CHRONIC EFFECTS OF ETHANOL ON NEURAL CELLS IN CULTURE

腺苷是脑内的一种全局抑制性神经调质， 介导许多对乙醇的急性和慢性CNS反应。 我们已经展示了在 培养的细胞系，乙醇增加细胞外腺苷 导致cAMP信号转导的异源脱敏。 这种脱敏作用可被腺苷受体拮抗剂阻断。 腺苷A1受体在脑中可能比A2受体更丰富， 乙醇诱导的细胞外腺苷增加应该激活 受体。 A1受体抑制cAMP的产生，而A2受体 激活腺苷酸环化酶。 因此，细胞对乙醇的反应 应部分由A1和A2的相对表达式确定 受体。 A1受体在小脑中大量表达， 海马体，乙醇在人脑中的主要目标。 增加A1 在这些区域中A2受体的一般背景上的受体可能是 与酒精中毒和对学习和记忆的影响有关。 我们 将确定腺苷A1受体在调节慢性 乙醇对NG 108 -15细胞cAMP信号转导的影响 表达A1和A2受体。 我们还将确定 的A1受体是由于乙醇调节蛋白激酶活性。 腺苷A2受体，激活腺苷酸环化酶，调节细胞的增殖。 多巴胺D2受体在纹状体的同一细胞中的反应， 类似的变化可能发生在与乙醇有关的丘脑核中， 强化行为，以及其他区域。 为了理解 腺苷A_2受体和多巴胺D_2受体介导慢性脑缺血 乙醇的影响，多巴胺D2受体将在NG 108 -15中表达 细胞，我们将确定急性和慢性暴露于乙醇是否 改变多巴胺D2受体信号传导，以及这是否由 腺苷A2受体。 在NG 108 -15细胞中已经确定了病理生理机制。 这些 稳定的神经元模型将用于了解乙醇如何改变D2 受体信号传导，并确定乙醇诱导的 细胞外腺苷调节更复杂的受体反应。 这些 研究可能导致新的治疗药物的开发，以防止 酒精中毒的一些病理生理效应

Adenosine is a global inhibitory neuromodulator in brain and appears to mediate many acute and chronic CNS responses to ethanol. We have shown in cultured cell lines that ethanol increases extracellular adenosine resulting in a heterologous desensitization of cAMP signal transduction. This desensitization is blocked by an adenosine receptor antagonist. Adenosine A1 receptors may be more abundant in brain than A2 receptors and ethanol-induced increases in extracellular adenosine should activate both receptors. A1 receptors inhibit cAMP production whereas A2 receptors activate adenylyl cyclase. Therefore, the response of cells to ethanol should be determined, in part, by the relative expression of A1 and A2 receptors. A1 receptors are expressed abundantly in the cerebellum and hippocampus, major targets for ethanol in human brain. Increased A1 receptors on a general background of A2 receptors in these regions may be related to ethanol intoxication and effects on learning and memory. We will determine the role of adenosine A1 receptors in regulating chronic ethanol-induced changes in cAMP signal transduction in NG108-15 cells expressing A1 and A2 receptors. We will also determine whether the effects of A1 receptors are due to ethanol regulation of protein kinase activities. Adenosine A2 receptors, which activate adenylyl cyclase, regulate the responses of dopamine D2 receptors in the same cell in the striatum and similar changes may occur int eh nucleus accumbens, implicated in ethanol- reinforced behavior, and in other regions. To understand the role of adenosine A2 receptors and dopamine D2 receptors in mediating the chronic effects of ethanol, dopamine D2 receptors will be expressed in NG108-15 cells and we will determine whether acute and chronic exposure to ethanol alters dopamine D2 receptor signalling and whether this is mediated by adenosine A2 receptors. Pathophysiologic mechanisms have ben identified in NG108-15 cells. These stable neuronal models will be used to understand how ethanol alter D2 receptor signalling and to determine how ethanol-induced increases in extracellular adenosine regulate more complex receptor responses. These studies may lead to the development of new therapeutic agents to prevent some of the pathophysiologic effects of alcoholism.