Antagonist functional selectivity: 5-HT2A serotonin receptor antagonists differentially regulate 5-HT2A receptor protein level in vivo

J Pharmacol Exp Ther. 2011 Oct;339(1):99-105. doi: 10.1124/jpet.111.183780. Epub 2011 Jul 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Benzodiazepines / pharmacology
  • Blotting, Western
  • Clozapine / pharmacology
  • Dopamine Antagonists / pharmacology
  • Dose-Response Relationship, Drug
  • Haloperidol / pharmacology
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Olanzapine
  • Phencyclidine / pharmacology
  • Radioligand Assay
  • Receptor, Serotonin, 5-HT2A / biosynthesis*
  • Receptor, Serotonin, 5-HT2A / drug effects*
  • Receptor, Serotonin, 5-HT2A / genetics
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Serotonin 5-HT2 Receptor Antagonists / pharmacology*
  • Serotonin Receptor Agonists / pharmacology
  • Stereotyped Behavior / drug effects
  • Up-Regulation / drug effects

Substances

  • Dopamine Antagonists
  • Receptor, Serotonin, 5-HT2A
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Receptor Agonists
  • Serotonin Uptake Inhibitors
  • Benzodiazepines
  • Phencyclidine
  • Clozapine
  • Haloperidol
  • Olanzapine