Lamberts S W, van Koetsveld P M, Hofland L J
Department of Medicine, Erasmus University, Rotterdam, The Netherlands.
Life Sci. 1990;46(14):1013-9. doi: 10.1016/0024-3205(90)90025-m.
Clozapine is an antipsychotic drug which is unusual in that it has no dopamine receptor-blocking activity. Previous studies gave conflicting results whether administration of clozapine induces hyperprolactinemia. In the present study it was shown that a wide concentration range of clozapine does not interfere with dopamine-mediated inhibition of prolactin (PRL) secretion by normal cultured rat pituitary cells. This in contrast to other neuroleptics, like haloperidol and trifluoperazine. Clozapine does also not antagonize norepinephrine-mediated inhibition of PRL secretion. Clozapine exerts at micromolar concentrations a direct inhibitory action on PRL release by cultured normal rat pituitary cells. In cultured rat pituitary tumor cells, these high concentrations of clozapine directly inhibit PRL release as well as the DNA content of the cells, suggesting a direct antimitotic action. In this model clozapine was about 5-10 times less potent than trifluperazine. Clozapine and trifluoperazine exert an additive inhibitory action both on PRL release and on the DNA content of the pituitary tumor cells. It is concluded that clozapine does not interfere at the pituitary level with dopamine-mediated inhibition of PRL release. At micromolar concentrations clozapine may act on lactotrophs as a calmodulin-inhibitor. These observations suggest that the transient PRL-releasing effects which have been observed in both animal and human studies after clozapine administration are mediated via supra-pituitary actions of the drug.
氯氮平是一种抗精神病药物，其不同寻常之处在于它没有多巴胺受体阻断活性。先前的研究对于服用氯氮平是否会诱发高催乳素血症给出了相互矛盾的结果。在本研究中发现，氯氮平在很宽的浓度范围内都不会干扰多巴胺对正常培养的大鼠垂体细胞催乳素（PRL）分泌的抑制作用。这与其他抗精神病药物如氟哌啶醇和三氟拉嗪形成对比。氯氮平也不会拮抗去甲肾上腺素对PRL分泌的抑制作用。氯氮平在微摩尔浓度时对培养的正常大鼠垂体细胞的PRL释放具有直接抑制作用。在培养的大鼠垂体肿瘤细胞中，这些高浓度的氯氮平直接抑制PRL释放以及细胞的DNA含量，提示有直接的抗有丝分裂作用。在这个模型中，氯氮平的效力比三氟拉嗪弱约5至10倍。氯氮平和三氟拉嗪对垂体肿瘤细胞的PRL释放和DNA含量都有相加的抑制作用。得出的结论是，氯氮平在垂体水平不会干扰多巴胺介导的PRL释放抑制作用。在微摩尔浓度时，氯氮平可能作为一种钙调蛋白抑制剂作用于催乳素细胞。这些观察结果表明，在动物和人体研究中服用氯氮平后观察到的短暂PRL释放效应是通过该药物的垂体上作用介导的。
