Glutamate Receptors in Excessive Ethanol Drinking

慢性乙醇暴露已被证明可以增加小鼠和大鼠脑中NMDA受体和受体亚基蛋白的水平。海马NMDA受体的增加已被认为与乙醇戒断性癫痫发作的发生有关，也可能与认知的改变以及乙醇的强化作用有关。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，杏仁核和伏隔核中NMDA受体在慢性乙醇暴露和戒断期间的变化尚未被研究。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

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.