Mechanism of Action of Various Psychotropic Agents on Monoaminergic Receptors and Transmembrane signal Control.

各种精神药物对单胺能受体的作用机制和跨膜信号控制。

• 批准号: 60570490
• 负责人: MIKUNI Masahiko
• 金额: $ 1.34万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1985
• 资助国家: 日本
• 起止时间: 1985 至 1986
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-60570490/
• 关键词: antidepressant agent; neuroleptic agent; monoaminergic receptors; phosphatidylinositol hydrolysis; human platelet; 膜内情報伝達系

The metabolism of inositol phospholipids in response to 5HT was investigated in human platelets using the sensitive radioisotopicmethod of Berridge (1983), since it is well-known that ketanserin antagonizes 5HT-induced shape change and rise of intracellular free Ca ion. In platelets prelabeled with <^3H> -myo inositol, in Ca ion free HEPES buffer containing 10mM Licl and l <micro> M fluoxetine, 5HT caused a dose-dependent accumulation of inositol-l-phosphate(IP-l) during 15 min incubation. A maximal increase in IP-l formation was observed at 30 <micro> M of 5HT and its <EC_(50)> value was 4 <micro> M. Ketanserin, a selective 5HT-2 antagonist, was a potent inhibitor of 5HT-stimulated IP-l accumulation with a Ki value of 12nM, but a selective 5HT-l antagonist, (-)-propranolol(l <micro> M), failed to block the 5HT response. Metergoline, a mixed 5HT-l and 5HT-2 antagonist, caused almost the same reduction in 5HT-stimulated IP-l formation, with a Ki value of 5nM, as ketanserin. These results indicate that 5HT is activating 5HT-2,but not 5HT-l receptors in human platelets. Moreover, chlorpromazine and imipramine inhibited 5HT-stimulated IP-l accumulation, with Ki values of 124nM and 2560nM, respectively. Spiperone(l <micro> M) inhibitedcompletely, and clozapine(l <micro> M) and amitriptyline(l <micro> M) reduced partially(80-50%), 5HT-induced IP-l accumulation; sulpiride(l <micro> M) failed to block the 5HT response. The potencies of these compounds to inhibit 5HT-stimulated IP-l accumulation in human platelets correlates positively with the affinities to 5HT-2 receptors as defined by radioligand binding in rat cerebral cortical membranes. This extends the usefulness of the platelets as a model for 5HT-2 receptors since ligand binding studies can be complemented by measurements of a defined biochemical response.

由于众所周知酮色林拮抗5-HT诱导的形状变化和细胞内游离Ca离子的升高，因此，采用Berridge（1983）灵敏的放射性同位素方法研究了人血小板中肌醇磷脂对5-HT的代谢反应。在用&lt;^3H&gt; -肌醇预标记的血小板中，在含有10 mM LiCl和1 M氟西汀的无钙HEPES缓冲液<micro>中，5 HT在15分钟孵育期间引起肌醇-1-磷酸（IP-1）的剂量依赖性积累。30 M的5 HT使IP-1的生成量最大<micro>，其&lt;EC_（50）&gt;值为4 <micro>M。选择性5 HT-2拮抗剂Ketanserin能有效抑制5 HT诱导的IP-1蓄积，Ki值为12 nM，而选择性5 HT-1拮抗剂（-）-普萘洛尔（1 <micro>M）不能阻断5 HT诱导的IP-1蓄积。Metergoline是一种混合的5 HT-1和5 HT-2拮抗剂，与酮色林一样，其对5 HT刺激的IP-1形成的抑制作用几乎相同，Ki值为5 nM。这些结果表明，5 HT激活人血小板中的5 HT-2受体，但不激活5 HT-1受体。此外，氯丙嗪和丙咪嗪抑制5 HT刺激的IP-1积累，Ki值分别为124 nM和2560 nM。螺哌隆（1 <micro>M）可完全抑制5 HT诱导的IP-1蓄积，氯氮平（1 <micro>M）和阿米替林（1 <micro>M）可部分抑制（80-50%）5 HT诱导的IP-1蓄积，舒必利（1 <micro>M）不能阻断5 HT诱导的IP-1蓄积。这些化合物抑制人血小板中5 HT-刺激的IP-1积累的效力与通过大鼠大脑皮质膜中的放射性配体结合所定义的对5 HT-2受体的亲和力正相关。这扩展了血小板作为5 HT-2受体模型的有用性，因为配体结合研究可以通过测量定义的生化反应来补充。

项目成果

三國雅彦: 北海道医学雑誌. 62. (1987)

三国正彦：北海道医学杂志 62。（1987）

三國雅彦: 薬物・精神・行動. 5. 57-58 (1985)

三国正彦：毒品、思想和行为。5. 57-58 (1985)

三國雅彦: 神経化学. 25. 304-306 (1986)

三国正彦：神经化学 25. 304-306 (1986)

Masahiko Mikuni: "Effects of acute or subchronic administration of antidepressant agents on monoaminergic receptor binding sites in rat cerebral cortex: a comparison with effects of neuroleptics." Japanese J. of Psychopharmacology. 5. 57-58 (1985)

Masahiko Mikuni：“急性或亚慢性服用抗抑郁药对大鼠大脑皮层单胺能受体结合位点的影响：与精神安定药的效果比较。”

Masahiko Mikuni: "Advances in the research on the mechanisms of action of antidepressant agents." Japanese J. of Neuropsychopharmacology. 9. 78-92 (1987)

三国正彦：“抗抑郁药作用机制的研究进展。”