title: Clozapine and other 5-hydroxytryptamine-2A receptor antagonists alter the subcellular distribution of 5-hydroxytryptamine-2A receptors in vitro and in vivo.
abstract: 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.
authors.affiliation: Department of Psychiatry, Case Western Reserve University Medical School, Cleveland, OH 44106, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Willins
authors.forename: S A
authors.initials: SA
authors.lastname: Berry
authors.forename: L
authors.initials: L
authors.lastname: Alsayegh
authors.forename: J R
authors.initials: JR
authors.lastname: Backstrom
authors.forename: E
authors.initials: E
authors.lastname: Sanders-Bush
authors.forename: L
authors.initials: L
authors.lastname: Friedman
authors.forename: B L
authors.initials: BL
authors.lastname: Roth
mesh_terms: D016475:3T3 Cells; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001569:Benzodiazepines; D002460:Cell Line; D003024:Clozapine / Q000494:pharmacology*; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D005464:Fluorobenzenes / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008803:Mianserin / Q000494:pharmacology; D051379:Mice; D000077152:Olanzapine; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology; D016713:Ritanserin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014162:Transfection
chemical_list: D014150:Antipsychotic Agents; D005464:Fluorobenzenes; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D001569:Benzodiazepines; D016713:Ritanserin; D008803:Mianserin; D010890:Pirenzepine; C079049:volinanserin; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine