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

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。

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.