Biochemical and Pharmacological Research on Affective Disorders from the Aspect of the Mechanism of Neural Transmission and Intracellural Signal Transduction

从神经传递和细胞内信号转导机制角度进行情感障碍的生化和药理学研究

基本信息

批准号：
63304044
负责人：
HIGUCHI Teruhiko
金额：
$ 7.74万
依托单位：
Gunma University Scholl of Medicine (1989-1990)Saitama Medical University (1988)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Co-operative Research (A)
财政年份：
1988
资助国家：
日本
起止时间：
1988 至 1990
项目状态：
已结题

项目摘要

The remarkable results in this project are as follows.1. Antidepressants act directly on the second messenger system of 5HT_2 receptor and the direct action on the GTP binding proteins is considered to be important for the mode of action of antidepressants.2. Protein kinase C (phospholipid-independent/Ca^<++>-dependent kinase) in rat brain membrane was increased by the chronic treatment with antidepressants. This result indicates that antidepressants may keep the continuous activation of PKC.3. Ca^<++> response with 5HT in the platelets was investigated in the patients with major depression compared to normal controls. Ca^<++> response was much greater in the patients with major depression than in the controls. This result will support the serotonergic supersensitive theory of depression.4. Chronic treatment of antidepressants causes enhanced coupling of Gs to adenylate cyclase as well as exerting influence on the interaction of Gs and Gi/o.The classic monoamine hypothesis of depression in which affective disorders are associated with the decrease of NE or 5HT release has been revised in these few years. Recently, the great advances have clarified the second messenger systems and the new direction to study the action for the antidepressants has been shown. In this research project, we found the direct action of antidepressants on the second messenger systems. In addition, in clinical investigation, we found the increased response of second messenger systems in the patients with major depression. Taken together, we present hypothesis that the functional abnormality may exist in the second messenger systems in affective disorders and the action of antidepressants may normalize this abnormality.

本项目取得的显著成果如下： 1．抗抑郁药直接作用于5HT_2受体第二信使系统，而直接作用于GTP结合蛋白被认为是抗抑郁药作用方式的重要组成部分。 2．大鼠脑膜中的蛋白激酶C(磷脂非依赖性/Ca ++ 依赖性激酶)因抗抑郁药的长期治疗而增加。这一结果表明抗抑郁药可以保持PKC.3的持续激活。与正常对照相比，研究了患有重度抑郁症的患者的血小板中对5HT的Ca ++ 反应。重度抑郁症患者的Ca^++反应比对照组大得多。这一结果将支持抑郁症的5-羟色胺超敏感理论。4．抗抑郁药的长期治疗会导致 Gs 与腺苷酸环化酶的偶联增强，并对 Gs 和 Gi/o 的相互作用产生影响。经典的抑郁症单胺假说（其中情感障碍与 NE 或 5HT 释放减少相关）已被修改这几年。近年来，第二信使系统的研究取得了重大进展，为抗抑郁药作用的研究提供了新的方向。在这个研究项目中，我们发现抗抑郁药对第二信使系统的直接作用。此外，在临床调查中，我们发现重度抑郁症患者的第二信使系统反应增强。综上所述，我们提出这样的假设：情感障碍的第二信使系统中可能存在功能异常，而抗抑郁药的作用可能使这种异常正常化。