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.结论：1.抗抑郁药直接作用于5HT2受体的第二信使系统，对GTP结合蛋白的直接作用对抗抑郁药的作用方式具有重要意义。慢性抗抑郁药物治疗可使大鼠脑膜蛋白激酶C(磷脂非依赖性/钙依赖性蛋白激酶)增加。这一结果表明，抗抑郁剂可能保持了PKC.3的持续激活。以正常对照组为对照，观察了抑郁症患者血小板对5-羟色胺的反应。重度抑郁症患者的CA^lt；&gt；反应比对照组大得多。这一结果将支持抑郁症的5-羟色胺能超敏感学说。抗抑郁药物的长期治疗导致Gs与腺苷环化酶偶联增强，并对Gs与Gi/o的相互作用产生影响。经典的抑郁症单胺假说认为，情感障碍与去甲肾上腺素或5-羟色胺释放减少有关，近年来得到了修订。近年来，第二信使系统的研究取得了很大进展，为研究抗抑郁药的作用提供了新的方向。在本研究项目中，我们发现了抗抑郁药物对第二信使系统的直接作用。此外，在临床研究中，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，我们提出的假设是，情感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会使这种异常恢复正常。

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.