Nicotine Addiction: Learning, Neural & Genetic Process

描述(由申请人提供)：1988年，美国卫生局局长得出结论，烟草产品会上瘾，尼古丁是烟草中导致烟草上瘾的主要药理物质。尽管有压倒性的证据表明吸烟对健康有害，但据估计，美国有6880万美国人使用烟草产品，美国每年发生40万与烟草有关的死亡事件。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，尼古丁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作为学习基础的突触可塑性的长期变化。研究表明，尼古丁最初能促进学习，但随着持续使用，耐受性会增强，当停止使用时，学习会出现缺陷。大脑边缘区域同时参与学习和成瘾，因此，尼古丁在该区域的作用可能对成瘾的认知影响起到中介作用。这一建议的假设是尼古丁在学习过程中改变海马体的功能，产生一种不同于在没有药物的情况下学习的学习状态，这种学习可能涉及不同于在没有药物的可比学习期间激活的细胞信号和基因激活的模式。尼古丁改变学习过程和潜在神经功能的能力可能会促进成瘾，因为它会导致与戒断相关的学习缺陷，并形成与药物相关的长期记忆，即使在长期戒烟后，这种记忆也可能导致渴望和复发。为了支持这一点，急性尼古丁被证明可以增强一种长期的情境恐惧条件反射，这是一种涉及海马体的经典条件反射，但慢性尼古丁的戒断会扰乱这种学习。已知的长期记忆存储涉及基因表达的改变，由这些诱导基因编码的蛋白质，如丝裂原激活蛋白激酶(MAPK)，导致神经功能的长期变化；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。拟议的实验将确定尼古丁对海马体依赖学习的影响的神经底物，确定海马亚区在尼古丁对学习的影响中的特定作用，并确定参与尼古丁对学习的影响的突触可塑性变化的MAPK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，将加强对成瘾的理解，并有助于尼古丁成瘾的治疗开发。 与公共健康相关：尼古丁是最容易上瘾的毒品之一，但为什么要完全弄清楚原因还很难理解。尼古丁改变大脑功能的能力，即使在戒烟一段时间后仍能保持长期的行为变化，这可能是尼古丁强烈成瘾效应的一个因素。这项建议研究尼古丁在学习中产生的长期变化和潜在的细胞过程，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.