FUNCTIONAL ACTIVITY OF MESOLIMBIC NICOTINIC RECEPTORS

中脑边缘烟碱受体的功能活性

• 批准号: 6175618
• 负责人: PETER P ROWELL
• 金额: $ 9.98万
• 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 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6175618
• 关键词: blood chemistry; brain metabolism; dopamine; drug habituation; drug metabolism; glutamates; laboratory rat; limbic system; microdialysis; neurotransmitter transport; nicotine; nicotinic receptors; nucleus accumbens; receptor sensitivity; reinforcer; rubidium; stimulus /response; tegmentum

Cigarette smoking is a major public health problem in the United States, and nicotine is the principal pharmacological component of tobacco which reinforces smoking behavior. There is compelling evidence that nicotine produces its reinforcing effects by acting on nicotinic cholinergic receptors located on mesolimbic neurons in the brain which release dopamine from terminals of the nucleus accumbens. Studies of nicotinic receptors in other brain areas or in peripheral nerves have shown that, while brief exposure to nicotine produces receptor activation, prolonged exposure to even very low concentrations of nicotine (below the threshold for stimulation) results in receptor desensitization, whereupon subsequent exposure to nicotine does not produce the characteristic functional response. When one considers the blood and brain concentration of nicotine which are present in cigarette smokers throughout the day, it would seem that their receptors should be in a continual state of desensitization. How, then, could nicotine produce any significant reinforcing activity if the receptors upon which it acts have been rendered non-functional? There are a number of possible explanations which will be investigated in the present project. (1) It is possible that the receptors on the mesolimbic neurons do not display the desensitization characteristics determined in previous studies in other tissues and preparations. (2) It is also likely that, even during prolonged desensitization, the nicotine receptors on mesolimbic neurons exhibit sufficient basal or persistent activity to remain functionally responsive to nicotine. (3) There is evidence that glutamate neurons at the somatodendrites or the terminals of mesolimbic neurons can contribute to and perhaps enhance nicotine-stimulated dopamine release. (4) It is possible that the increased number of nicotinic receptors which result from chronic drug administration produces an increased response or that these receptors display different desensitization characteristics. These possibilities will be investigated by measuring the functional activity of mesolimbic receptors in intact slices of the ventral tegmental area and nucleus accumbens from nicotine-treated and nontreated rats. The nicotine-stimulated efflux of rubidium following various nicotine treatment schedules, coupled with assays of nicotine brain levels and receptors, will provide valuable new information about how mesolimbic neurons respond to nicotine. These studies are important as we attempt to understand the mechanisms responsible for cigarette smoking and nicotine dependence, as new nicotine replacement therapies become available for smoking cessation, and as nicotine and nicotine analogs find a place in therapeutics for such diseases as Alzheimer's, Parkinson's, ulcerative cholitis, schizophrenia and others.

吸烟在美国是一个主要的公共健康问题，尼古丁是烟草中加强吸烟行为的主要药理成分。有令人信服的证据表明，尼古丁通过作用于位于大脑中边缘神经元上的尼古丁胆碱能受体产生强化效应，这些受体从伏隔核的末端释放多巴胺。对大脑其他区域或周围神经中尼古丁受体的研究表明，虽然短暂暴露于尼古丁会产生受体激活，但长时间暴露于非常低浓度的尼古丁（低于刺激阈值）会导致受体脱敏，因此随后暴露于尼古丁不会产生典型的功能反应。考虑到吸烟者血液和大脑中的尼古丁浓度，他们的受体似乎处于持续的脱敏状态。那么，如果尼古丁作用的受体已经失去功能，那么尼古丁怎么可能产生任何显著的增强活性呢？有许多可能的解释将在本项目中进行调查。(1)可能中边缘神经元上的受体在其他组织和制剂中没有表现出以往研究中确定的脱敏特性。(2)也有可能，即使在长时间的脱敏过程中，中边缘神经元上的尼古丁受体表现出足够的基础或持续活性，以保持对尼古丁的功能反应。(3)有证据表明，位于躯体树突或中边缘神经元末端的谷氨酸神经元可能有助于并可能增强尼古丁刺激的多巴胺释放。(4)可能是由于长期给药导致尼古丁受体数量增加，导致反应增加，或者这些受体表现出不同的脱敏特性。这些可能性将通过测量尼古丁治疗和未治疗大鼠腹侧被盖区和伏隔核完整切片中边缘受体的功能活性来研究。在不同的尼古丁治疗方案下，尼古丁刺激的铷外排，加上尼古丁脑水平和受体的测定，将提供关于中边缘神经元如何对尼古丁反应的有价值的新信息。这些研究很重要，因为我们试图了解吸烟和尼古丁依赖的机制，因为新的尼古丁替代疗法可以用于戒烟，因为尼古丁和尼古丁类似物在治疗阿尔茨海默氏症、帕金森症、溃疡性胆囊炎、精神分裂症等疾病中找到了一席之地。