SYNAPTIC MECHANISMS OF ACUTE ETHANOL TOLERANCE

某些生物因素可能会增加个体发展的风险 导致酒精滥用或酒精中毒的病理性酒精消耗。 对“风险因素”的定性被认为是 制定有效措施，以确定易受感染的个人， 预防潜在的酒精中毒在这方面，急性耐受性 乙醇可能在心理疾病的发生中起重要作用。 依赖 有人提出，急性耐受烦躁的中枢神经系统， 乙醇的破坏作用间接加强了 药物的影响。目前，对细胞的了解还很少。 对乙醇急性耐受的机制。最近我们 确定了一个潜在的“急性乙醇耐受性”突触模型 其中药物对NMDA介导的树突状EPSP的抑制作用 在大鼠海马脑片的CA1区， 持续乙醇暴露15分钟。这个项目是一个努力 利用体外电生理学方法（细胞外和细胞内 或膜片钳记录）来表征和鉴定细胞 这种快速丧失乙醇抑制的机制。的时间过程 急性耐受的形成和丧失以及对突触的依赖性 涉及神经调质的激活和突触前或突触后可塑性 将被确定。急性耐受发生的可能性 更有效的醇（即，1-丁醇和 异戊醇）或可在其它脑区域中诱导（即，牙科健身房， 新皮层、杏仁核和杏仁核）进行检查。最后 体内乙醇治疗导致急性中毒和 慢性功能性耐受和身体依赖 将评价对乙醇的耐受性。总之，这些研究应该 帮助确定是否失去乙醇对NMDA介导的EPSP的抑制 是一个有用的体外急性耐受模型，应测试 假设“切片中的急性耐受性是由于突触后 阻断乙醇对NMDA抑制作用的机制 受体的"

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."