Ethanol Modulation of Glycine Receptor Mediated Currents in the Striatum

描述(申请人提供)：酒精中毒是一种慢性、不可治愈和反复发作的疾病。目前，酒精发挥醉人和强化作用的机制尚不完全清楚，但酒精寻求、依赖、戒断甚至急性醉酒的发展至少部分涉及酒精对神经的作用。 牵涉到纹状体的回路。此外，乙醇对体内多个离子通道的作用 已经建立了CNS。士的宁敏感的甘氨酸受体(GlyRs)是酒精的目标之一，最近的证据表明GlyRs在包括纹状体在内的前脑区域表达。行为药理学研究表明，GlyRs，特别是伏隔核中的GlyRs，与饮酒有关。然而，这些特殊的GlyRs的生理机制还不是很清楚，乙醇对纹状体中天然GlyRs的影响也不清楚。本项目将使用切片电生理学和分子生物学技术专门研究纹状体中的GlyR生理学和乙醇药理学。我们的初步数据表明，腹侧纹状体存在外源性和强直激活的GlyR电流。目的1研究GlyR介导的电流和乙醇对纹状体(背侧和腹侧)GlyR功能的调节作用，以验证GlyR是神经元兴奋性的重要介质以及乙醇对GlyR的作用可能改变纹状体神经元活动的假说。目的2利用GlyR？亚基敲除(KO)小鼠，确定哪些GlyR？亚基参与乙醇对纹状体GlyR电流的调节，以验证含有？2和/或？3亚基的GlyR可能在介导纹状体GlyR激活和乙醇调节GlyR功能的效应中特别重要的假说。总体而言，这些实验的发现将为GlyR激活对纹状体神经元兴奋性的影响提供新的见解，并有助于更好地理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了解，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。

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.