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

使用Berridge（1983）的灵敏放射性同位素法研究了5HT对人血小板肌醇磷脂代谢的影响，因为众所周知，酮色林可以拮抗5HT诱导的形状改变和细胞内游离钙离子的升高。在预先标记为< 3H> -肌醇的血小板中，在含有10mM Licl和1 <微> - M氟西汀的无钙HEPES缓冲液中，5HT在15分钟的培养过程中引起肌醇-磷酸（ip - 1）的剂量依赖性积累。5HT-2选择性拮抗剂Ketanserin能有效抑制5HT刺激下的ip - 1积累，Ki值为12nM，但选择性5HT- 1拮抗剂(-)-propranolol（l <micro> M）不能阻断5HT反应。美特高林是5ht - 1和5HT-2的混合拮抗剂，其对5ht刺激的ip - 1形成的减少几乎相同，Ki值为5nM，与酮色林相同。这些结果表明5HT可以激活人血小板中的5HT-2受体，而不是5HT- 1受体。氯丙嗪和丙咪嗪抑制5ht刺激的ip - 1积累，Ki值分别为124nM和2560nM。Spiperone（l <micro> M）完全抑制，氯氮平（l <micro> M）和阿米替林（l <micro> M）部分降低（80-50%），5ht诱导的ip - 1积累；舒必利（l <微> M）未能阻断5HT反应。这些化合物抑制5ht刺激的ip - 1在人血小板中积累的能力与5HT-2受体的亲和力呈正相关，这是由大鼠大脑皮质膜中的放射性配体结合所定义的。这扩展了血小板作为5HT-2受体模型的实用性，因为配体结合研究可以通过测量确定的生化反应来补充。

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.