SYNAPTIC MECHANISMS OF ACUTE ETHANOL TOLERANCE

某些生物因素可能会增加个体发育的风险 病理性饮酒导致酗酒或酗酒。 对“风险因素”的定性被认为是 制定有效措施，以确定易感人群和 防止潜在的酒精病理。在这方面，对 酒精可能在心理疾病的发生中起重要作用 依赖。已有研究提出对焦虑性中枢神经系统的急性耐受 乙醇的损伤作用间接加强了这种增强作用 药物的作用。目前，人们对细胞的了解很少。 急性乙醇耐受的潜在机制。最近，我们有 发现一种潜在的“急性酒精耐受”突触模型 药物对NMDA介导的树突状EPSP的抑制作用 在大鼠海马片的CA1区， 作为持续15分钟的酒精暴露。这个项目是一项努力 利用体外电生理方法(细胞外和细胞内 或膜片钳记录)来表征和识别细胞 酒精抑制作用迅速消失的机制。的时间进程 急性耐受的形成和丧失及其对突触的依赖 涉及神经调节剂的激活和突触前或突触后可塑性 将会被确定。急性耐受发生的可能性 更强的醇(如正丁醇和正丁醇)的抑制作用 异戊醇)或可在其他大脑区域(即，齿状回， 将检查新皮质、伏隔核和杏仁核)。最后， 体内乙醇处理对急性中毒和急性酒精中毒的影响 慢性功能耐受性和身体依赖的体外急性 将评估对乙醇的耐受性。总而言之，这些研究应该 帮助确定酒精丢失是否抑制NMDA介导的EPSPS 是一个有用的急性耐受的体外模型，应该测试 “脑片急性耐受是由于突触后形成的”假说 阻断乙醇抑制NMDA作用的机制 接收器。“

Certain biological factors may increase risk individual for developing pathological alcohol consumption leading to alcohol abuse or alcoholism. Characterization of "risk factors" is considered an important step in designing effective measures to identify susceptible individuals and prevent potential alcohol pathology. In this regard, acute tolerance to ethanol may play an important role in the genesis of psychological dependence. It has been proposed that acute tolerance to dysphoric CNS impairing actions of ethanol indirectly strengthens the reinforcing effects of the drug. At present, very little is known about the cellular mechanisms underlying acute tolerance to ethanol. Recently, we have identified a potential synaptic model of "acute tolerance to ethanol" where the inhibitory action of the drug on NMDA-mediated dendritic EPSPs in the CA1 region of rat hippocampal slices is swiftly lost over as little as 15 min of continuing ethanol exposure. This project is an effort utilizing in vitro electrophysiological methods (extra- and intracellular or patch clamp recordings) to characterize and identify cellular mechanisms of this swift loss of ethanol inhibition. The time course of acute tolerance development and loss as well as its dependence on synaptic activation and pre- or postsynaptic plasticity involving neuromodulators will be determined. The likelihood that acute tolerance occurs to inhibitory effects of more potent alcohols (ie., 1-butanol and isopentanol) or can be induced in other brain regions (ie., dentate gyms, neocortex, nucleus accumbens and amygdala) will be examined. Finally, the impact of in vivo ethanol treatment leading to both acute intoxication and chronic functional tolerance and physical dependence on in vitro acute tolerance to ethanol will be evaluated. Together, these studies should help determine whether loss of ethanol inhibition of NMDA-mediated EPSPs is a useful in vitro model of acute tolerance and should test the hypothesis that "acute tolerance in the slice develops due to postsynaptic mechanisms that block the inhibitory effects of ethanol on the NMDA receptor."