ANTIDEPRESSANTS: SIGNAL TRANSDUCTION AND GENE EXPRESSION

重度抑郁症是缓解慢性但不是急性 给予抗抑郁药物或电休克治疗。 虽然抗抑郁作用的生化机制不是 清楚地理解，这些治疗效果的延迟 治疗导致了一种假设，即一些适应性的改变， 神经元功能必须随着时间的推移而发生。 最具适应性的- 慢性抗抑郁药治疗的生化效应 动物是一个下调的B-肾上腺素能受体（BAR）-耦合 腺苷酸环化酶系统。 这个系统也是由垂体调节的- 肾上腺激素和临床研究表明， 是许多抑郁症患者体内激素系统的功能障碍。 综合这些发现， 不平衡可能导致生化改变， 萧条 这项研究计划的长远目标是 将以前的工作扩展到受体结合位点的水平之外， 通过研究抗抑郁药和垂体-肾上腺 BARs和G蛋白在基因水平的激素调控 表情 BARs和G蛋白信使RNA的调节 抗抑郁药和激素治疗将通过北方印迹来确定 使用特异性cDNA探针进行分析，而G蛋白水平 亚基将通过定量免疫标记和ADP- 核糖基化 初步研究表明， 丙咪嗪治疗调节BAR mRNA的水平， 抗抑郁药和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研究，并扩大到一个 检查其时间依赖性、药理学和区域 特异性和基因转录率将被直接检查 通过核径流分析。 最后，神经递质受体-G蛋白 腺苷酸环化酶的调节将被研究， 抗抑郁药和激素诱导的生理相关性 改变。 这些研究可以阐明适应性分子 调节抗抑郁治疗的机制以及 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.