Ethanol Modulation of Glycine Receptor Mediated Currents in the Striatum

乙醇调节纹状体甘氨酸受体介导的电流

• 批准号: 8844190
• 负责人: Lindsay M. McCracken
• 金额: $ 1.75万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8844190
• 关键词: Ethanol; Modulation; Glycine; Receptor; Mediated

DESCRIPTION (provided by applicant): Alcoholism is a chronic, cureless, and relapsing condition. Currently, the mechanisms by which alcohol exerts its intoxicating and reinforcing effects are not completely understood, but the development of alcohol seeking, dependence, withdrawal, and even acute intoxication involve, at least in part, the actions of alcohol on neural circuits involving the striatum. In addition, the actions of ethanol on a number of ion channels in the CNS have been established. Strychnine-sensitive glycine receptors (GlyRs) are among such targets of alcohol, and recent evidence demonstrates that GlyRs are expressed in forebrain regions including the striatum. Behavioral pharmacology studies suggest that GlyRs, specifically in the nucleus accumbens, are involved in alcohol consumption. However, the physiology of these particular GlyRs is not well defined, and the effects of ethanol action on native GlyRs in the striatum are not known. This project will specifically investigate GlyR physiology and ethanol pharmacology in the striatum using slice electrophysiology and molecular biology techniques. Our preliminary data suggest the presence of exogenously and tonically activated GlyR currents in the ventral striatum. Aim 1 will characterize GlyR mediated currents and ethanol modulation of GlyR function in the striatum (dorsal and ventral) to test the hypothesis that GlyRs are important mediators of neuronal excitability and that ethanol action at GlyRs may alter striatal neuron activity. Aim 2 will determine which GlyR ¿ subunits are involved in ethanol modulation of striatal GlyR currents using GlyR ¿ subunit knock-out (KO) mice to test the hypothesis that GlyRs containing ¿2 and/or ¿3 subunits may be particularly important for mediating the effects of striatal GlyR activation and ethanol modulation of GlyR function. Overall, findings from these experiments will provide novel insights into the effects of GlyR activation on neuronal excitabilit in the striatum and will contribute to a better understanding of how ethanol modulates striatal activity. Ultimately, by improving our knowledge of the mechanisms by which alcohol exerts its effects, new pharmacotherapies and enhanced treatment options can be developed for the treatment of alcoholism.

描述（由申请人提供）：酒精中毒是一种慢性，不可治愈，复发性疾病。目前，酒精发挥其致醉和强化作用的机制尚不完全清楚，但酒精寻求、依赖、戒断甚至急性中毒的发展至少部分涉及酒精对神经系统的作用。 涉及纹状体的回路此外，乙醇对一些离子通道的作用， CNS已经建立。士的宁敏感的甘氨酸受体（GlyR）是酒精的目标之一，最近的证据表明，GlyR在前脑区域，包括纹状体表达。行为药理学研究表明，GlyR，特别是在神经核中，参与酒精消费。然而，这些特定的GlyR的生理学还没有很好地定义，乙醇作用对纹状体中天然GlyR的影响尚不清楚。本计画将利用切片电生理学与分子生物学技术，特别探讨纹状体内甘氨酰受体的生理学与乙醇药理学。我们的初步数据表明，存在外源性和紧张性激活的GlyR电流在腹侧纹状体。目的1将表征GlyR介导的电流和乙醇调制的GlyR功能在纹状体（背侧和腹侧），以测试假设GlyR是神经元兴奋性的重要介质，乙醇作用于GlyR可能会改变纹状体神经元的活动。目的2将使用GlyR <$亚基敲除（KO）小鼠来确定哪些GlyR <$亚基参与纹状体GlyR电流的乙醇调节，以测试含有<$2和/或<$3亚基的GlyR可能对于介导纹状体GlyR激活和GlyR功能的乙醇调节的作用特别重要的假设。总的来说，这些实验的结果将提供新的见解GlyR激活对纹状体神经元兴奋性的影响，并将有助于更好地了解乙醇如何调节纹状体活动。最终，通过提高我们对酒精发挥作用的机制的认识，可以开发新的药物疗法和增强的治疗方案来治疗酒精中毒。