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Cellular Mechanisms Mediating the Somnogenic Effects of Ethanol

介导乙醇催眠作用的细胞机制

基本信息

批准号：
7933557
负责人：
MAHESH M THAKKAR
金额：
$ 18.64万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2012-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Considerable evidence exists to suggest that ethanol consumption has significant impact on nocturnal sleep and daytime alertness in humans. While low to moderate intake of ethanol in non-alcoholics improves sleep, high doses of ethanol intake produces severe sleep disruptions. Alcoholics, both during drinking period as well as during withdrawal suffer from a multitude of sleep disturbances including difficulty in initiating and maintaining sleep during the night. The broad objective of this program of research is to understand the cellular and molecular mechanisms mediating the somnogenic effects of ethanol and thereby provide a sound basis to the understanding and treatment of ethanol related sleep disorder. The key techniques to be used are novel combinations of multi-disciplinary methods including the: A) in vivo "on-line" microdialysis sampling coupled with HPLC measurement of adenosine and electrographic monitoring of sleep-wakefulness following ethanol administration. B) In vivo "off line" c-Fos immunohistochemistry to determine the neuronal phenotypes mediating the somnogenic effects of ETOH. Our broad hypothesis is that adenosine via A1 receptor is responsible for mediating the somnogenic effects of ethanol. We predict that acute ethanol administration will increase extracellular levels of adenosine in the cholinergic basal forebrain. Increased adenosine, acting via adenosine A1 receptor, will inhibit the wake-promoting cholinergic neurons of the basal forebrain as evidenced by a reduction in number of cholinergic neurons with c-Fos immunoreactivity. Furthermore, blockade of adenosine transmission by local infusion of adenosine A1 receptors antagonist into the basal forebrain will attenuate the somnogenic effects of ethanol. . PUBLIC HEALTH RELEVANCE: The broad objective of this research program is to understand the cellular and molecular mechanisms responsible for the somnogenic effects of ethanol and thereby to provide a sound basis for the understanding and treatment of sleep disorder associated with ethanol.

描述(由申请人提供)：有相当多的证据表明，酒精消费对人类的夜间睡眠和白天的警觉性有重大影响。虽然非酒精者摄入低到中等剂量的乙醇可以改善睡眠，但高剂量的乙醇摄入会导致严重的睡眠中断。酗酒者在饮酒期间和戒酒期间都会受到多种睡眠障碍的困扰，包括在夜间难以入睡和维持睡眠。本研究的主要目的是了解乙醇催眠的细胞和分子机制，从而为了解和治疗酒精相关的睡眠障碍提供良好的基础。将使用的关键技术是多学科方法的新组合，包括：a)活体“在线”微透析采样与腺苷的高效液相测定相结合，以及乙醇给药后睡眠觉醒的电子图像学监测。B)体内“离线”c-Fos免疫组织化学，以确定介导乙醇催眠效应的神经元表型。我们的广泛假设是，腺苷通过A1受体负责调节乙醇的催眠效应。我们预测，急性酒精注射将增加胆碱能基底前脑细胞外腺苷的水平。通过腺苷A1受体作用的腺苷增加，将抑制基底前脑中促进觉醒的胆碱能神经元，这从具有c-Fos免疫反应的胆碱能神经元的数量减少可见一斑。此外，在基底前脑局部注入腺苷A1受体拮抗剂阻断腺苷传递将减弱乙醇的催眠效应。。公共卫生相关性：这项研究计划的广泛目标是了解乙醇催眠效应的细胞和分子机制，从而为理解和治疗与酒精相关的睡眠障碍提供可靠的基础。