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.

说明(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上，但有越来越多的证据表明，其他烟草成分，如单胺氧化酶(MAO)抑制剂，可能会增加烟草使用的成瘾倾向。本研究的目的是阐明MAO抑制对烟草精神活性的影响。我们将使用大鼠作为模型来检验MAO抑制增强尼古丁对吸烟开始和依赖的影响的假设。我们基于先前的发现：i)MAO是大脑奖励系统中单胺类物质的重要调节器，ii)吸烟降低大脑MAO活性，从而增加大脑单胺类物质，以及iii)MAO抑制增强尼古丁诱导的运动敏感化和奖赏。我们拟从行为、生化和解剖学水平探讨MAO抑制对尼古丁诱导的作用的影响。具体目的是：1.确定MAO抑制剂增强尼古丁增强作用的选择性要求。我们将使用成年雄性和雌性大鼠来评估MAO抑制剂的选择性如何影响尼古丁自我给药的获得；2.确定MAO抑制如何改变尼古丁诱导的局部脑活动的变化。我们将使用神经解剖学和神经化学方法来评估MAO抑制剂三羟环丙胺增强尼古丁奖赏的神经回路；3.确定三羟环丙胺与其他精神刺激剂相比是否选择性地增强尼古丁奖赏。我们将比较三羟环丙胺预处理对尼古丁、可卡因和苯丙胺自我给药的影响。如果观察到对尼古丁的选择性，我们将在两级选择范式中测试MAO抑制是否改变尼古丁的相对奖励强度；4.确定MAO抑制是否增加尼古丁戒断作为依赖的衡量标准。长期注射尼古丁的动物将接受生理盐水或三环丙胺治疗，并比较甲乙胺和纳洛酮沉淀的戒断症状和条件性场所厌恶。这些研究的结果应该会促进我们对尼古丁与其他烟草成分相互作用的理解，并导致改进的吸烟动物模型，这将加强我们对烟草成瘾的原因和治疗方法的探索。