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

用Berbridge(1983)灵敏的放射性同位素方法研究了5-羟色胺对人血小板肌醇磷脂代谢的影响，因为众所周知，酮丝氨酸能拮抗5-羟色胺引起的形态改变和细胞内游离钙离子的升高。在预先标记肌醇的血小板上，在含10 mM氯化锂和L微氟西汀的无钙HEPES缓冲液中，5-羟色胺可引起肌醇-L-磷酸(IP-L)在15min内呈剂量依赖性蓄积。5-羟色胺诱导的IP-L积聚在30℃时最大，其EC_(50)&gt；值为4&lt；Micro&gt；M，选择性5HT-2拮抗剂酮色林能有效抑制5HT刺激的IP-L蓄积，Ki值为12 nm，而选择性5-羟色胺-L拮抗剂(-)-普奈洛尔(L&lt；Micro&gt；M)不能阻断5HT反应。5-羟色胺-L和5-羟色胺-2拮抗剂美特灵对5-羟色胺刺激的IP-L形成的抑制作用与酮丝林几乎相同，Ki值为5 nm。这些结果表明，5-羟色胺激活人血小板上的5-羟色胺-2受体，但不激活5-羟色胺-L受体。氯丙嗪和丙咪嗪抑制5-羟色胺刺激的IP-L蓄积，Ki分别为124 nM和2560 nM。螺环酮(L)完全抑制，氯氮平(L)和阿米替林(L)部分抑制(80-50%)，5-羟色胺诱导的IP-L蓄积，舒必利(L)不能阻断5-羟色胺反应。这些化合物抑制5-羟色胺刺激的人血小板IP-L蓄积的能力与其与5-羟色胺-2受体的亲和力呈正相关，该亲和力由大脑皮层放射性配基结合来确定。这扩大了血小板作为5-羟色胺-2受体模型的用途，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.