Nicotine Addiction: Learning, Neural & Genetic Process

尼古丁成瘾：学习，神经

• 批准号: 8050353
• 负责人: Thomas J Gould
• 金额: $ 28.67万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050353
• 关键词: Abstinence; Acute; Affect; Affinity; American; Area; Behavior; Behavioral; Brain; CREB1 gene; Cell physiology; Cells; Cessation of life; Chronic; Cognitive; Cognitive deficits; Complex; Development; Disease; Dorsal; Drosophila acetylcholine receptor alpha-subunit; Family; Funding; Gene Activation; Gene Expression; Genes; Genetic Processes; Goals; Grant; Health; Hippocampus (Brain); Infusion procedures; JUN gene; Lead; Learning; Maintenance; Mediating; Memory; Mitogen-Activated Protein Kinases; Modification; Molecular; N-terminal; Nature; Neurons; Neurophysiology - biologic function; Nicotine; Nicotine Dependence; Pathway interactions; Pattern; Pharmaceutical Preparations; Phosphotransferases; Polymerase Chain Reaction; Process; Protein Analysis; Proteins; Relapse; Research; Role; Signal Pathway; Signal Transduction; Smoking; Surgeon; Synaptic plasticity; Testing; Tobacco; Tobacco use; United States; Withdrawal; addiction; cell type; chromatin immunoprecipitation; classical conditioning; conditioned fear; craving; drug seeking behavior; granule cell; hippocampal subregions; interest; long term memory; member; mossy fiber; novel; receptor; relating to nervous system; research study; stress-activated protein kinase 1; therapeutic development; transcription factor

DESCRIPTION (provided by applicant): In 1988, the US Surgeon General concluded that tobacco products are addictive and nicotine is the main pharmacological agent in tobacco responsible for tobacco's addictive nature. Despite overwhelming evidence of the adverse health effects of smoking, it is estimated that 68.8 million Americans use tobacco products and 400,000 tobacco-related deaths occur in the United States each year. However, it is not completely understood why nicotine is addictive. One reason for this incomplete understanding of nicotine addiction may be that addiction is a complex disorder with many factors contributing to the disease. Possible factors that may contribute to nicotine addiction include long-lasting change in learning and long-lasting changes in the synaptic plasticity that underlies learning. Studies suggest that initially nicotine enhances learning but with continued use tolerance develops and deficits in learning emerge when administration ceases. The limbic area of the brain is involved in both learning and addiction and thus the effects of nicotine in this area may mediate cognitive influences on addiction. It is the hypothesis of this proposal that nicotine alters the function of the hippocampus during learning, producing a learned state that is different from learning in the absence of the drug, and that this learning may involve different patterns of cell signaling and gene activation than those activated during comparable learning without drug. The ability of nicotine to alter learning processes and the underlying neural function may facilitate addiction by contributing to withdrawal-related deficits in learning and the formation of long-lasting drug-associated memories that could precipitate craving and relapse even after long periods of abstinence. In support of this, acute nicotine has been shown to enhance a long-lasting form of contextual fear conditioning, a type of classical conditioning that involves the hippocampus but withdrawal from chronic nicotine disrupts this learning. Long-term memory storage is known to involve alteration in gene expression, and the proteins encoded by these induced genes, such as mitogen activate protein kinases (MAPK), result in long-lasting changes in neuronal function; recent evidence suggests that nicotine and learning interact to alter signaling through the MAPK pathway. Proposed experiments will identify the neural substrates that underlie the effects of nicotine on hippocampus-dependent learning, identify the specific role of hippocampal subregions in the effects of nicotine on learning, and identify the downstream targets of MAPK mediating the changes in synaptic plasticity involved in the effects of nicotine on learning. Investigating the effects of nicotine on learning from the behavioral level to changes in cell signaling will enhance understanding of addiction and aid in therapeutic development for nicotine addiction. PUBLIC HEALTH RELEVANCE: Nicotine is one of the most addictive drugs but complete understanding of why is elusive. The ability of nicotine to alter brain function producing long-lasting changes in behavior that remain even after periods of abstinence may be one factor for the strong addictive effects of nicotine. This proposal investigates the long-lasting changes produced by nicotine in learning and the underlying cellular processes in order to understand how nicotine changes the brain and to provide new targets for the development of therapeutics to treat nicotine addiction.

描述（由申请人提供）： 1988 年，美国卫生局局长得出结论，烟草产品具有成瘾性，而尼古丁是烟草中的主要药理成分，导致烟草具有成瘾性。尽管有大量证据表明吸烟对健康产生不利影响，但据估计，美国每年有 6880 万美国人使用烟草制品，并且有 40 万人因烟草相关死亡。然而，目前尚不完全清楚尼古丁为何会让人上瘾。对尼古丁成瘾的不完全理解的一个原因可能是成瘾是一种复杂的疾病，有许多因素导致该疾病。可能导致尼古丁成瘾的因素包括学习的长期变化和学习背后的突触可塑性的长期变化。研究表明，尼古丁最初可以增强学习能力，但随着继续使用，耐受性会发展，并且当停止使用时会出现学习缺陷。大脑边缘区域与学习和成瘾有关，因此尼古丁在该区域的作用可能会介导对成瘾的认知影响。该提议的假设是，尼古丁在学习过程中改变了海马体的功能，产生了一种与没有药物的情况下的学习不同的学习状态，并且这种学习可能涉及与那些不同的细胞信号传导和基因激活模式。在没有药物的情况下的类似学习过程中被激活。尼古丁改变学习过程和潜在神经功能的能力可能会导致与戒断相关的学习缺陷，并形成持久的药物相关记忆，从而促进成瘾，即使在长期戒烟后，这些记忆也可能导致渴望和复发。支持这一点的是，急性尼古丁已被证明可以增强持久形式的情境恐惧调节，这是一种涉及海马体的经典调节，但长期尼古丁的戒断会破坏这种学习。众所周知，长期记忆存储涉及基因表达的改变，而这些诱导基因编码的蛋白质，例如丝裂原激活蛋白激酶（MAPK），会导致神经元功能的长期变化；最近的证据表明，尼古丁和学习相互作用，通过 MAPK 途径改变信号传导。拟议的实验将确定尼古丁对海马依赖性学习影响的神经底物，确定海马亚区域在尼古丁对学习的影响中的具体作用，并确定 MAPK 介导参与学习的突触可塑性变化的下游靶标。尼古丁对学习的影响。研究尼古丁对从行为水平到细胞信号变化的学习的影响将增强对成瘾的理解并有助于尼古丁成瘾治疗的发展。 公众健康相关性：尼古丁是最容易上瘾的药物之一，但对其原因的完全理解却难以捉摸。尼古丁能够改变大脑功能，从而产生持久的行为变化，即使在戒烟一段时间后这种变化仍然存在，这可能是尼古丁产生强烈成瘾作用的因素之一。该提案研究了尼古丁对学习和潜在细胞过程产生的持久变化，以了解尼古丁如何改变大脑，并为开发治疗尼古丁成瘾的疗法提供新的靶点。