MOLECULAR PHARMACOLOGY AND PHYSIOLOGY OF NICOTINE

尼古丁的分子药理学和生理学

• 批准号: 2123944
• 负责人: ANTONIUS M VANDONGEN
• 金额: $ 10.67万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-15 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2123944
• 关键词: Xenopus; Xenopus oocyte; acetylcholine; cholinergic receptors; drug interactions; mecamylamine; neuropharmacology; nicotine; receptor binding; recombinant proteins; voltage /patch clamp

DESCRIPTION: (Applicant's Abstract) The long term objective of this research is to understand the molecular basis of nicotine addiction, associated with the usage of tobacco. Nicotinic acetylcholine receptors (nAChRs) are ligand gated ion channels that are the primary central target of nicotine. A diverse family of nAChRs is expressed in the central nervous system, where their pharmacology and physiological roles are only partially understood. The availability of recombinant neuronal nAChRs subunits now makes it possible to characterize the interaction of nicotine and acetylcholine with specific nicotinic receptor subtypes. Nicotine has a dual agonist-antagonist action because it can desensitize its receptor. Preliminary data show that central nAChRs receptor subunits vary dramatically in their desensitization properties and pharmacology. In this project we will characterize the pharmacology and physiology of five recombinant nAChRs expressed in Xenopus oocytes. Receptors will be functionally characterized using whole cell voltage clamp and single channel patch clamp techniques. Special attention will be given to the antagonist mecamylamine (MECA), which facilitates smoking abstinence in nicotine patch therapy. The specific aims of this project are: (i) to define the pharmacological profiles of the specific recombinant receptors, (ii) to determine the potency of nicotine as an agonist, during prolonged drug application, (iii) to characterize the role of subunits in desensitization by acetylcholine and nicotine, and (iv) to characterize the physiological interaction of acetylcholine, nicotine and mecamylamine. These experiments will establish a molecular basis for the pharmacology and physiology of specific neuronal nAChRs. The role of individual subunits in determining the dual pharmaco-logical action of nicotine will be defined. The results will be important for understanding both the development of tobacco dependence during smoking, as well as its reversion during smoking cessation therapy.

描述：（申请人摘要） 这项研究的长期目标是了解分子 尼古丁成瘾的基础，与烟草的使用有关。 烟碱乙酰胆碱受体 (nAChR) 是配体门控离子通道 这是尼古丁的主要中心目标。 nAChR 的多样化家族 在中枢神经系统中表达，其药理学和 生理作用仅被部分了解。 的可用性 重组神经元 nAChR 亚基现在可以表征 尼古丁和乙酰胆碱与特定烟碱的相互作用 受体亚型。 尼古丁具有双重激动剂-拮抗剂作用，因为它 可以使其受体脱敏。 初步数据显示，中枢 nAChR 受体亚基的脱敏特性差异很大 药理。 在这个项目中，我们将描述五种药物的药理学和生理学特征 在非洲爪蟾卵母细胞中表达的重组 nAChR。 受体将是 使用全细胞电压钳和单通道进行功能表征 膜片钳技术。 对手将受到特别关注 美加明 (MECA)，可通过尼古丁贴片促进戒烟 治疗。 该项目的具体目标是： (i) 定义药理学 特定重组受体的概况，（ii）确定 在长期用药过程中尼古丁作为激动剂的效力，(iii) 表征亚基在乙酰胆碱脱敏中的作用和 尼古丁，以及（iv）表征生理相互作用 乙酰胆碱、尼古丁和美加明。 这些实验将建立 特定神经元的药理学和生理学的分子基础 nAChR。 各个亚基在确定双重作用中的作用 将定义尼古丁的药理作用。 结果将是 对于了解烟草依赖的发展很重要 吸烟期间的情况，以及戒烟治疗期间的逆转。