Willins D L, Berry S A, Alsayegh L, Backstrom J R, Sanders-Bush E, Friedman L, Roth B L
Department of Psychiatry, Case Western Reserve University Medical School, Cleveland, OH 44106, USA.
Neuroscience. 1999;91(2):599-606. doi: 10.1016/s0306-4522(98)00653-8.
In this study, we demonstrate that clozapine and other atypical antipsychotic drugs induce a paradoxical internalization of 5-hydroxytryptamine-2A receptors in vitro and a redistribution of 5-hydroxytryptamine-2A receptors in vivo. We discovered that clozapine, olanzapine, risperidone and the putative atypical antipsychotic drug MDL 100,907 all induced 5-hydroxytryptamine-2A receptor internalization in fibroblasts stably expressing the 5-hydroxytryptamine-2A receptor in vitro. Two 5-hydroxytryptamine-2A antagonists (mianserin and ritanserin), which have been demonstrated to reduce negative symptoms in schizophrenia, also caused 5-hydroxytryptamine-2A receptor internalization. Four different drugs, each devoid of 5-hydroxytryptamine-2A antagonist activity, had no effect on the subcellular distribution of 5-hydroxytryptamine-2A receptors in vitro. Treatment of rats for seven days with clozapine induced an increase in intracellular 5-hydroxytryptamine-2A receptor-like immunoreactivity in pyramidal neurons, while causing a decrease in labeling of apical dendrites in the medial prefrontal cortex. This redistribution of 5-hydroxytryptamine-2A receptors in pyramidal neurons was also seen when rats were chronically treated with another atypical antipsychotic drug, olanzapine. The typical antipsychotic drug haloperidol, however, did not induce a redistribution of 5-hydroxytryptamine-2A receptors in pyramidal neurons in the medial prefrontal cortex. Taken together, these results demonstrate that several atypical antipsychotic drugs with high 5-hydroxytryptamine-2A receptor affinities induce a redistribution of 5-hydroxytryptamine-2A receptors both in vivo and in vitro. It is conceivable that the loss of 5-hydroxytryptamine-2A receptors from the apical dendrites of pyramidal neurons is important for the beneficial effects of atypical antipsychotic drugs and other 5-hydroxytryptamine-2A antagonists in schizophrenia.
在本研究中，我们证明氯氮平和其他非典型抗精神病药物在体外可诱导5-羟色胺-2A受体发生反常内化，并在体内导致5-羟色胺-2A受体重新分布。我们发现，氯氮平、奥氮平、利培酮以及推定的非典型抗精神病药物MDL 100,907在体外均可诱导稳定表达5-羟色胺-2A受体的成纤维细胞中5-羟色胺-2A受体发生内化。两种已被证明可减轻精神分裂症阴性症状的5-羟色胺-2A拮抗剂（米安色林和利坦色林）也会引起5-羟色胺-2A受体内化。四种不同的药物，每种均缺乏5-羟色胺-2A拮抗剂活性，在体外对5-羟色胺-2A受体的亚细胞分布没有影响。用氯氮平对大鼠进行为期七天的治疗，可诱导锥体神经元内细胞内5-羟色胺-2A受体样免疫反应性增加，同时导致内侧前额叶皮质顶端树突的标记减少。当用另一种非典型抗精神病药物奥氮平对大鼠进行长期治疗时，也可观察到锥体神经元中5-羟色胺-2A受体的这种重新分布。然而，典型抗精神病药物氟哌啶醇并未诱导内侧前额叶皮质锥体神经元中5-羟色胺-2A受体重新分布。综上所述，这些结果表明，几种具有高5-羟色胺-2A受体亲和力的非典型抗精神病药物在体内和体外均可诱导5-羟色胺-2A受体重新分布。可以想象，锥体神经元顶端树突上5-羟色胺-2A受体的缺失对于非典型抗精神病药物和其他5-羟色胺-2A拮抗剂在精神分裂症中的有益作用至关重要。
