated nicotine administration; and 3) Test the hypothesis that the enhanced induction of TH in the LC is due to repeated stimulation of intracellular signaling pathways. by active nAChRs.

描述（改编自申请人的摘要）： 这是得分为 189 分的竞争性续订的第一个修订版 （29.8）来自罗彻斯特大学的一位副教授，他一直 研究酪氨酸羟化酶多年。他的研究主要有 专注于压力相互作用，但他现在有兴趣调查 尼古丁对这种调节酶表达的复杂影响 儿茶酚胺合成。 尼古丁增加肾上腺儿茶酚胺的释放和生物合成 髓质和大脑中。对肾上腺髓质的影响可能介导 尼古丁的外周作用，例如对心血管系统。然而， 大脑对儿茶酚胺能系统的影响可能会介导一些尼古丁的作用 令人上瘾的特性。酪氨酸羟化酶 (TH) 基因表达增强 每天两次后肾上腺髓质和蓝斑 (LC) 注射尼古丁14天；单次注射不会诱发 TH。 重复注射尼古丁会导致多种信号的重复激活 儿茶酚胺能细胞中的途径。烟碱拮抗剂并不完全 阻断尼古丁对 TH 的诱导，表明诱导可能涉及 跨突触信号通路。此外，诱导TH基因表达 假设涉及转录和转录后 机制。研究人员将使用两种动物模型（大鼠和转基因 小鼠）和组织培养系统（PC12细胞，大鼠嗜铬细胞瘤） 1)测试是否观察到TH基因表达的增强诱导 重复尼古丁治疗是通过转录和/或 转录后机制； 2）测试哪个肾上腺嗜铬细胞 受体参与 TH 基因表达的增强诱导 重复使用尼古丁后发生； 3）检验假设 LC 中 TH 诱导的增强是由于重复刺激 细胞内信号通路。通过活性 nAChR。