Glucocorticoid receptor antagonism augments fluoxetine-induced downregulation of the 5-HT transporter (2009)

Author(s): Johnson DA, Ingram CD, Grant EJ, Craighead M, Gartside SE

  • : Glucocorticoid receptor antagonism augments fluoxetine-induced downregulation of the 5-HT transporter

Abstract: The effects of combined treatment with a glucocorticoid receptor (GR) antagonist, Org 34850, and a selective serotonin reuptake inhibitor (SSRI), fluoxetine, were investigated on pre- and postsynaptic aspects of 5-HT neurotransmission. Rats were treated for 14 days with Org 34850 (15 mg per kg per day subcutaneously), fluoxetine (10 mg per kg per day intraperitoneally), or a combination of both drugs. [(3)H]-citalopram binding (an index of 5-HT transporter (5-HTT) expression) was only slightly affected by Org 34850 alone: decreased in cortex and midbrain and increased in hippocampus. In contrast, chronic fluoxetine markedly decreased 5-HTT levels in all regions. Importantly, this decrease was significantly enhanced by combined Org 34850/fluoxetine treatment. There were no changes in the expression of 5-HTT mRNA, suggesting these effects were not due to changes in gene transcription. Expression of tryptophan hydroxylase mRNA and both 5-HT(1A) autoreceptor mRNA and protein (assessed using [(3)H]-8-OH-DPAT binding) were unchanged by any treatment. The expression of postsynaptic 5-HT(1A) receptor protein in the forebrain was unaltered by fluoxetine, Org 34850 or the combined Org 34850/fluoxetine treatment. This downregulation of 5-HTT by fluoxetine and its enhancement by Org 34850 can explain our recent observation that GR antagonists augment the SSRI-induced increase in extracellular 5-HT. In addition, these data suggest that the augmentation of forebrain 5-HT does not result in downregulation of forebrain 5-HT(1A) receptor expression. Given the importance of 5-HT(1A) receptor-mediated transmission in the forebrain to the antidepressant response, these data indicate that co-administration of GR antagonists may be effective in augmenting the antidepressant response to SSRI treatment.

Notes: Johnson, Daniel Anthony Ingram, Colin David Grant, Emma Jane Craighead, Mark Gartside, Sarah Elizabeth Research Support, Non-U.S. Gov't United States Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Neuropsychopharmacology. 2009 Jan;34(2):399-409. Epub 2008 May 21.

  • Short Title: Glucocorticoid receptor antagonism augments fluoxetine-induced downregulation of the 5-HT transporter
  • Date: January 2009
  • Journal: Neuropsychopharmacology
  • Volume: 34
  • Issue: 2
  • Pages: 399-409
  • Publisher: Nature Publishing Group
  • Publication type: Article
  • Bibliographic status: Published

Keywords: 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology Analysis of Variance Animals Autoradiography Brain/drug effects/*metabolism Citalopram/pharmacology Densitometry Down-Regulation/drug effects Fluoxetine/*pharmacology In Situ Hybridization Male RNA, Messenger/metabolism Rats Receptor, Serotonin, 5-HT1A/agonists/metabolism Receptors, Glucocorticoid/*antagonists & inhibitors Serotonin Plasma Membrane Transport Proteins/*metabolism Serotonin Uptake Inhibitors/*pharmacology Steroids/*pharmacology Sulfones/*pharmacology Tritium/pharmacology Tryptophan Hydroxylase/metabolism


Dr Sasha Gartside
Senior Lecturer