title: Antagonist functional selectivity: 5-HT2A serotonin receptor antagonists differentially regulate 5-HT2A receptor protein level in vivo.
abstract: Dysregulation of the 5-HT(2A) receptor is implicated in both the etiology and treatment of schizophrenia. Although the essential role of 5-HT(2A) receptors in atypical antipsychotic drug actions is widely accepted, the contribution of 5-HT(2A) down-regulation to their efficacy is not known. We hypothesized that down-regulation of cortical 5-HT(2A) receptors contributes to the therapeutic action of atypical antipsychotic drugs. To test this hypothesis, we assessed the effect of chronically administered antipsychotics (clozapine, olanzapine, and haloperidol) and several 5-HT(2A) antagonists [ketanserin, altanserin, α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (M100907), α-phenyl-1-(2-phenylethyl)-4-piperidinemethano (M11939), 4-[(2Z)-3-{[2-(dimethylamino)ethoxy]amino}-3-(2-fluorophenyl)prop-2-en-1-ylidene]cyclohexa-2,5-dien-1-one (SR46349B), and pimavanserin], on the phencyclidine (PCP)-induced hyperlocomotor response and cortical 5-HT(2A) receptor levels in C57BL/6J mice. Clozapine and olanzapine, but not haloperidol, induced receptor down-regulation and attenuated PCP-induced locomotor responses. Of the selective 5-HT(2A) antagonists tested, only ketanserin caused significant receptor protein down-regulation, whereas SR46349B up-regulated 5-HT(2A) receptors and potentiated PCP-hyperlocomotion; the other 5-HT(2A) receptor antagonists were without effect. The significance of these findings with respect to atypical antipsychotic drug action is discussed.
authors: Department of Pharmacology, University of North Carolina, Chapel Hill Medical School, Chapel Hill, North Carolina 27599, USA.
authors: Prem N
authors: PN
authors: Yadav
authors: Wesley K
authors: WK
authors: Kroeze
authors: Martilias S
authors: MS
authors: Farrell
authors: Bryan L
authors: BL
authors: Roth
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology; D015153:Blotting, Western; D003024:Clozapine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D000077152:Olanzapine; D010622:Phencyclidine / Q000494:pharmacology; D011869:Radioligand Assay; D044402:Receptor, Serotonin, 5-HT2A / Q000096:biosynthesis* / Q000187:drug effects* / Q000235:genetics; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001569:Benzodiazepines; D003024:Clozapine; D018492:Dopamine Antagonists; D006220:Haloperidol; D000077152:Olanzapine; D010622:Phencyclidine; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors