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

Lookup NU author(s): Dr Daniel Johnson, Professor Colin Ingram, Dr Sasha Gartside

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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.


Publication metadata

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

Publication type: Article

Journal: Neuropsychopharmacology

Year: 2009

Volume: 34

Issue: 2

Pages: 399-409

Print publication date: 01/01/2009

ISSN (print): 0893-133X

ISSN (electronic): 1740-634X

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/npp.2008.70

DOI: 10.1038/npp.2008.70

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.


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