Assié M B, Cosi C, Koek W
Neurobiology Division II, Centre de Recherche Pierre Fabre, Castres, France.
Eur J Pharmacol. 1997 Sep 10;334(2-3):141-7. doi: 10.1016/s0014-2999(97)01207-7.
5-HT1A receptor agonists are thought to enhance the antipsychotic-like effects of dopamine D2 receptor antagonists while reducing their potential to produce extrapyramidal side effects. Thus, 5-HT1A receptor agonist properties of mixed 5-HT1A receptor agonists/D2 receptor antagonists might be of clinical importance. The antipsychotics, clozapine and nemonapride, and the putative antipsychotic, bromerguride, have intermediate to high affinity for 5-HT1A receptors. The present study examined the 5-HT1A receptor agonist activity of nemonapride and bromerguride, in comparison with clozapine, which has partial 5-HT1A receptor agonist properties in vitro. Here, 5-HT1A receptor activation was examined in vitro, by measuring forskolin-stimulated cAMP accumulation in HeLa cells expressing human 5-HT1A receptors, and in vivo, by using microdialysis to measure the extracellular concentration of hippocampal 5-hydroxytryptamine (5-HT) in rats. Nemonapride markedly decreased both forskolin-stimulated cAMP accumulation and the extracellular concentration of 5-HT; both effects were antagonized by the 5-HT1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY100635). In contrast, clozapine only partially decreased forskolin-stimulated cAMP accumulation and extracellular 5-HT, and only its effects on cAMP accumulation were attenuated by WAY100635. Bromerguride decreased neither forskolin-stimulated cAMP accumulation nor extracellular 5-HT; instead, it antagonized the decrease of cAMP accumulation produced by 5-HT and the decrease of extracellular 5-HT produced by the 5-HT1A agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The selective D2 receptor antagonist, raclopride, affected neither forskolin-stimulated cAMP in vitro nor extracellular 5-HT in vivo. Thus, in contrast with clozapine and bromerguride, only the novel antipsychotic, nemonapride, exhibited marked 5-HT1A receptor agonist properties both in vitro and in vivo; conceivably, these properties may play a role in its preclinical and clinical effects.
5-羟色胺1A（5-HT1A）受体激动剂被认为可增强多巴胺D2受体拮抗剂的类抗精神病作用，同时降低其产生锥体外系副作用的可能性。因此，5-HT1A受体激动剂/ D2受体拮抗剂混合物的5-HT1A受体激动剂特性可能具有临床重要性。抗精神病药物氯氮平和奈莫必利，以及假定的抗精神病药物溴麦角环肽，对5-HT1A受体具有中等至高亲和力。本研究检测了奈莫必利和溴麦角环肽的5-HT1A受体激动剂活性，并与在体外具有部分5-HT1A受体激动剂特性的氯氮平进行比较。在此，通过测量表达人5-HT1A受体的HeLa细胞中福斯高林刺激的环磷酸腺苷（cAMP）积累，在体外检测5-HT1A受体激活情况；在体内，通过微透析测量大鼠海马中5-羟色胺（5-HT）的细胞外浓度来检测。奈莫必利显著降低了福斯高林刺激的cAMP积累和5-HT的细胞外浓度；这两种作用均被5-HT1A受体拮抗剂N-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]-N-(2-吡啶基)环己烷甲酰胺（WAY100635）拮抗。相比之下，氯氮平仅部分降低了福斯高林刺激的cAMP积累和细胞外5-HT，并且只有其对cAMP积累的作用被WAY100635减弱。溴麦角环肽既未降低福斯高林刺激的cAMP积累，也未降低细胞外5-HT；相反，它拮抗了5-HT产生的cAMP积累减少以及5-HT1A激动剂（±）-8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）产生的细胞外5-HT减少。选择性D2受体拮抗剂雷氯必利在体外对福斯高林刺激的cAMP或在体内对细胞外5-HT均无影响。因此，与氯氮平和溴麦角环肽不同，只有新型抗精神病药物奈莫必利在体外和体内均表现出显著的5-HT1A受体激动剂特性；可以想象，这些特性可能在其临床前和临床效应中发挥作用。
