RECEPTORS, CALCIUM AND MECHANISMS OF ECT

该提案的目的是解决临床的作用机制， 通过定位电休克（ECS）诱导的区域进行EGT 受体、第二信使系统和离子通道的变化。 它将 更具体地关注那些以前已经发生变化的系统， 在慢性ECS中观察到，钙是最终的共同输出， 调解员 它们是：与磷脂酰肌醇连接的α 1受体 系统; β和D1受体，与腺苷酸有刺激性连接 环化酶第二信使系统和D2受体，与 腺苷酸环化酶。 腺苷酸环化酶系统的激活可导致 钙离子通道的磷酸化，间接改变钙离子通道的磷酸化， 流入神经元。 磷脂酰肌醇系统导致直接 从细胞内储存中释放钙，也能够 磷酸化离子通道。 离子通道的数量可以调节为 好. 因此，慢性ECS直接影响 L型和N型电压依赖性钙通道的调节将 也要检查。 用于测定ECS诱导的与 受体及其效应系统的定量放射自显影。 这些变化的时间进程将被确定为动力学 绑定分析。 第二组实验将评估 这些ECS诱导的变化随不同ECS刺激电极而不同 放置，类似于单侧和双侧电极放置 临床使用。 它还将评估刺激强度的影响， 这些变化的波形。 最后，ECS引起的变化， 与受体、钙通道和第二信使组分结合 将这些正常大鼠的系统与ECS诱导的变化进行比较 在两种抑郁症动物模型中;习得性无助（行为上 和遗传诱导的）和皮质损伤诱导的中风后模型 萧条 这些研究的长期目标是了解 电休克治疗（ECT）。 ECT仍然是有效的 治疗严重抑郁症，特别是用于治疗 精神情感障碍 更好地理解其机制 因此，采取行动可能有助于设计更有效的治疗方法， 对于这些疾病。 它还可以提供一个框架， 抑郁症的潜在病理生理学

The aim of this proposal is to address mechanisms of action for clinical EGT by localizing regions where electroconvulsive shock (ECS) induces changes in receptors, second messenger systems and ion channels. It will focus more specifically on systems in which changes have previously been seen with chronic ECS and which have calcium as a final common output and mediator. These are: alpha1 receptors with links to phosphatidylinositol system; beta and D1 receptors, with stimulatory links to the adenylate cyclase second messenger system and D2 receptors, with inhibitory links to the adenylate cyclase. Activation of the adenylate cyclase system can lead to phosphorylation of calcium ion channels, indirectly altering calcium influx into neurons. The phosphatidylinositol system leads to direct release of calcium from intracellular stores and is also capable of phosphorylating ion channels. Numbers of ion channels can be regulated as well. Therefore, the possibility that chronic ECS directly effects regulation of L-type and N-type voltage dependent calcium channels will also be examined. The principal method used to determine ECS-induced changes in binding to receptors and their effector systems will be quantitative autoradiography. The time course of these alterations will be determined as will kinetic analysis of binding. A second group of experiments will assess whether these ECS-induced changes differ with various ECS stimulus electrode placements, analogous to the unilateral and bilateral electrode placements used clinically. It will also assess effects of stimulus intensity and waveform on these alterations. Finally, the changes which ECS induces in binding to receptors, calcium channels and components of second messenger systems in these normal rats will be compared with changes induced by ECS in two animal models of depression; learned helplessness (both behaviorally and genetically induced) and cortical lesion-induced model of post stroke depression. The long term goal of these studies is to understand the mechanism of action of electroconvulsive therapy (ECT). ECT remains an effective treatment for severe depression and is especially useful in treating psychotic affective disorders. An improved understanding of its mechanism of action may, therefore, aid in the design of more effective treatments for these illnesses. It may also provide a framework for understanding the underlying pathophysiologies of depression.