FUNCTIONAL ACTIVITY OF PRESYNAPTIC NICOTINIC RECEPTORS

突触前烟碱受体的功能活性

• 批准号: 2119993
• 负责人: PETER P ROWELL
• 金额: $ 7.06万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-29 至 1994-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2119993
• 关键词: FUNCTIONAL; ACTIVITY; PRESYNAPTIC; NICOTINIC; RECEPTORS

Studies have shown that the terminals of specialized neurons of the brain contain presynaptic nicotinic receptors which, when stimulated, cause the release of neurotransmitters. The nicotine-induced release of dopamine from terminals of the mesolimbic and nigrostriatal systems is thought to produce the positively reinforcing properties of nicotine responsible for cigarette smoking. Although considerable research has been conducted on the molecular structure, localization and ligand binding properties of central nicotinic receptors; their functional properties have not been well characterized. Our recent studies have shown that prior nicotine treatment results in a desensitization of nicotine-stimulated dopamine release from striatal synaptosomes. Using the technique of in vitro superfusion, we plan to extend our studies to investigate the effects of intermittent schedules of treatment, temperature dependence and regional differences in nicotine-inducted desensitization of neurotransmitter release. In addition, the effect of the active nicotine metabolite, nornicotine, will be investigated, as will the apparent ability of low concentrations of nicotine to enhance basal neurotransmitter release with prolonged exposure. The ability of nicotine to desensitize receptor in vivo has been suggested as the mechanism by which chronic administration of the drug results in the development of nicotine tolerance and increased nicotinic receptor density. In particular, the concentration of nicotine, brain area affected, and time-course of treatment appear to be important determinants of the drug's effect. In this project we plan to investigate the ability of various nicotine administration protocol to upregulate nicotinic receptors in rat striatum and cerebral cortex. This will be coupled with measurements of plasma and brain levels of nicotine and nornicotine during administration. The overall objective of these studies is to characterize the effects of prior nicotine exposure with respect to desensitization and long-term regulation of central nicotinic receptors. This characterization will increase our understanding of how nicotine influences central neurotransmission and how the responses which it produces are affected by the time course, schedule and duration of its delivery. The processes of receptor desensitization and upregulation could have important implications on cigarette smoking where nicotine is taken at intermittent schedules for long periods of time. A better understanding of the dynamics of nicotine's effects on neurotransmitter systems in the brain is crucial in our attempts to develop successful smoking cessation programs as well as our ability to understand the central reinforcing pathways upon which nicotinic drugs exert their effects.

研究表明，大脑的特殊神经元末端 含有突触前烟碱受体，当受到刺激时，会导致 神经递质的释放。 尼古丁诱导的多巴胺释放 据认为，来自中脑边缘和黑质纹状体系统的末端 产生尼古丁的积极增强特性，负责 吸烟。 尽管已经进行了大量研究 的分子结构、定位和配体结合特性 中枢烟碱受体；它们的功能特性尚未被 特征良好。 我们最近的研究表明，先前的尼古丁治疗会导致 尼古丁刺激纹状体释放多巴胺的脱敏 突触体。 利用体外灌注技术，我们计划 扩展我们的研究以调查间歇性日程安排的影响 治疗、温度依赖性和地区差异 尼古丁诱导的神经递质释放脱敏。 在 此外，活性尼古丁代谢物去甲尼古丁的作用将 进行研究，低浓度的表观能力也将被研究 尼古丁可延长基础神经递质的释放 接触。 尼古丁使体内受体脱敏的能力 被认为是长期给药的机制 药物会导致尼古丁耐受性的发展并增加 烟碱受体密度。 特别是，浓度 尼古丁、受影响的大脑区域和治疗时间似乎是 药物作用的重要决定因素。 在这个项目中我们计划 研究各种尼古丁给药方案的能力 上调大鼠纹状体和大脑皮层的烟碱受体。 这 将结合血浆和大脑尼古丁水平的测量 和给药期间的去甲尼古丁。 这些研究的总体目标是表征 先前接触过尼古丁以进行脱敏和长期治疗 中枢烟碱受体的调节。 这种表征将 增加我们对尼古丁如何影响中枢神经系统的了解 神经传递及其产生的反应如何受到影响 其交付的时间进程、时间表和持续时间。 的过程 受体脱敏和上调可能具有重要意义 间歇性服用尼古丁对吸烟的影响 长时间的日程安排。 更好地理解 尼古丁对大脑神经递质系统影响的动态 对于我们成功戒烟的尝试至关重要 计划以及我们理解核心强化的能力 烟碱类药物发挥作用的途径。