Role of Monoamine Oxidases in Tobacco Addiction

单胺氧化酶在烟草成瘾中的作用

• 批准号: 7379939
• 负责人: FRANCES M. LESLIE
• 金额: $ 24.85万
• 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 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7379939
• 关键词: Acetaldehyde; Adrenergic Receptor; Adult; Affect; Amphetamines; Animal Model; Animals; Attention; Behavioral; Biochemical; Brain; Chronic; Classification; Cocaine; Condition; Daily; Dependence; Dose; Evaluation; FOS gene; Female; Goals; Implant; Injection of therapeutic agent; Lead; Measures; Mecamylamine; Messenger RNA; Microdialysis; Modeling; Monoamine Oxidase; Monoamine Oxidase A; Monoamine Oxidase B; Monoamine Oxidase Inhibitors; Naloxone; Neurons; Nicotine; Nicotine Withdrawal; Nicotinic Receptors; Opioid Receptor; Pharmaceutical Preparations; Phase; Procedures; Rate; Rattus; Relapse; Relative (related person); Reporting; Research; Research Personnel; Rewards; Role; Saline; Self Administration; Smoking; System; Techniques; Testing; Tobacco; Tobacco Dependence; Tobacco smoke; Tobacco use; Tranylcypromine; Withdrawal; Withdrawal Symptom; base; cigarette smoking; cigarette smoking; day; design; drug of abuse; improved; male; monoamine; neural circuit; neurochemistry; programs; psychologic; psychostimulant; research study; response

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.

尽管目前对吸烟原因的研究主要集中在尼古丁，但仍在积累 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毛的贡献 抑制烟草的精神活性作用。我们将使用大鼠作为模型来检验以下假设。 MAO抑制作用增强了尼古丁对吸烟启动和依赖性的影响。我们以此为基础 关于先前发现的假设：i）MAO是大脑奖励系统中单胺的重要调节剂， ii）吸烟减少脑MAO活动，从而增加脑单胺，iii）MAO抑制作用 增强尼古丁引起的运动敏化和奖励。我们建议探索毛的影响 抑制尼古丁诱导的行为，生化和解剖学水平的作用。具体 目的是：1。确定MAO抑制剂增强尼古丁的选择性要求 加强行动。我们将使用成年男性和雌性大鼠评估MAO抑制剂的选择性 影响尼古丁自我管理的获取； 2。确定毛抑制如何改变尼古丁 - 诱导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 评估MAO抑制剂增强尼古丁奖励的神经回路， tranylcypromine; 3。确定三甲基丙啶是否有选择地增强尼古丁奖励 与其他精神刺激剂相比。我们将比较tranylcypromine预处理对 获得尼古丁，可卡因和苯丙胺自我管理。如果观察到尼古丁的选择性， 我们将测试MAO抑制是否会在2级选择范式中改变尼古丁的相对奖励强度； 4。 确定MAO抑制是否会增加尼古丁的戒断，以衡量依赖性。动物 长期注入尼古丁是否会接受盐水或tranylcypromine治疗，并比较 美甲基胺和纳洛酮的戒断症状和条件性的场所厌恶。这 这些研究的结果应提高我们对尼古丁与其他烟草相互作用的理解 成分，并导致改善的吸烟动物模型，从而加强我们对烟草的搜索 成瘾的原因和治愈方法。