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）：尽管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，如单胺氧化酶（MAO）抑制剂，可能会增加烟草使用的成瘾倾向。这项研究的目的是阐明单胺氧化酶抑制对烟草的精神作用的贡献。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起始和依赖性的作用的假设。我们基于先前的发现，即：i）单胺氧化酶是脑奖励系统中单胺的重要调节剂，ii）吸烟降低脑单胺氧化酶活性，从而增加脑单胺，iii）单胺氧化酶抑制增强尼古丁诱导的运动敏化和奖励。我们建议探讨的影响，单胺氧化酶抑制尼古丁诱导的行动在行为，生化和解剖水平。具体目标是：1.确定单胺氧化酶抑制剂增强尼古丁强化作用的选择性要求。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.确定单胺氧化酶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的方法来评估的神经回路的基础上，提高尼古丁奖励的单胺氧化酶抑制剂，反苯环丙胺; 3。确定反苯环丙胺与其他精神兴奋剂相比是否选择性增强尼古丁奖赏。我们将比较反苯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2-杠杆选择范例中测试MAO抑制是否改变尼古丁的相对奖励强度; 4.确定MAO抑制是否会增加尼古丁戒断，作为依赖性的衡量标准。将用生理盐水或反苯环丙胺对长期输注尼古丁的动物进行处理，并比较美加明和纳洛酮诱发的戒断症状和条件性位置厌恶。这些研究的结果应该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原因和治疗方法的研究。