Alcohol Modulation of Cerebellar Synaptic Currents

酒精对小脑突触电流的调节

• 批准号: 6917519
• 负责人: WILLIAM R PROCTOR
• 金额: $ 7.56万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917519
• 关键词: GABA receptor; NMDA receptors; alcoholic beverage consumption; alcoholism /alcohol abuse; balance; blood tests; cerebellar Purkinje cell; cerebellum; dosage; ethanol; gamma aminobutyrate; genetically modified animals; glutamate receptor; hippocampus; intraperitoneal injections; laboratory mouse; neural degeneration; neural inhibition; neural plasticity; neurotransmitter agonist; physical chemical interaction; psychomotor function; receptor sensitivity; sleep deprivation

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.

描述（由申请人提供）：科学研究得出的结论是，自然（遗传学）和养育（环境）均导致酒精中毒的发展，这种疾病影响了美国近1400万人。医学研究还表明，酗酒父母的后代对酒精的影响不太敏感，并且对酒精中毒的发展风险更高。因此，对酒精的敏感性低可能是酒精中毒的生物标志物。找到基因并确定这些基因如何发育酒精中毒是当今研究的重要焦点。由于人类研究中的方法论和伦理问题，开发了一种高灵敏度（LS）的小鼠模型和对酒精的催眠/产生作用的低灵敏度（SS），以促进对酒精中毒的敏感性的基因和脑机制的科学研究。在给定剂量的酒精时，近交LS小鼠（ILS）的睡眠时间比近交SS小鼠（ISS）长约十倍，这使这两种菌株成为研究大脑中酒精作用的宝贵工具。饮酒的消费会导致精细运动行为的丧失，这表明酒精在小脑中的神经元位点相互作用，在该小脑中破坏了精细的运动控制。证明通过GABA受体抑制Purkinje细胞活性与小鼠的平衡损失相关。由于深脑核（DCN）神经元是小脑的主要输出途径，因此我们假设酒精可能会减少兴奋性谷氨酸能（NMDA和/或AMPA）受体介导的电流，并且可以增强DCN神经元中抑制性GABA>的抑制性GABA抗（GABAAS）水流。这些涉及小脑神经细胞的作用可能导致酒精降低酒精引发了酒精敏感的ILS小鼠与酒精不敏感的ISS小鼠之间的行为障碍。我们提出的遗传研究的结合可能有助于鉴定更敏感的药物靶标，并开发新的药物，以实现酒精中毒的理性治疗方法。