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

本项目取得的显著成果如下：1.抗抑郁药直接作用于5HT_2受体的第二信使系统，对GTP结合蛋白的直接作用被认为是抗抑郁药作用方式的重要方面.抗抑郁药慢性治疗可增加大鼠脑细胞膜蛋白激酶C（磷脂非依赖性/Ca^++依赖性激酶）。这一结果表明，抗抑郁药可能会保持PKC的持续激活.本文研究了抑郁症患者和正常人血小板内Ca^++与5-HT的反应。抑郁症患者的Ca^<++>反应明显高于对照组。这一结果将支持抑郁症的神经递质超敏感理论.抗抑郁药的慢性治疗导致增强耦合的Gs腺苷酸环化酶，以及施加影响的相互作用的Gs和Gi/O。经典的抑郁症的单胺假说，其中情感障碍与NE或5 HT释放的减少，在这几年中已被修订。近年来，第二信使系统的研究取得了重大进展，为抗抑郁药物的作用研究指明了新的方向。在这个研究项目中，我们发现了抗抑郁药对第二信使系统的直接作用。另外，在临床研究中，我们发现抑郁症患者的第二信使系统反应性增强。综上所述，我们提出了这样的假设，即情感性精神障碍的第二信使系统可能存在功能异常，抗抑郁药的作用可能使这种异常正常化。

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.