ACTIONS OF ALCOHOL IN PRIMATE CEREBELLUM

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 该项目旨在确定介导酒精对大脑的急性和长期作用的分子机制。确定酒精的分子靶点对于制定预防滥用酒精的发展和设计酒精成瘾治疗方法的策略至关重要。我们将使用膜片钳记录颗粒细胞在急性制备的小脑切片，以确定分子和细胞的反应，急性酒精暴露。具体来说，我们正在测试的作用，这是已知的相互作用与GABA能系统在小脑，在介导酒精诱导的增加小脑颗粒细胞GABA能传输的分子机制。 我们还将确定慢性自愿饮酒是否会导致小脑GABA能传递的长期分子适应。对慢性酒精消耗的分子适应可能有助于戒断症状，从而有助于成瘾。最后，我们将确定小脑颗粒细胞对酒精敏感性的个体差异是否是酒精诱导的运动障碍敏感性的个体差异的基础。对酒精引起的运动障碍的敏感性被认为是人类酒精滥用的遗传预测因子，因此确定其分子基础应该有助于筛选人类对酒精滥用的偏好。拟议实验的成功完成将提高我们对酒精分子靶点的理解，并将确定小脑对酒精滥用和成瘾的分子贡献。

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.