title: 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.
authors.affiliation: Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Daniel Anthony
authors.initials: DA
authors.lastname: Johnson
authors.forename: Colin David
authors.initials: CD
authors.lastname: Ingram
authors.forename: Emma Jane
authors.initials: EJ
authors.lastname: Grant
authors.forename: Mark
authors.initials: M
authors.lastname: Craighead
authors.forename: Sarah Elizabeth
authors.initials: SE
authors.lastname: Gartside
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D015283:Citalopram / Q000494:pharmacology; D003720:Densitometry; D015536:Down-Regulation / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology*; D017403:In Situ Hybridization; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D058825:Serotonin 5-HT1 Receptor Agonists; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013256:Steroids / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D014316:Tritium / Q000494:pharmacology; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D015283:Citalopram; D005473:Fluoxetine; D012333:RNA, Messenger; D044282:Receptor, Serotonin, 5-HT1A; D011965:Receptors, Glucocorticoid; D058825:Serotonin 5-HT1 Receptor Agonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013256:Steroids; D013450:Sulfones; D014316:Tritium; D014365:Tryptophan Hydroxylase; C526063:Org 34850