Alcohol Modulation of Cerebellar Synaptic Currents

酒精对小脑突触电流的调节

• 批准号: 7046847
• 负责人: WILLIAM R PROCTOR
• 金额: $ 7.38万
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046847
• 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）：科学研究得出结论，自然（遗传学）和后天（环境）都有助于酗酒的发展，酗酒是一种影响美国近1400万人的疾病。医学研究还表明，酗酒父母的后代对酒精的影响不太敏感，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生物标志。寻找基因并确定这些基因如何工作以发展酒精中毒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，开发了对酒精催眠/共济失调作用的高敏感性（LS）和低敏感性（SS）小鼠模型，以促进对预先决定酒精中毒敏感性的基因和脑机制的科学研究。在给定剂量的酒精下，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，这使得这两种品系成为研究酒精在大脑中作用的宝贵工具。饮酒可导致精细运动行为的丧失，这表明酒精在小脑的神经元部位相互作用，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活性与小鼠的平衡丧失相关。由于小脑深核（DCN）神经元是小脑的主要输出通路，我们推测，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，并可能增强抑制性GABA能（GABAA）电流在DCN神经元。这些涉及小脑神经细胞的行为可能导致酒精敏感的ILS小鼠和酒精不敏感的ISS小鼠之间的差异酒精触发的行为障碍。结合我们提出的和正在进行的遗传学研究可能有助于确定更敏感的药物靶点和开发合理治疗酒精中毒的新药。

项目成果

Functional adaptation of the N-methyl-D-aspartate receptor to inhibition by ethanol is modulated by striatal-enriched protein tyrosine phosphatase and p38 mitogen-activated protein kinase.

N-甲基-D-天冬氨酸受体对乙醇抑制的功能适应受到纹状体富集的蛋白酪氨酸磷酸酶和 p38 丝裂原激活蛋白激酶的调节。

• DOI: 10.1124/mol.110.068643
• 发表时间: 2011
• 期刊: Molecular pharmacology
• 影响因子: 3.6
• 作者: Wu,PeterH;Coultrap,StevenJ;Browning,MichaelD;Proctor,WilliamR
• 通讯作者: Proctor,WilliamR