Alcohol Modulation of Cerebellar Synaptic Currents

描述(由申请人提供)：科学研究得出结论，先天(遗传)和后天(环境)都有助于酒精中毒的发展，这是一种在美国影响近1400万人的疾病。医学研究还表明，酗酒父母的子女对酒精的影响不那么敏感，患酒精中毒的风险更高。因此，对酒精的低敏感性可能是酒精中毒的一个生物学标志。寻找基因并确定这些基因是如何导致酒精中毒的，是当今研究的重要焦点。由于人类研究中的方法学和伦理学问题，建立了对酒精的催眠/共济失调效应具有高敏感性(LS)和低敏感性(SS)的小鼠模型，以促进对预先确定酒精中毒敏感性的基因和脑机制的科学研究。在给定的酒精剂量下，近交系LS小鼠(ILS)的睡眠时间大约是近交系SS小鼠(ISS)的十倍，这使得这两个品系成为研究酒精在大脑中作用的宝贵工具。饮酒会导致精细运动行为的丧失，这表明酒精与小脑中的神经元相互作用，在那里精细运动控制被破坏。酒精通过GABA受体抑制浦肯野细胞的活性与小鼠的平衡失调有关。由于小脑深部核(DCN)神经元是小脑的主要输出通路，我们推测酒精可降低兴奋性谷氨酸(NMDA)和/或AMPA受体介导的电流，并可能增强DCN神经元的抑制性GABA能(GABAA)电流。这些涉及小脑神经细胞的活动可能导致酒精敏感的ILS小鼠和酒精不敏感的ISS小鼠之间的不同酒精引发的行为障碍。我们建议的和正在进行的基因研究相结合，可能有助于识别更敏感的药物靶点，并开发用于合理治疗酒精中毒的新药。

DESCRIPTION (provided by applicant): Scientific research has concluded that both nature (genetics) and nurture (environment) contribute to the development of alcoholism, a disease that affects nearly 14 million people in the United States. Medical studies have also shown that the offspring of alcoholic parents are less sensitive to the effects of alcohol and are at higher risk for the development of alcoholism. Thus, low sensitivity to alcohol may be a biological marker for alcoholism. Finding genes and determining how these genes work to develop alcoholism are important foci of research today. Because of methodological and ethical issues in human studies, a mouse model of high sensitivity (LS) and low sensitivity (SS) to the hypnotic/ataxic effect of alcohol was developed to facilitate the scientific research of genes and brain mechanisms that pre-determine the sensitivity of alcohol intoxication. At a given dose of alcohol, inbred LS mice (ILS) sleep about ten times longer than inbred SS mice (ISS), which makes these two strains valuable tools for studying the alcohol actions in the brain. Consumption of alcohol can cause the loss of fine motor behavior, suggesting that alcohol interacts at neuronal sites in the cerebellum where fine motor control is disrupted. Alcohol inhibition of Purkinje cell activity via GABA receptors was shown to correlate with loss of balance in mice. Since the deep cerebellar nuclei (DCN) neurons are the major output pathway from the cerebellum, we postulate that alcohol may reduce excitatory glutamatergic (NMDA and/or AMPA) receptor-mediated currents, and may enhance inhibitory GABAergic (GABAA) currents in DCN neurons. These actions involving nerve cells in the cerebellum may contribute to the differential alcohol triggered behavioral impairments between alcohol sensitive ILS mice and alcohol insensitive ISS mice. The combination of our proposed and ongoing genetic studies may aid the identification of more sensitive drug targets and the development of novel drugs for rational therapeutic approaches to alcoholism.