Nicotine Addiction: Learning, Neural & Genetic Process

描述（由申请人提供）：1988年，美国卫生部长得出结论，烟草产品具有成瘾性，尼古丁是烟草中导致烟草成瘾性的主要药理学物质。尽管有压倒性的证据表明吸烟对健康有不利影响，但据估计，美国每年有6880万人使用烟草产品，40万人死于烟草相关疾病。然而，人们并不完全理解尼古丁为什么会上瘾。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，有许多因素导致这种疾病。可能导致尼古丁成瘾的因素包括学习的长期变化和学习基础突触可塑性的长期变化。研究表明，尼古丁最初可增强学习能力，但随着持续使用，耐受性会发展，停止使用时会出现学习缺陷。大脑边缘系统区域参与学习和成瘾，因此尼古丁在该区域的作用可能介导成瘾的认知影响。这一提议的假设是，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学习不同的学习状态，并且这种学习可能涉及与没有药物的类似学习过程中激活的细胞信号传导和基因激活模式不同的模式。尼古丁改变学习过程和潜在神经功能的能力可能通过促进学习中与戒断相关的缺陷和形成持久的药物相关记忆而促进成瘾，即使在长期戒断后也可能诱发渴望和复发。为了支持这一点，急性尼古丁已被证明可以增强一种持久形式的背景恐惧条件反射，这是一种涉及海马体的经典条件反射，但从慢性尼古丁中戒断会破坏这种学习。已知长期记忆储存涉及基因表达的改变，并且由这些诱导基因编码的蛋白质，如促分裂原激活蛋白激酶（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，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，确定海马亚区在尼古丁对学习影响中的特定作用，并确定MAPK介导尼古丁对学习影响中涉及的突触可塑性变化的下游靶点。研究尼古丁对学习的影响，从行为水平到细胞信号的变化，将增强对成瘾的理解，并有助于尼古丁成瘾的治疗开发。 公共卫生相关性：尼古丁是最容易上瘾的药物之一，但完全理解为什么是难以捉摸的。尼古丁能够改变大脑功能，产生持久的行为变化，即使在禁欲期后仍然存在，这可能是尼古丁强烈成瘾作用的一个因素。该提案研究了尼古丁在学习和潜在细胞过程中产生的长期变化，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。

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.