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。尽管有令人印象深刻的证据表明吸烟对健康有害，但据估计，美国每年仍有6880万美国人使用烟草产品，并发生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遗传和学习。许多研究表明，尼古丁有助于学习。具体地说，大脑的边缘区域与学习和成瘾都有关，因此，尼古丁对该区域的影响可能会对成瘾的认知产生影响。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。尼古丁增强学习过程的能力可能会促进成瘾，因为它会促进与毒品有关的联系，从而引发渴望和复发。为了支持这一点，尼古丁已经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。众所周知，长期记忆存储涉及基因表达的变化，这些诱导基因编码的蛋白质，如MAP激酶，会导致神经元功能的长期变化。尼古丁还可以改变MAP激酶的激活。拟议的实验将确定烟碱型乙酰胆碱能受体亚型，确定作用的神经部位，并确定参与尼古丁长期增强背景恐惧条件反射的MAP激酶。研究尼古丁对学习的影响，从受体激活的水平到细胞信号的变化，将加强对成瘾的理解，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