ANTIDEPRESSANTS: SIGNAL TRANSDUCTION AND GENE EXPRESSION

严重的抑郁症可通过慢性而非急性缓解。 服用抗抑郁药物或电休克治疗。 尽管抗抑郁作用的生化机制不是 显然，这些药物治疗效果的延迟 治疗导致了一种假设，即某些适应性变化 神经功能必须随着时间的推移而发生。最一致的适应性- 慢性抗抑郁药治疗对大鼠生化指标的影响 动物是一种下调的B-肾上腺素能受体(BAR)偶联 腺苷环化酶系统。这个系统也受到脑下垂体的调节- 肾上腺激素和临床研究表明， 在许多抑郁症患者中是这种激素系统的功能障碍。 综上所述，这些发现表明，一种垂体-肾上腺激素 失衡可能是导致生化改变的原因之一。 抑郁症。这项研究建议的长期目标是 将以前的工作扩展到受体结合位点和 研究抗抑郁药和垂体-肾上腺的第二信使 BAR和G蛋白在基因水平上的激素调节 表情。BAR和G蛋白信使RNA的调节 用Northern印迹法确定抗抑郁药物和激素治疗 用特异的c DNA探针分析G蛋白水平 亚基的研究将通过定量免疫标记和ADP- 核糖化。初步研究表明，慢性 丙咪嗪治疗调节bar mRNA水平，而两者 抗抑郁药与糖皮质激素给药差异调节 特定G蛋白亚基的信息和蛋白质水平。 这些影响将被进一步调查并扩展到 对它们的时间依赖性、药理学和地域性的检查 将直接检测基因转录的特异性和速率。 通过核径流分析。最后，神经递质受体-G蛋白 将研究腺苷酸环化酶的调节，以获得 抗抑郁剂与激素诱导的生理学相关性 改装。这些研究可以阐明适应性分子。 介导抗抑郁治疗的机制及其作用 垂体-肾上腺激素在抑郁症病因中的作用。

Major depressive illness is alleviated by chronic but not acute administration of antidepressant drugs or electroconvulsive therapy. Although the biochemical mechanisms of antidepressant action are not clearly understood, the delay in the therapeutic efficacy of these treatments has led to the hypothesis that some adaptive alteration in neuronal function must occur over time. The most consistent adaptive- biochemical effect of chronic antidepressant treatment in experimental animals is a down-regulation of the B-adrenergic receptor (BAR)-coupled adenylate cyclase system. This system is also regulated by pituitary- adrenal hormones and clinical investigations have indicated that there is a dysfunction of this hormone system in many depressed patients. Taken together these findings suggest that a pituitary-adrenal hormone imbalance may contribute to the biochemical alterations which underlie depression. The long-term objective of this research proposal is to extend previous work beyond the level of receptor binding sites and second messengers by studying antidepressant and pituitary-adrenal hormone regulation of BARs and G proteins at the level of gene expression. The regulation of BARs and G protein messenger RNA by antidepressant and hormone treatment will be determined by Northern blot analysis using specific cDNA probes while the levels of G protein subunits will be studied by quantitative immunolabeling and ADP- ribosylation. Preliminary studies have demonstrated that chronic imipramine treatment regulates the level of BAR mRNA while both antidepressant and glucocorticoid administration differentially regulate the levels of message and protein for specific G protein subunits. These effects will be further investigated and extended to an examination of their time dependence, pharmacology and regional specificity and the rate of gene transcription will be directly examined by nuclear runoff assays. Finally, neurotransmitter receptor-G protein regulation of adenylate cyclase will be studied to access the physiological relevance of the antidepressant and hormone induced alterations. These studies could elucidate the adaptive-molecular mechanisms which mediate antidepressant therapy as well as the role of pituitary-adrenal hormones in the etiology of depression.