Evaluation of Buproprion in Nicotine Dependence Model

这项建议的广泛目标是确定临床上有用的 抗抑郁剂和戒烟助剂安非他酮。驱动这一应用程序的潜在假设是 一个成功的戒烟药物疗法至少要包括一个阻断活动 单胺转运体和C413_nAChR亚型。该组件将首先确定电势(_4132 安非他酮、羟基安非他酮和3-苯基托烷类似物的nAChR拮抗特性 (由项目1提供)关于尼古丁对小鼠的急性影响。发现具有体外功能的化合物 DA和NE转运体和c_4132nAChR亚型的阻断活性(由项目1和2提供)将是 评估其阻断尼古丁对伤害性感觉、体温和 小鼠的运动活性将被选择效力高于安非他酮的类似物进行测试 尼古丁依赖模型。这些类似物将在与尼古丁依赖相关的两个方面进行评估 模拟尼古丁的主观特性和身体依赖产生影响的小鼠行为： 毒品歧视和戒毒迹象。这些发现还将使人们能够定义 项目1和2提供的药物在体外对Net、DAT或nAChR功能的影响以及药物的疗效 尼古丁依赖模型，从而帮助将分子靶向分布与对尼古丁的影响相关联 依赖。显示部分或全部取代性质和逆转尼古丁戒断的化合物 体征随后将在大鼠静脉注射中进行测试。自治 在这项工作的基础上，将出现治疗尼古丁依赖的新药开发。 我们的研究将提供有关生物靶标(转运体和尼古丁受体)的信息。 参与安非他酮的治疗益处，并将改善目前吸烟的有限疗效 戒烟的药理学策略。

The broad objective of this proposal is to determine mechanisms of action of the clinically useful antidepressant and smoking cessation aid, bupropion. The underlying hypothesis driving this application is that a successful smoking cessation pharmacotherapy would at least include a blocking activity at monoamine transporters and c_413_nAChR subtype. This component will first determine the potential (_4132 nAChR antagonistic properties of selected bupropion, hydroxybupropion and 3-phenyltropane analogs (provided by Project # 1) on nicotinic acute effects in mice. Compounds found to possess in vitro functional blocking activity at DA and NE transporters and c_4132nAChR subtype (provided by Projects 1 & 2) will be assessed for their ability to block the acute effects of nicotine on nociception, body temperature and locomotor activity in miceAnalogs with potency higher than that of bupropion will be selected for testing in the nicotine dependence models. These analogs will be evaluated in two nicotine dependence-related behaviors in mice that models subjective properties and physical dependence-producing effects of nicotine: drug discrimination and withdrawal signs. These findings also will allow relationships to be defined between effects of drugs on NET, DAT, or nAChR function in vitro provided in Projects 1 and 2 and drug efficacy in the nicotine dependence models, thus helping to correlate molecular target profiles with effects on nicotine dependence. Compounds showing partial or total substitution properties and reversing nicotine withdrawal signs will be subsequently tested in rat i.v. self-administration Out of this work leads for new medications development for treatment of nicotine dependence will come. Our studies will yield information concerning the biological targets (transporters and nicotinic receptors) involved in bupropion's therapeutic benefits and will improve the limited efficacy of the current smoking cessation pharmacological strategies.