CHRONIC EFFECTS OF ETHANOL ON NEURAL CELLS IN CULTURE

腺苷是大脑中的一种全局抑制性神经调节剂，似乎 介导许多急性和慢性中枢神经系统对乙醇的反应。我们已经在 乙醇增加胞外腺苷的培养细胞系 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受体在大脑中可能比A2受体更丰富 乙醇诱导的胞外腺苷增加应能激活两者 感受器。A1受体抑制cAMP的产生，而A2受体 激活腺苷环化酶。因此，细胞对乙醇的反应 应该部分由A1和A2的相对表达式决定 感受器。A1受体在小脑和脑内大量表达 海马体，人类大脑中乙醇的主要靶点。增加的A1 这些区域中A2受体的一般背景上的受体可能是 与酒精中毒以及对学习和记忆的影响有关。我们 将确定腺苷A1受体在调节慢性前列腺癌中的作用 乙醇对NG108-15细胞cAMP信号转导的影响 表达A1和A2受体。我们还将确定是否会产生影响 的A1受体是由于乙醇对蛋白激酶活性的调节。 腺苷A2受体激活腺酰环化酶，调节 纹状体内同一细胞内多巴胺D2受体的反应 伏隔核也可能发生类似的变化，这与乙醇有关- 强化了行为，在其他地区也是如此。要理解的作用 腺苷A2受体和多巴胺D2受体在慢性阻塞性肺疾病中的作用 乙醇、多巴胺D2受体的作用将在NG108-15中表达 细胞，我们将确定急性和慢性酒精暴露 改变多巴胺D2受体信号，以及这是否通过 腺苷A2受体。 NG108-15细胞的病理生理机制已被证实。这些 稳定的神经元模型将被用来理解乙醇如何改变D2 受体信号转导，并确定乙醇如何诱导细胞内 胞外腺苷调节更复杂的受体反应。这些 研究可能会导致开发新的治疗药物来预防 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.