Mechanisms of nicotine-induced neuroplasticity

尼古丁诱导神经可塑性的机制

• 批准号: 8215891
• 负责人: KATUMI SUMIKAWA
• 金额: $ 29.68万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215891
• 关键词: Acetylcholinesterase; Acute; Addictive Behavior; Adenovirus Vector; Adenoviruses; Agonist; Alzheimer' s Disease; Animals; Behavior; Biological; Brain; Brain region; CAR receptor; Chronic; Dominant-Negative Mutation; Exposure to; Glutamates; Goals; Health; Hippocampus (Brain); Human; Knockout Mice; Knowledge; Lead; Learning; Life; Link; Long-Term Potentiation; Mediating; Memory; Metabotropic Glutamate Receptors; Modification; Molecular; Muscarinic Acetylcholine Receptor; Muscarinic M1 Receptor; Muscarinics; N-Methyl-D-Aspartate Receptors; NR2B NMDA receptor; Neuronal Plasticity; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Pathway interactions; Pharmaceutical Preparations; Process; Protein Biosynthesis; Proteins; Pyramidal Cells; Rattus; Receptor Activation; Recombinants; Relapse; Research; Role; Signal Pathway; Signal Transduction; Synapses; Synaptic plasticity; Testing; Transgenic Organisms; Tyrosine Phosphorylation; Vertebral column; addiction; base; brain pathway; cholinergic; cholinergic synapse; density; effective therapy; in vivo; inhibitor/antagonist; interest; nicotine abuse; postsynaptic; presynaptic; prevent; receptor function; receptor-mediated signaling; relating to nervous system; research study; response; smoking cessation; social; src-Family Kinases; therapy development

DESCRIPTION (provided by applicant): Nicotine addiction is a major social and health problem in the world today. Nicotine produces extremely stable changes in the brain that underlie long-lived addictive behavior. The long-term objective of this research is to understand how nicotine produces such long-lasting neural changes in the hippocampus, a brain region involved in the formation of memories and the context-dependent learning of drug-associated behaviors. Such knowledge will likely lead to a better understanding of addiction processes and may aid in developing therapies for preventing the relapse, and thereby promoting smoking cessation. Increasing evidence indicates that addictive drugs such as nicotine produce addictive behavior by causing long- lasting modifications of synapses. The N-methyl-D-aspartate receptor (NMDAR) is critical for such long-lasting modifications of synapses. Our study shows that in vivo exposure to nicotine causes the enhancement of NR2B-containing NMDAR-mediated responses via tyrosine phosphorylation, leading to long-lasting long-term potentiation (LTP; considered to be a cellular substrate of learning and memory) in the hippocampus. The effect of nicotine on NMDAR is mimicked by anti-acetylcholinesterase drugs for Alzheimer's disease and prevented by coadministration of a muscarinic receptor antagonist. These observations suggest not only a common signaling pathway stimulated by cholinergic memory enhancing drugs, but also that NR2B-NMDARs are a point of convergence of cholinergic and glutamatergic pathways involved in learning and memory. We hypothesize that nicotine produces long-lasting neural changes by usurping this signaling pathway. The proposed experiments will test this hypothesis by elucidating the nicotine-induced signaling cascade that leads to NR2B-NMDAR-dependent long-lasting synaptic modifications. The specific aims are to determine the roles of: 1) nicotinic acetylcholine receptors in the proposed pathway, 2) acetylcholine and muscarinic receptors in the nicotine-induced enhancement of NR2B-NMDAR responses; 3) muscarinic receptor-Src tyrosine kinase signaling pathway in the effect of nicotine; and 4) nicotine-induced enhancement of NR2B-NMDAR responses in long-lasting synaptic modifications. The proposed research will be carried out using nicotine- and other drug- exposed animals with a combination of electrophysiological, molecular biological, and morphological approaches. In addition to muscarinic receptor knockout mice, recombinant adenovirus vectors will be used to alter the activity of proteins in the proposed signaling pathway. Results from these studies will not only help determine the cellular basis of nicotine-mediated neuroplasticity, but also aid in developing effective treatments for smoking cessation. Nicotine abuse is one of the major health problems in the world today. Increasing evidence indicates that addictive drugs such as nicotine produce addictive behavior by causing long-lasting neural changes in brain pathways subserving learning and memory. The goal of this project is to determine how nicotine produces such changes in the hippocampus, a brain region involved in context-dependent learning of drug-associated behaviors. Results from this study will likely lead to a better understanding of addiction processes and may aid in developing therapies for preventing the relapse, and thereby promoting smoking cessation.

描述（由申请人提供）：尼古丁成瘾是当今世界的一个主要社会和健康问题。尼古丁会在大脑中产生极其稳定的变化，这是长期成瘾行为的基础。这项研究的长期目标是了解尼古丁如何在海马体中产生如此持久的神经变化，海马体是参与记忆形成和药物相关行为的情境依赖性学习的大脑区域。这些知识可能会导致人们更好地了解成瘾过程，并可能有助于开发预防复发的疗法，从而促进戒烟。越来越多的证据表明，尼古丁等成瘾药物通过引起突触的长期改变而产生成瘾行为。 N-甲基-D-天冬氨酸受体（NMDAR）对于突触的这种持久修饰至关重要。我们的研究表明，体内接触尼古丁会通过酪氨酸磷酸化增强含有 NR2B 的 NMDAR 介导的反应，从而导致海马体中持久的长时程增强（LTP；被认为是学习和记忆的细胞底物） 。治疗阿尔茨海默病的抗乙酰胆碱酯酶药物可模仿尼古丁对 NMDAR 的作用，并可通过联合使用毒蕈碱受体拮抗剂来预防。这些观察结果表明，NR2B-NMDAR 不仅是胆碱能记忆增强药物刺激的常见信号通路，而且是参与学习和记忆的胆碱能和谷氨酸通路的汇聚点。我们假设尼古丁通过篡夺这一信号通路来产生持久的神经变化。拟议的实验将通过阐明尼古丁诱导的信号级联导致 NR2B-NMDAR 依赖性持久突触修饰来检验这一假设。具体目标是确定以下作用：1) 烟碱乙酰胆碱受体在所提出的途径中，2) 乙酰胆碱和毒蕈碱受体在尼古丁诱导的 NR2B-NMDAR 反应增强中的作用； 3)毒蕈碱受体-Src酪氨酸激酶信号通路在尼古丁作用中的作用； 4) 尼古丁诱导的持久突触修饰中 NR2B-NMDAR 反应的增强。拟议的研究将使用尼古丁和其他药物暴露的动物进行，并结合电生理学、分子生物学和形态学方法。除了毒蕈碱受体敲除小鼠外，重组腺病毒载体还将用于改变所提出的信号通路中蛋白质的活性。这些研究的结果不仅有助于确定尼古丁介导的神经可塑性的细胞基础，而且有助于开发有效的戒烟治疗方法。尼古丁滥用是当今世界主要的健康问题之一。越来越多的证据表明，尼古丁等成瘾药物会导致促进学习和记忆的大脑通路发生持久的神经变化，从而产生成瘾行为。该项目的目标是确定尼古丁如何在海马体中产生这种变化，海马体是参与药物相关行为的情境依赖性学习的大脑区域。这项研究的结果可能会导致人们更好地了解成瘾过程，并可能有助于开发预防复发的疗法，从而促进戒烟。