Role of Monoamine Oxidases in Tobacco Addiction

单胺氧化酶在烟草成瘾中的作用

• 批准号: 7077928
• 负责人: FRANCES M. LESLIE
• 金额: $ 26.22万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7077928
• 关键词: amine oxidase (flavin); nicotine; role; tobacco

DESCRIPTION (provided by applicant): Although current research into the causes of smoking focuses largely on nicotine, there is accumulating evidence that other tobacco constituents, such as monoamine oxidase (MAO) inhibitors, may increase the addictive liability of tobacco use. The goal of the proposed research is to elucidate the contribution of MAO inhibition to the psychoactive effects of tobacco. We will use the rat as a model to test the hypothesis that MAO inhibition enhances the effects of nicotine on smoking initiation and dependence. We base this hypothesis on prior findings that i) MAO is an important modulator of monoamines in brain reward systems, ii) smoking reduces brain MAO activity thereby increasing brain monoamines, and iii) MAO inhibition enhances nicotine-induced locomotor sensitization and reward. We propose to explore the effects of MAO inhibition on nicotine-induced actions at the behavioral, biochemical and anatomical levels. The specific aims are: 1. To determine the selectivity requirements for MAO inhibitor enhancement of nicotine's reinforcing actions. We will use adult male and female rats to evaluate how the selectivity of MAO inhibitors affects the acquisition of nicotine self-administration; 2. To determine how MAO inhibition alters nicotine- induced changes in regional brain activity. We will use neuroanatomical and neurochemical approaches to evaluate the neural circuitry underlying the enhancement of nicotine reward by the MAO inhibitor, tranylcypromine; 3. To determine whether tranylcypromine selectively enhances nicotine reward as compared to other psychostimulants. We will compare the effect of tranylcypromine pretreatment on the acquisition of nicotine, cocaine and amphetamine self-administration. If selectivity for nicotine is observed, we will test whether MAO inhibition alters nicotine's relative reward strength in a 2-lever choice paradigm; 4. To determine if MAO inhibition increases nicotine withdrawal as a measure of dependence. Animals which are chronically infused with nicotine will be treated with saline or tranylcypromine and compared for mecamylamine- and naloxone-precipitated withdrawal symptoms and conditioned place aversion. The results of these studies should advance our understanding of the interaction of nicotine with other tobacco constituents, and lead to improved animal models of smoking that will strengthen our search for tobacco addiction's causes and cures.

描述（由申请人提供）：尽管目前对吸烟原因的研究主要集中在尼古丁，但仍有证据表明，其他烟草成分，例如单胺氧化酶（MAO）抑制剂，可能会增加烟草使用的上瘾责任。拟议的研究的目的是阐明MAO抑制对烟草的精神活性的贡献。我们将使用大鼠作为模型来检验以下假设：MAO抑制可以增强尼古丁对吸烟起始和依赖性的影响。我们基于先前的发现，即i）MAO是脑奖励系统中单胺的重要调节剂，ii）吸烟会减少脑MAO活性，从而增加脑单胺，iii）MAO抑制作用增强了尼古丁引起的运动运动敏感性和奖励。我们建议探索MAO抑制对行为，生化和解剖学水平上尼古丁诱导的作用的影响。具体目的是：1。确定MAO抑制剂增强尼古丁加强作用的选择性要求。我们将使用成年男性和雌性大鼠评估MAO抑制剂的选择性如何影响尼古丁自我给药的获取； 2。确定MAO抑制如何改变尼古丁诱导的区域大脑活动的变化。我们将使用神经解剖学和神经化学方法来评估MAO抑制剂tranylcypromine增强尼古丁奖励的神经回路； 3。确定与其他精神刺激物相比，tranylcypromine是否有选择地增强尼古丁奖励。我们将比较tranylcypromine预处理对获得尼古丁，可卡因和苯丙胺自我给药的影响。如果观察到尼古丁的选择性，我们将测试MAO抑制作用是否会改变尼古丁在2级选择范式中的相对奖励强度。 4。确定MAO抑制是否会增加尼古丁的戒断，以衡量依赖性。长期注入尼古丁的动物将用盐水或tranylcypromine治疗，并比较美甲基胺和纳洛酮预测的戒断症状和条件性的场所厌恶。这些研究的结果应提高我们对尼古丁与其他烟草成分相互作用的理解，并导致改善吸烟动物模型，从而加强我们对烟草成瘾的原因和治愈的搜索。