Abnormal Olivocerebellar Synchrony: A Possible Cause of Alcohol Withdrawal Tremor

橄榄小脑同步异常：酒精戒断性震颤的可能原因

• 批准号: 7471667
• 负责人: ERIC J LANG
• 金额: $ 19.45万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7471667
• 关键词: Acute; Adult; Affect; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Blood alcohol level measurement; Brain; Cessation of life; Characteristics; Chronic; Complex; Data; Depressed mood; Electrodes; Electromyography; Ethanol; Figs - dietary; Fire - disasters; Future; Health; Inferior; Investigation; Ketamine; Link; Mediating; Medical; Microinjections; Motor; Movement; Muscle; N-Methylaspartate; Neurotransmitters; Olives - dietary; Pattern; Periodicity; Process; Rate; Risk; Series; Site; System; Testing; Traffic accidents; Transcriptional Activation; Tremor; United States; Up-Regulation; Withdrawal; Withdrawal Symptom; Xylazine; alcohol exposure; base; chronic alcohol ingestion; design; problem drinker; research study; tool

DESCRIPTION (provided by applicant): The experiments of this proposal will test the hypothesis that abnormally high levels of complex spike (CS) synchrony and rhythmicity in the olivocerebellar system underlie the tremor observed during alcohol withdrawal. This hypothesis is motivated by a series of findings. CS activity when normally synchronized is associated with coordinated movement, but when hypersynchronized causes tremors. These tremors show similarities to withdrawal tremor and can be antagonized by ethanol. Moreover, ethanol affects olivocerebellar firing rates, acutely and chronically, and our preliminary data suggests that acutely ethanol acts to suppress CS synchrony. These findings are in line with the general idea that ethanol acutely acts to depress brain activity in large part via a reduction of NMDA-mediated activity and/or an increase in GABA-A-mediated activity, and that with prolonged ethanol exposure, compensatory down and up regulation of GABA-A and NMDA functioning, respectively, occurs. Loss of GABA-A activity, in particular, in the inferior olive (IO), leads to hypersynchronized CS activity and tremor. Thus, we are led to the hypothesis that during withdrawal, abnormal neurotransmitter functioning in the IO leads to hypersynchronized CS activity that in turn causes tremor. There are two specific aims in this proposal related to testing this hypothesis. The first aim centers on using multiple electrode recording of CS activity during the withdrawal process to determine the patterns of CS synchrony and rhythmicity during withdrawal, and to correlate these patterns with the tremor characteristics. The second aim centers on establishing a causal link between olivocerebellar activity and the tremor's characteristics. To this end the characteristics of olivocerebellar activity will be pharmacologically manipulated using direct microinjections into the IO while EMG recordings are being made of the tremor in order to assess the resulting changes in muscle activity patterns. It is hoped that by using tremor as a tool for demonstrating that the olivocerebellar system is a site at which alcohol acts to cause movement abnormalities, the results of these initial studies will form a basis for future investigations into whether alcohol's action on olivocerebellar activity underlies, at least in part, alcohol's disruptive effects on motor coordination. The proposed experiments will provide information on the specific changes in brain activity that underlie alcohol withdrawal tremor, which may aid in designing new and more successful treatments not only for withdrawal symptoms, but for the motor coordination problems associated with acute and chronic alcohol use and abuse. In particular, demonstration of the olivocerebellar system as a target of alcohol's actions should increase our understanding of how alcohol affects motor coordination. With an estimated 17.6 million adults being either alcoholics or alcohol abusers with an increased risk of becoming alcoholics, alcoholism is clearly a major health problem in the United States. Moreover, with impaired motor coordination a major reason for alcohol being a factor in traffic accidents and deaths, understanding alcohol's actions on motor systems is of obvious medical significance.

描述（由申请人提供）：本提案的实验将检验以下假设：橄榄小脑系统中异常高水平的复杂尖峰（CS）同步性和节律性是酒精戒断期间观察到的震颤的基础。这一假设是由一系列发现引发的。正常同步时的 CS 活动与协调运动相关，但过度同步时会导致颤抖。这些震颤与戒断性震颤相似，可以被乙醇拮抗。此外，乙醇会急性和慢性影响橄榄小脑放电率，我们的初步数据表明乙醇会急性抑制 CS 同步性。这些发现与一般观点一致，即乙醇在很大程度上通过减少 NMDA 介导的活性和/或增加 GABA-A 介导的活性来急剧抑制大脑活动，并且随着长时间的乙醇暴露，代偿性下降GABA-A 和 NMDA 功能分别发生上调。 GABA-A 活性的丧失，尤其是下橄榄 (IO) 中的 GABA-A 活性的丧失，会导致 CS 活性过度同步和震颤。因此，我们得出这样的假设：在戒断过程中，IO 中异常的神经递质功能会导致 CS 活动过度同步，从而导致震颤。该提案中有两个与检验该假设相关的具体目标。第一个目标集中于在撤回过程中使用多电极记录 CS 活动来确定撤回过程中 CS 同步性和节律性的模式，并将这些模式与震颤特征相关联。第二个目标集中于建立橄榄小脑活动与震颤特征之间的因果关系。为此，将通过直接显微注射到 IO 中来对橄榄小脑活动的特征进行药理学操作，同时对震颤进行肌电图记录，以评估肌肉活动模式的变化。希望通过使用震颤作为工具来证明橄榄小脑系统是酒精作用导致运动异常的部位，这些初步研究的结果将为未来研究酒精对橄榄小脑活动是否起作用提供基础。至少部分是酒精对运动协调性的破坏性影响。拟议的实验将提供有关酒精戒断性震颤背后的大脑活动具体变化的信息，这可能有助于设计新的、更成功的治疗方法，不仅可以治疗戒断症状，​​还可以治疗与急性和慢性酒精使用和滥用相关的运动协调问题。特别是，证明橄榄小脑系统作为酒精作用的目标应该会增加我们对酒精如何影响运动协调的理解。据估计，有 1,760 万成年人酗酒或酗酒，并且酗酒的风险增加，酗酒显然是美国的一个主要健康问题。此外，由于运动协调受损是酒精导致交通事故和死亡的主要原因，因此了解酒精对运动系统的作用具有明显的医学意义。