Glucocorticoid receptor antagonism augments fluoxetine-induced downregulation of the 5-HT transporter.
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.
Johnson
Daniel Anthony
DA
Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
Ingram
Colin David
CD
Grant
Emma Jane
EJ
Craighead
Mark
M
Gartside
Sarah Elizabeth
SE
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
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