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: 7286039
• 负责人: ARNOLD WILLIAM Tank
• 金额: $ 26.51万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7286039
• 关键词: Acute; Adrenal Medulla; Anabolism; Animals; Anterior; Arousal; Autonomic nervous system; Binding; Binding Proteins; Biological Models; Blood; Blood Circulation; Brain; Catecholamines; Cells; Cholinergic Agents; Chromaffin Cells; Chromosome Pairing; Chronic; Coupled; Daily; Development; Elevation; Enzymes; Gene Expression; Genes; Hour; Human; Injection of therapeutic agent; Intake; Laboratories; Lead; Mediating; Messenger RNA; Modeling; Mus; Nerve; Nervous System Physiology; Neurons; Neurotransmitters; Nicotine; Norepinephrine; Pain; Pathway interactions; Perception; Peripheral; Physical Dependence; Physiological Processes; Play; Pontine structure; Process; Protein Isoforms; Proteins; RNA Primary Transcript; Rate; Rattus; Regulation; Role; Signal Pathway; Subcutaneous Injections; Sympathetic Ganglia; Sympathetic Nervous System; Synapses; Testing; Thinking; Tissues; Transcriptional Activation; Tyrosine 3-Monooxygenase; Untranslated Regions; Up-Regulation; base; cholinergic; day; drug of abuse; locus ceruleus structure; mRNA Stability; neuronal cell body; receptor; research study; response; subcutaneous; vigilance

DESCRIPTION (provided by applicant): Chronic nicotine administration increases catecholamine release and biosynthesis in locus coeruleus (LC) neurons. Catecholamine biosynthesis is controlled by the activity of tyrosine hydroxylase (TH). In rats and mice, TH gene expression is up-regulated in the LC after daily repeated injections of nicotine for 14 days. This up-regulation of TH gene expression and the consequent increase in norepinephrine biosynthetic capacity in LC neurons may be one of the many changes that lead to physical dependence to nicotine. The experiments in this proposal are aimed at increasing our understanding of the mechanisms responsible for this up-regulation. The studies in this proposal test the following overall hypothesis: Repeated nicotine injections (twice per day) result in the repeated activation of LC neurons and consequent repeated enhanced release of norepinephrine (NE) in nerve terminal regions. These repeated responses lead to adaptive changes in the expression of specific genes, one of which is TH. In the LC, TH is induced via both transcriptional and post-transcriptional mechanisms in response to chronic nicotine. This proposal focuses on studying the post-transcriptional mechanisms. The specific aims are: (1) To test whether the induction of TH mRNA in the LC in response to chronic nicotine treatment is mediated by increased TH mRNA stability or a sustained transcriptional response coupled to more efficient or alternative processing of TH RNA primary transcripts to the mature TH mRNA isoform(s). (2) To test whether polyC-binding protein (PCBP) isoforms are expressed in TH-positive neurons in the LC and whether chronic nicotine treatment induces PCBP. (3) To test whether PCBP and the polyC-rich sequence to which it binds in the 3' UTR of TH mRNA participate in the stabilization of TH mRNA in response to the activation of signaling pathways that mediate the response to nicotine.

描述（由申请人提供）：慢性尼古丁给药增加蓝斑（LC）神经元中儿茶酚胺的释放和生物合成。儿茶酚胺的生物合成受酪氨酸羟化酶（TH）活性的控制。在大鼠和小鼠中，每天重复注射尼古丁14天后，LC中TH基因表达上调。这种TH基因表达的上调和相应的LC神经元去甲肾上腺素生物合成能力的增加可能是导致尼古丁物理依赖的众多变化之一。本提案中的实验旨在增加我们对这种上调机制的理解。本提案中的研究验证了以下总体假设：反复注射尼古丁（每天两次）导致LC神经元的反复激活，从而导致神经末梢区域去甲肾上腺素（NE）的释放反复增强。这些重复的反应导致特定基因表达的适应性变化，TH就是其中之一。在LC中，TH是通过转录和转录后机制诱导的，以响应慢性尼古丁。本研究的重点是研究其转录后机制。具体目的是：(1)测试慢性尼古丁治疗对LC中TH mRNA的诱导是通过TH mRNA稳定性的增加介导的，还是通过持续的转录反应，再加上将TH RNA初级转录物更有效地加工成成熟的TH mRNA亚型。(2)检测多c结合蛋白（polyc binding protein， PCBP）异构体是否在LC th阳性神经元中表达，以及慢性尼古丁治疗是否诱导PCBP。(3)检测PCBP及其在TH mRNA 3′UTR上结合的富含polyc的序列是否参与TH mRNA的稳定，以响应介导尼古丁应答的信号通路的激活。