Mechanisms of nicotine-induced neuroplasticity

尼古丁诱导神经可塑性的机制

• 批准号: 8040989
• 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/8040989
• 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上一个主要的社会和健康问题。尼古丁在大脑中产生极为稳定的变化，这是长期存在的成瘾行为。这项研究的长期目标是了解尼古丁如何在海马中产生这种长期的神经变化，海马，一个与记忆形成的大脑区域以及与药物相关行为的上下文相关学习。这种知识可能会导致对成瘾过程的更好理解，并可能有助于开发防止复发的疗法，从而促进戒烟。越来越多的证据表明，诸如尼古丁之类的成瘾药物通过引起长期持久的突触改造而产生成瘾行为。 N-甲基-D-天冬氨酸受体（NMDAR）对于突触的这种长期修饰至关重要。我们的研究表明，体内暴露于尼古丁会导致通过酪氨酸磷酸化增强含NR2B的NMDAR介导的反应，从而导致长期长期增强（LTP；被认为是学习和记忆的细胞底物）。尼古丁对NMDAR的影响被抗乙酰胆碱酯酶药物模仿阿尔茨海默氏病，并通过共同给药的毒桃体受体拮抗剂而阻止。这些观察结果不仅表明胆碱能记忆增强药物刺激的常见信号通路，而且还表明NR2B-NMDAR是胆碱能和谷氨酸能途径涉及的学习和记忆的融合点。我们假设尼古丁通过篡夺此信号通路会产生持久的神经变化。提出的实验将通过阐明尼古丁诱导的信号传导级联反应来检验该假设，从而导致NR2B-NMDAR依赖性长期突触修饰。具体目的是确定：1​​）烟碱乙酰胆碱受体在拟议的途径中，2）乙酰胆碱和毒蕈碱受体在NR2B-NMDAR反应的增强中的增强中； 3）毒蕈碱受体-SRC酪氨酸激酶信号传导途径在尼古丁的作用中； 4）尼古丁诱导的长期突触修饰中NR2B-NMDAR响应的增强。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，分子生物学和形态学方法。除了毒蕈碱受体基因敲除小鼠外，重组腺病毒载体还将用于改变所提出的信号传导途径中蛋白质的活性。这些研究的结果不仅有助于确定尼古丁介导的神经塑性的细胞基础，而且还有助于开发有效的戒烟治疗方法。尼古丁滥用是当今世界上主要的健康问题之一。越来越多的证据表明，诸如尼古丁之类的成瘾性药物通过在脑通路中引起持久的神经变化，从而产生上瘾的行为。该项目的目的是确定尼古丁如何在海马中产生这种变化，海马是涉及与药物相关行为的上下文依赖性学习的大脑区域。这项研究的结果可能会导致对成瘾过程有更好的了解，并可能有助于开发防止复发的疗法，从而促进戒烟。