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，美国每年有40万人死于与烟草有关的疾病。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遗传和学习。许多研究表明尼古丁能提高学习能力。具体来说，大脑的边缘区域参与学习和成瘾，因此尼古丁对该区域的影响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。尼古丁增强学习过程的能力可能通过促进药物环境的关联而促进成瘾，从而促成渴望和复发。为了支持这一观点，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。众所周知，长期记忆储存涉及基因表达的改变，而这些诱导基因编码的蛋白质，如MAP激酶，导致神经元功能的长期变化。尼古丁也可以改变MAP激酶的激活。本实验将确定尼古丁乙酰胆碱能受体亚型，确定作用的神经部位，并确定MAP激酶参与尼古丁对情境恐惧条件反射的长期增强。研究尼古丁对学习的影响，从受体激活水平到细胞信号的变化，将增强对成瘾的理解，并有助于开发尼古丁成瘾的治疗方法

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 over whelming 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 genetics and learning. Many studies suggest that nicotine enhances learning. Specifically, the limbic area of the brain is involved in both learning and addiction and thus nicotine effects on 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 enhance learning processes may facilitate addiction by contributing to drug-context associations that could precipitate craving and relapse. In support of this, nicotine has been shown to enhance a long-lasting form of contextual fear conditioning, a type of classical conditioning that involves the hippocampus. Long-term memory storage is known to involve alteration in gene expression, and the proteins encoded by these induced genes, such as MAP kinases, result in long-lasting changes in neuronal function. Nicotine can also alter activation of MAP kinases. Proposed experiment will identify the nicotinic acetylcholinergic receptor subtypes, identify the neural site of action, and identify MAP kinases involved in the long-lasting enhancement of contextual fear conditioning by nicotine. Investigating the effects of nicotine on learning from the level of receptor activation to changes in cell signaling will enhance understanding of addiction and aid in development of treatments for nicotine addiction