Glutamate Receptors in Excessive Ethanol Drinking

研究表明，长期酒精暴露会增加小鼠和大鼠大脑中NMDA受体和受体亚单位蛋白的水平。海马区NMDA受体的增加可能与乙醇戒断惊厥的发生有关，也可能与认知的改变有关，也可能与乙醇的强化作用有关。在杏仁核，慢性酒精和戒断诱导的NMDA受体功能增强可能与酒精戒断的焦虑效应有关，而证据表明伏隔核NMDA受体功能的改变可能与乙醇强化的变化有关。然而，在慢性酒精暴露和戒断期间，杏仁核和伏隔核中NMDA受体的变化还没有被检测到。此外，很少有人关注乙醇对非NMDA(AMPA)谷氨酸受体的影响。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单位蛋白水平的增加，而且还改变了受体的细胞表面表达和/或细胞定位。我们建议评估NMDA和非NMDA谷氨酸受体的这些适应，遵循产生酒精剥夺效应的慢性乙醇治疗和戒断范例。这种受体变化(例如，与学习、焦虑症或酒精强化有关)可以 在这一模型中观察到的乙醇消耗量增加的原因。利用生化和免疫组织化学技术，在目标1和目标2中，我们将研究由印第安纳动物核心提供的反复饮酒和剥夺循环的P和HAD大鼠脑内谷氨酸受体水平、突触定位和细胞表面表达的适应性。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，其中已有更长时间的酒精剥夺效应的报道。这些研究将允许在目标3中更详细地研究导致与酒精剥夺效应相关的NMDA和/或AMPA受体特性变化的分子机制。

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.