Role of Monoamine Oxidases in Tobacco Addiction

单胺氧化酶在烟草成瘾中的作用

基本信息

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
项目类别：
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

项目摘要

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上，但越来越多的研究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成瘾责任。拟议研究的目标是阐明 MAO 的贡献抑制烟草的精神作用。我们将使用老鼠作为模型来检验以下假设： MAO 抑制增强尼古丁对吸烟开始和依赖的影响。我们以此为基础基于先前发现的假设 i) MAO 是大脑奖励系统中单胺的重要调节剂， ii) 吸烟会降低大脑 MAO 活性，从而增加大脑单胺含量，以及 iii) MAO 抑制增强尼古丁诱导的运动敏感性和奖励。我们建议探索 MAO 的影响在行为、生化和解剖水平上抑制尼古丁诱导的作用。具体的目标是： 1. 确定 MAO 抑制剂增强尼古丁的选择性要求加强行动。我们将使用成年雄性和雌性大鼠来评估 MAO 抑制剂的选择性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- 引起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，反苯环丙明； 3. 确定反苯环丙明是否选择性地增强尼古丁奖励与其他精神兴奋剂相比。我们将比较反苯环丙明预处理对自我管理获取尼古丁、可卡因和安非他明。如果观察到对尼古丁的选择性，我们将在 2 杆选择范例中测试 MAO 抑制是否会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。哪些动物长期注射尼古丁的患者将接受生理盐水或反苯环丙明治疗，并进行比较美加明和纳洛酮会引发戒断症状和条件性地方厌恶。这这些研究的结果应该增进我们对尼古丁与其他烟草相互作用的理解成分，并导致改进吸烟动物模型，这将加强我们对烟草的探索成瘾的原因和治疗方法。