CELLULAR/MOLECULAR MECHANISMS UNDERLYING NEUROADAPTATION TO CHRONIC ALCOHOL

这些关于酒精对中枢神经系统神经元作用的持续研究将 确定长期接触酒精是否会产生长期的适应性 参与兴奋性突触传递的细胞通路的变化。 酒精对突触功能的影响对细胞内 和神经元间的通信将被检查，包括：（a） 由突触输入启动细胞内Ca 2+信号传导，（B）神经类固醇 调节突触传递和长时程增强（LTP），以及 (c)发射机相互作用。这些突触功能将被评估 在三种情况下：（a）对照基线，（B）慢性酒精后 暴露，（c）戒酒一段时间后。的比较 结果将揭示酒精诱导的这些突触的改变， 功能和变化的相对持久性。各种策略 将用于确定酒精的细胞部位和机制 行动上研究的主要递质是谷氨酸， 通过NMDA受体。酒精对阿片受体相关钙离子的作用 还将评估信令。来自两个大脑区域的神经元， 海马体和杏仁核，将被研究。这两个大脑区域都被认为 参与酒精的行为影响。的具体目标 研究内容包括：（1）研究慢性酒精对 由突触输入激活的细胞内Ca2+信号事件， 谷氨酸和阿片受体，并确定慢性酒精是否 诱导受体连接的Ca2+信号通路的长期变化， 在学校禁欲期间保持。(2)以确定是否 兴奋性突触传递和LTP的神经类固醇调节是 酒精治疗模式改变，产生依赖， 动物模型中的禁欲。(3)目的：建立一种鼠体培养模型， 杏仁核神经元用于研究酒精对突触系统的影响 被认为与成瘾行为直接相关。体外培养 和切片制剂将用于这些研究，因为它们提供了 电生理学和显微镜Ca2+的技术优势 使用的成像技术。这些研究的结果将有助于 这对理解神经适应性变化有重要意义， 酒精依赖和戒酒条件下的酒精，并可能 揭示一般原则，这将有助于理解 研究酒精作用的基本神经机制， TSRI-ARC的其他组件。

These continuing studies of alcohol's actions on CNS neurons will determine if chronic exposure to alcohol produces long-lasting adaptive changes in cellular pathways involved in excitatory synaptic transmission. Alcohol's effects on synaptic functions that are critical to intracellular and interneuronal communication will be examined including: (a) intracellular Ca2+ signaling initiated by synaptic input, (b) neurosteroid modulation of synaptic transmission and long-term potentiation (LTP), and (c) transmitter interactions. These synaptic functions will be assessed under three conditions: (a) control baseline, (b) after chronic alcohol exposure and, (c) after a period of alcohol abstinence. A comparison of results will reveal alcohol-induced alterations in these synaptic functions and the relative permanence of the changes. Various strategies will be used to identify the cellular sites and mechanisms of alcohol action. The main transmitter to be studied is glutamate, and its actions via the NMDA receptor. Alcohol's action on opiate receptor-linked Ca2+ signaling will also be assessed. Neurons from two brain regions, the hippocampus and amygdala, will be studied. Both brain regions are known to be involved in the behavioral effects of alcohol. The Specific Aims of the studies are: (1) to investigate effects of chronic alcohol on intracellular Ca2+ signaling events activated by synaptic input and linked to glutamate and opiate receptors, and to determine if chronic alcohol induces long-term changes in receptor-linked Ca2+ signaling pathways that are maintained during abstinence from school. (2) To determine if neurosteroid modulation of excitatory synaptic transmission and LTP is altered by alcohol treatment paradigms that produce dependence and abstinence in animal models. (3) To establish a rodent culture model of amygdala neurons for studies of alcohol's effects on synaptic systems thought to be directly involved in addictive behavior. In vitro culture and slice preparations will be used for these studies because they offer technical advantages for the electrophysiological and microscopic Ca2+ imaging techniques to be used. Results from these studies will contribute significantly to an understanding of the neuroadaptive changes induced by alcohol under conditions of alcohol dependence and abstinence, and may reveal general principles that will contribute to an understanding of the basic neuronal mechanisms underlying alcohol's actions being studied in other components of the TSRI-ARC.