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，美国外科医生得出结论，烟草产品令人上瘾，尼古丁是负责烟草上瘾性的烟草中的主要药理剂。尽管有大量证据表明吸烟对健康的不利影响，但据估计，每年在美国发生了6880万美国人使用烟草产品和40万种与烟草有关的死亡。但是，尚不完全理解为什么尼古丁会上瘾。这种对尼古丁成瘾的不完全理解的原因之一可能是成瘾是一种复杂的疾病，有许多导致该疾病的因素。可能导致尼古丁成瘾的可能因素包括学习的长期变化以及构成学习的突触可塑性的持久变化。研究表明，尼古丁最初会增强学习，但随着行政管理停止时，持续使用耐受性会发展出来。大脑的边缘区域参与学习和成瘾，因此尼古丁在该领域的影响可能介导认知对成瘾的影响。这一提议的假设是，尼古丁在学习过程中改变了海马的功能，产生了一种与没有药物的学习不同的学习状态，该状态与在没有药物的情况下不同，并且与没有药物相比学习期间激活的细胞信号传导和基因激活模式不同。尼古丁改变学习过程和潜在的神经功能的能力可能会通过导致与戒断相关的学习和长期持续相关的记忆的形成，从而促进成瘾，即使在长期以来，这种记忆也可能导致渴望和复发。为了支持这一点，急性尼古丁已被证明可以增强上下文恐惧条件的长期形式，这种恐惧条件是一种涉及海马的经典条件，但从慢性尼古丁中退出会破坏这一学习。已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（例如有丝分裂原基因激活蛋白激酶（MAPK））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以通过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，确定海马子区域在尼古丁在学习中的影响中的特定作用，并确定MAPK的下游靶标，介导了MAPK的下游靶标，从而介导了尼古丁对学习影响的突触可塑性的变化。研究尼古丁对从行为水平学习到细胞信号变化的影响将增强对成瘾的理解，并有助于尼古丁成瘾的治疗发展。 公共卫生相关性：尼古丁是最令人上瘾的药物之一，但完全了解为什么难以捉摸。尼古丁改变大脑功能会导致行为的长期变化，即使在禁欲之后，行为的长期变化可能是尼古丁的强烈成瘾作用的一个因素。该提案调查了尼古丁在学习和潜在的细胞过程中产生的持久变化，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标。