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，烟草制品具有成瘾性，尼古丁是烟草中导致烟草成瘾性的主要药物。尽管有大量证据表明吸烟对健康有害，但据估计，有6880万美国人使用烟草制品，美国每年发生40万与烟草有关的死亡事件。然而，人们还没有完全理解为什么尼古丁会上瘾。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，有许多因素导致了这种疾病。可能导致尼古丁成瘾的因素包括学习能力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，尼古丁最初可以增强学习能力，但随着持续使用，耐受性逐渐增强，停止使用后，学习能力就会下降。大脑的边缘区域涉及学习和成瘾，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，尼古丁改变了学习过程中海马体的功能，产生了一种与没有药物的学习不同的学习状态，这种学习可能涉及不同的细胞信号传导和基因激活模式，而不是在没有药物的情况下激活的模式。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，因为它会导致戒断相关的学习缺陷，并形成持久的药物相关记忆，即使在长时间的戒断后，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一种长期形式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，但长期尼古丁的戒断会破坏这种学习。众所周知，长期记忆储存涉及基因表达的改变，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通路改变信号。拟开展的实验将确定尼古丁对海马依赖学习影响的神经基础，确定海马亚区在尼古丁对学习影响中的具体作用，并确定MAPK介导尼古丁对学习影响中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，将有助于加深对成瘾的理解，并有助于尼古丁成瘾的治疗发展。

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.