Role of Monoamine Oxidases in Tobacco Addiction

单胺氧化酶在烟草成瘾中的作用

• 批准号: 7198110
• 负责人: FRANCES M. LESLIE
• 金额: $ 25.41万
• 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/7198110
• 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

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）：虽然目前对吸烟原因的研究主要集中在尼古丁上，但越来越多的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成瘾性。本研究的目的是阐明 MAO 抑制对烟草精神作用的影响。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。我们的这一假设基于先前的发现：i) MAO 是大脑奖励系统中单胺的重要调节剂，ii) 吸烟会降低大脑 MAO 活性，从而增加大脑单胺含量，iii) MAO 抑制会增强尼古丁诱导的运动敏化和奖励。我们建议在行为、生化和解剖水平上探索 MAO 抑制对尼古丁诱导作用的影响。具体目标是： 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区域大脑活动变化。我们将使用神经解剖学和神经化学方法来评估 MAO 抑制剂反苯环丙胺增强尼古丁奖励的神经回路； 3. 确定与其他精神兴奋剂相比，反苯环丙明是否选择性地增强尼古丁奖赏。我们将比较反苯环丙明预处理对尼古丁、可卡因和安非他明自我给药获得的影响。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 杆选择范例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戒断，作为依赖的衡量标准。长期注射尼古丁的动物将接受盐水或反苯环丙明治疗，并比较美加明和纳洛酮诱发的戒断症状和条件性地方厌恶。这些研究的结果应该增进我们对尼古丁与其他烟草成分相互作用的理解，并改进吸烟动物模型，从而加强我们对烟草成瘾原因和治疗方法的探索。