Sustained treatment with a 5-HT2A receptor agonist causes functional desensitization and reductions in agonist-labeled 5-HT2A receptors despite increases in receptor protein levels in rats

Ju Shi, Michelle Landry, Gonzalo A. Carrasco, George Battaglia, Nancy A. Muma

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Adaptive changes in serotonin2A (5-HT2A) receptor signaling are associated with the clinical response to a number of psychiatric drugs including atypical antipsychotics and selective serotonin reuptake inhibitors. The present study examined possible mechanisms of agonist-induced desensitization of 5-HT2A receptors in rat hypothalamic paraventricular nucleus (PVN) after 4 and 7 days of treatment with 1 mg/kg (-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI). The magnitude of 5-HT2A receptor-mediated oxytocin release decreased 78% after 4 days and 61% after 7 days of DOI treatment. Similarly, the magnitude of ACTH release following 1 mg/kg DOI decreased by 31% after 4 days and 38% after 7 days of DOI treatment. Treatment with DOI for either 4 or 7 days caused a significant decrease (by approximately 50%) in the high-affinity 5-HT2A receptor binding as measured by 125I-DOI binding compared to saline-treated control rats. In contrast, western blot analysis demonstrated a significant increase in 5-HT2A receptor protein levels with 4 or 7 days of DOI treatment to 167% and 191% of control levels, respectively. Real time quantitative RT-PCR analysis revealed a small but nonsignificant increase in the levels of 5-HT2A mRNA following treatment with DOI for 4 or 7 days. Taken together, the 5-HT2A receptor-stimulated hormone responses, agonist binding data and western blot data suggest that although agonist treatment increases the levels of 5-HT2A receptor protein in the cell membrane, there is a reduction in the population of 5-HT2A receptors capable of high-affinity binding and mediating a functional response.

Original languageEnglish (US)
Pages (from-to)687-692
Number of pages6
JournalNeuropharmacology
Volume55
Issue number5
DOIs
StatePublished - Oct 1 2008

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience
  • Pharmacology

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