Clozapine and other 5-hydroxytryptamine-2A receptor antagonists alter the subcellular distribution of 5-hydroxytryptamine-2A receptors in vitro and in vivo

In this study, we demonstrate that clozapine and other atypical antipsychot ic drugs induce a paradoxical internalization of 5-hydroxytryptamine-2A rec eptors in vitro and a redistribution of 5-hydroxytryptamine-2A receptors in vivo. We discovered that clozapine, olanzapine, risperidone and the putati ve atypical antipsychotic drug MDL 100,907 all induced 5-hydroxytryptamine- 2A receptor internalization in fibroblasts stably expressing the 5-hydroxyt ryptamine-2A receptor in vitro. Two 5-hydroxytryptamine-2A antagonists (mia nserin and ritanserin), which have been demonstrated to reduce negative sym ptoms in schizophrenia, also caused 5-hydroxytryptamine-2A receptor interna lization. Four different drugs, each devoid of 5-hydroxytryptamine-2A antag onist activity, had no effect on the subcellular distribution of 5-hydroxyt ryptamine-2A receptors in vitro. Treatment of rats for seven days with cloz apine induced an increase in intracellular 5-hydroxytryptamine-2A receptor- like immunoreactivity in pyramidal neurons, while causing a decrease in lab eling of apical dendrites in the medial prefrontal cortex. This redistribut ion 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 ne urons in the medial prefrontal cortex. Taken together, these results demonstrate that several atypical antipsychot ic drugs with high 5-hydroxytryptamine-2A receptor affinities induce a redi stribution of 5-hydroxytryptamine-2A receptors both in vivo and in vitro. I t is conceivable that the loss of 5-hydroxytryptamine-2A receptors from the apical dendrites of pyramidal neurons is important for the beneficial effe cts of atypical antipsychotic drugs and other 5-hydroxytryptamine-2A antago nists in schizophrenia. (C) 1999 IBRO, Published by Elsevier Science Ltd.