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）都是导致酗酒的原因，这种疾病影响着美国近1400万人。医学研究也表明，酗酒父母的后代对酒精的影响不太敏感，而且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生物学标志。寻找基因并确定这些基因如何导致酒精中毒是当今研究的重要焦点。由于人类研究的方法和伦理问题，建立了酒精催眠/失调性作用的高敏感性（LS）和低敏感性（SS）小鼠模型，以促进对酒精中毒敏感性的基因和大脑机制的科学研究。在一定剂量的酒精下，近亲繁殖的LS小鼠（ILS）的睡眠时间大约是近亲繁殖的SS小鼠（ISS）的10倍，这使得这两个品系成为研究酒精在大脑中的作用的有价值的工具。饮酒会导致精细运动行为的丧失，这表明酒精与小脑中精细运动控制被破坏的神经元部位相互作用。酒精通过GABA受体抑制浦肯野细胞活性与小鼠失去平衡有关。由于小脑深部核（DCN）神经元是小脑的主要输出通路，我们假设酒精可能会降低兴奋性谷氨酸能（NMDA和/或AMPA）受体介导的电流，并可能增强DCN神经元中的抑制性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小鼠之间酒精引发的不同行为障碍。我们提出的和正在进行的基因研究的结合可能有助于确定更敏感的药物靶点和开发用于酒精中毒合理治疗方法的新型药物。

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.