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.

长期接触乙醇已被证明会增加小鼠和大鼠大脑中的 NMDA 受体和受体亚基蛋白的水平。海马 NMDA 受体的增加被认为与乙醇戒断性癫痫发作的发生有关，也可能与认知的变化以及乙醇的强化作用有关。在杏仁核中，慢性乙醇和戒断引起的 NMDA 受体功能增加可能与乙醇戒断的焦虑作用有关，而证据表明伏核中 NMDA 受体功能的改变可能与乙醇强化的变化有关。然而，慢性乙醇暴露期间和戒断期间杏仁核和伏核中 NMDA 受体的变化尚未得到研究。此外，很少有人关注乙醇诱导的非 NMDA (AMPA) 谷氨酸受体的改变。 NMDA 和/或非 NMDA 的长期适应性变化 谷氨酸受体可能不仅涉及受体亚基蛋白水平的增加，还涉及受体的细胞表面表达和/或细胞定位的改变。我们建议在产生酒精剥夺效应的长期乙醇治疗和戒断范例之后评估 NMDA 和非 NMDA 谷氨酸受体的这些适应性。这种受体变化（例如，与学习、焦虑发生或乙醇强化相关）可能 导致该模型中观察到的乙醇消耗增加。在目标 1 和 2 中，我们将使用生化和免疫组织化学技术研究 P 和 HAD 大鼠大脑中谷氨酸受体水平、突触定位和细胞表面表达的适应性，这些大鼠经过反复饮酒和剥夺的循环，由印第安纳动物核心。随着模型的完善，我们还将研究斯克里普斯诊所提供的大鼠大脑中谷氨酸受体的适应情况，其中据报道，戒酒效果会更长。这些研究将允许在目标 3 中更详细地研究导致与戒酒效应相关的 NMDA 和/或 AMPA 受体特性变化的分子机制。