Glutamate Receptors in Excessive Ethanol Drinking

过量饮酒的谷氨酸受体

• 批准号: 6587904
• 负责人: Paula Hoffman
• 金额: $ 26.96万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6587904
• 关键词: AMPA receptors; NMDA receptors; SDS polyacrylamide gel electrophoresis; alcoholic beverage consumption; amygdala; cooperative study; crosslink; ethanol; fluorescence microscopy; hippocampus; immunocytochemistry; laboratory rat; neurons; neuroregulation; nucleus accumbens; receptor expression; synapses; tissue /cell culture; western blottings

Chronic ethanol exposure has been shown to increase NMDA receptors and the levels of receptor subunit proteins in mouse and rat brain. The increase in hippocampal NMDA receptors has been suggested to be related to the occurrence of ethanol withdrawal seizures, and could also be related to changes in cognition, as well as in the reinforcing effects of ethanol. In the amygdala, chronic ethanol and withdrawal-induced increases in NMDA receptor function may be associated with the anxiogenic effect of ethanol withdrawal, while evidence suggests that altered NMDA receptor function in the nucleus accumbens could be associated with changes in ethanol reinforcement. However, changes in NMDA receptors in the amygdala and nucleus accumbens during chronic ethanol exposure and during a period of withdrawal have not been examined. Furthermore, little attention has been given to ethanol-induced alterations in non-NMDA (AMPA) glutamate receptors. Long-term adaptive changes in NMDA and/or non-NMDA glutamate receptors may involve not only increases in receptor subunit protein levels, but also altered cell surface expression and/or cellular localization of the receptors. We propose to assess these adaptations in NMDA and non-NMDA glutamate receptors following the chronic ethanol treatment and withdrawal paradigm that produces the alcohol deprivation effect. Such receptor changes (e.g., associated with learning, anxiogenesis, or ethanol reinforcement) may contribute to the observed increase in ethanol consumption in this model. Using both biochemical and immunohoistochemical techniques, in Aims 1 and 2 we will investigate adaptations in glutamate receptor levels, synaptic localization and cell surface expression in brains from P and HAD rats that have been taken through repeated cycles of alcohol drinking and deprivation, provided by the Indiana Animal Core. As the models are refined, we will also investigate glutamate receptor adaptations in brains of rats provided by The Scripps Clinic, in which a more prolonged alcohol deprivation effect has been reported. These studies will allow a more detailed investigation in Aim 3 of molecular mechanisms leading to changes in NMDA and/or AMPA receptor properties associated with the alcohol deprivation effect.

已显示慢性乙醇暴露会增加NMDA受体和小鼠和大鼠脑中受体亚基蛋白的水平。已经建议海马NMDA受体的增加与乙醇戒断癫痫发作有关，也可能与认知变化以及乙醇的增强作用有关。在杏仁核中，慢性乙醇和戒断诱导的NMDA受体功能的增加可能与乙醇戒断的焦虑生成作用有关，而有证据表明，NMDA受体振容器中NMDA受体功能的改变可能与乙醇增强的变化有关。然而，尚未检查在慢性乙醇暴露期间和戒断期间杏仁核和伏伏核中NMDA受体的变化。此外，很少关注乙醇诱导的非NMDA（AMPA）谷氨酸受体的改变。 NMDA和/或非NMDA的长期自适应变化 谷氨酸受体不仅可能涉及受体亚基蛋白水平的升高，还涉及受体的细胞表面表达和/或细胞定位的改变。我们建议在慢性乙醇处理和戒断范式后，评估NMDA和非NMDA谷氨酸受体的这些适应性，从而产生酒精剥夺效果。这种受体变化（例如，与学习，焦虑生成或乙醇增强有关）可能 在该模型中观察到的乙醇消耗增加。在AIM 1和2中，使用生化和免疫化学技术，我们将研究谷氨酸受体水平的适应性，突触受体定位和P的大脑中的突触性定位和细胞表面表达，并通过反复的饮酒和剥夺的循环吸收了大鼠，由印第安纳动物核心提供。随着模型的完善，我们还将研究Scripps Clinic提供的大鼠大脑中谷氨酸受体适应，其中报道了较长的酒精剥夺效果。这些研究将允许在AIM 3的分子机制中进行更详细的研究，从而导致NMDA和/或AMPA受体特性变化与酒精剥夺效应相关。