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。 烟碱型乙酰胆碱受体(NAChRs)是配体门控离子通道 它们是尼古丁的主要中心目标。NAChRs家族的多样性 在中枢神经系统中表达，在那里他们的药理和 人们对生理作用的了解还只有一部分。是否可以使用 重组神经元nAChRs亚基现在可以表征 烟碱和乙酰胆碱与烟碱的相互作用 受体亚型。尼古丁具有双重的激动剂-拮抗剂作用，因为它 可以使其受体脱敏。初步数据显示，中枢nAChRs 受体亚基在脱敏特性和 药理学。 在这个项目中，我们将描述五种化合物的药理和生理学特征 重组nAChRs在非洲爪哇卵母细胞中的表达。受体将是 使用全电池电压钳位和单通道进行功能表征 膜片钳技术。我们会特别注意敌手 在尼古丁贴片中促进戒烟的甲戊胺(MECA) 心理治疗。 本项目的具体目标是：(I)界定药理作用 特异性重组受体的图谱，(Ii)测定 尼古丁作为激动剂在长期用药期间的效力，(Iii) 研究亚基在乙酰胆碱脱敏中的作用。 尼古丁，和(Iv)表征生理相互作用。 乙酰胆碱、尼古丁和甲基乙胺。这些实验将确定 特定神经元药理学和生理学的分子基础 NAChRs。单个亚基在决定对偶性中的作用 尼古丁的药理作用将被定义。结果将是 对于理解烟草依赖的发展 在吸烟期间，以及在戒烟治疗期间其逆转。