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）：该提案的实验将检验以下假设：橄榄球系统中异常高水平的复杂尖峰（CS）同步和节奏性是在戒酒过程中观察到的震颤的基础。该假设是由一系列发现的动机。通常同步时CS活性与协调运动有关，但是当超同步会引起震颤。这些震颤与撤回震颤的相似之处，可以被乙醇拮抗。此外，乙醇会急性和慢性地影响橄榄球的发射速率，我们的初步数据表明急性乙醇可以抑制CS同步。这些发现符合这样一个普遍的观念，即乙醇急性作用可通过减少NMDA介导的活性和/或GABA-A介导的活性的增加来降低大脑活性，并且随着乙醇暴露的延长，补偿性降低和加强，GABA-A和NMDA功能的调节也会出现。尤其是在下橄榄（IO）中，GABA-A活性的丧失会导致过度同步CS活性和震颤。因此，我们提出了这样一个假设，即在戒断过程中，在IO中发挥异常的神经递质会导致过度同步的CS活性，从而导致震颤。该提案与检验该假设有关。第一个目的集中在撤回过程中使用CS活性的多个电极记录，以确定撤回期间CS同步和节奏性的模式，并将这些模式与震颤特征相关联。第二个目标是建立橄榄球活动与震颤特征之间的因果关系。为此，橄榄球活动的特征将在药理学上使用直接的显微注射在IO中进行药理学操纵，而EMG记录则是震颤记录的，以评估肌肉活动模式的结果变化。希望通过使用震颤作为一种工具来证明橄榄球系统是酒精引起运动异常的地点，这些初步研究的结果将为未来研究酒精对橄榄球活动的作用的研究奠定基础，至少在某种程度上，酒精对运动均衡的损害对运动均衡作用是否影响。拟议的实验将提供有关大脑活动的特定变化的信息，这些变化是戒烟震颤的基础，这可能有助于设计新的，更成功的治疗方法，不仅用于戒断症状，​​而且还有助于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，将橄榄球系统作为酒精作用的目标的演示应提高我们对酒精如何影响运动协调的理解。据估计，有1760万成年人是酗酒者或酗酒的风险，酗酒显然是美国的主要健康问题。此外，随着运动协调受损的一个主要原因是酒精是交通事故和死亡的一个因素，了解酒精对运动系统的行为显然具有医学意义。