Ethanol Effects in the Mammalian Circadian Clock

描述(申请人提供)：拟议的实验研究乙醇对位于视交叉上核(SCN)的哺乳动物生物钟的影响。酗酒和戒酒对昼夜节律和睡眠都有影响。这两种现象可能是相互关联的，因为昼夜节律功能的中断是许多睡眠不规律的主要原因。由于睡眠问题既与酒精中毒的发展有关，也与戒酒过程中复发的可能性有关，因此更好地了解导致这些睡眠问题的神经过程是很重要的。乙醇的已知细胞靶标包括谷氨酸N-甲基-D-天冬氨酸(NMDA)受体。S。激活脊髓核内的N-甲基-D-天冬氨酸受体是生物钟与环境正确同步的必要条件。我们的初步数据显示，急性乙醇三醇组阻断了谷氨酸对SCN生物钟的刺激。我们建议通过追求以下特定目标来跟进这些初步实验：目的1：急性或慢性乙醇处理是否会影响体内的光相移？我们的初步数据涉及体外制剂，确定乙醇是否在体内具有类似的作用是很重要的。此外，考虑到急性和慢性乙醇暴露的许多差异，我们还将调查慢性乙醇治疗总体上如何影响昼夜节律，特别是光相移。目的2：体外急性乙醇处理是否通过直接或间接作用于谷氨酸能NMc NMDA受体来阻断谷氨酸诱导的相移？这些实验将研究乙醇抑制谷氨酸对生物钟相移效应的机制。在这个初始阶段，我们的目标是3：急性乙醇治疗是否会影响体外的非光性相移？虽然乙醇的许多作用似乎集中在NM周围的NMDA受体，但其他DA神经递质，如5-羟色胺，也受到酒精的影响。因此，我们将研究急性乙醇是否会改变由神经递质5-羟色胺诱导的体外相移。未来方向：这些研究的结果将为更广泛地研究急性和慢性乙醇以及乙醇戒断对哺乳动物生物钟的影响提供基础。

DESCRIPTION (provided by applicant): The proposed experiments investigate the effects of ethanol on the mammalian circadian clock located in the suprachiasmatic nucleus (SCN). Alcohol abuse and withdrawal have pro profo found und effects on circadian rhythms and sleep. These two phenomena are likely interrelated, since disruptions in circadian functioning are a major cause of many sleep irregularities. Since sleep problems have been linked to both the development of alcoholism and the likelihood of relapse in recovering alcoholics, it is important to better understand the neural processes that contribute to these sleep problems. Known cellular targets of ethanol include glutamate N-methyl-D-aspartate (NMDA) receptor receptors. s. NMDA receptor activation in the SCN is necessary for the circadian clock to properly synchronize to the environment. Our preliminary data show that acute eth ethanol tre anol treatment blocks glutamate stimulation of the SCN circadian clock. We propose to follow up thes these preliminary experiments by pursuing the following specific aims: AIM 1: Does acute or chronic ethanol treatment affect photic phase shifts in vivo? Our preliminary data involve an in vitro preparation, and it is important to determine wheth whether ethanol has similar effects in vivo. Furthermore, given the many differences in acute vs. chronic ethanol exposure, we will also investigate how chronic ethanol treatment affects circadian rhythms in general, and photic phase shifting in particular. AIM 2: Does acute ethanol treatment in vitro block glutamate-induced phase shifts through direct or indirect actions on glutamatergic NM c NMDA receptors? These experiments will DA in investigate vestigate the mechanisms through which ethanol inhibits the phase-shifting effects of glutamate on the circadian clock. In this initial stage we AIM 3: Does acute ethanol treatment affect non-photic phase shifts in vitro? While many of ethanol's effects appear to center a around NM round NMDA receptors, other DA neuroturotransmitters, such as serotonin, are also affected by alcohol. Thus, we will investi investigate gate whether acute ethanol alters in vitro phase shifts induced by the neurotransmitter, serotonin. Future Directions: The results of these studies will provide the basis of a more extensive investigation into the effects of acute and chronic ethanol, and ethanol withdrawal, on the mammalian circadian clock.