ACTIONS OF ALCOHOL IN PRIMATE CEREBELLUM

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目旨在确定酒精对大脑的急性和长期作用的分子机制。确定酒精的分子靶标对于制定防止滥用酒精的发展战略和设计酒精成瘾治疗方法至关重要。我们将使用从急性制备的小脑切片中的颗粒细胞进行的膜片钳记录来识别急性酒精暴露的分子和细胞反应。具体地说，我们正在测试四种已知与小脑GABA能系统相互作用的分子机制在介导酒精诱导的小脑颗粒细胞GABA能传递增加中的作用。我们还将确定长期自愿饮酒是否会导致小脑GABA能传递的长期分子适应。对长期饮酒的分子适应可能会导致戒断症状，从而导致成瘾。最后，我们将确定小脑颗粒细胞对酒精敏感性的个体差异性是否基于对酒精引起的运动损伤的个体差异性。众所周知，对酒精引起的运动损伤的敏感性是人类酗酒的可遗传预测因素，因此确定其分子基础应该有助于筛查人类酗酒的倾向。拟议中的实验的成功完成将提高我们对酒精分子靶标的理解，并将确定小脑对酒精滥用和成瘾的贡献的分子方面。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project is aimed at determining the molecular mechanisms that mediate acute and long term actions of alcohol on the brain. Identifying the molecular targets of alcohol is fundamental to developing strategies for preventing the development of abusive use of alcohol, and for designing therapies for alcohol addiction. We will use patch-clamp recording from granule cells in acutely prepared slices of cerebellum to identify molecular and cellular responses to acute alcohol exposure. Specifically, we are testing the role of four molecular mechanisms, which are known to interact with the GABAergic system in the cerebellum, in mediating the alcohol-induced increase in cerebellar granule cell GABAergic transmission. We will also determine if chronic, voluntary alcohol consumption leads to long-term molecular adaptations in cerebellar GABAergic transmission. Molecular adaptation to chronic alcohol consumption may contribute to withdrawal symptoms, and hence contribute to addiction. Finally, we will determine if individual variability in cerebellar granule cell sensitivity to alcohol underlies individual variability in sensitivity to alcohol-induced motor impairment. Sensitivity to alcohol-induced motor impairment is known to be a heritable predictor of alcohol abuse in humans, and thus determining its molecular underpinnings should help screen humans for predilection for alcohol abuse. The successful completion of the proposed experiments will improve our understanding of the molecular targets of alcohol, and will identify molecular aspects of cerebellar contribution to alcohol abuse and addiction.