Activation of glucocorticoid receptors increases 5-HT2A receptor levels.
Major depression is associated with both dysregulation of the hypothalamic pituitary adrenal axis and serotonergic deficiency, not the least of the 5-HT2A receptor. However, how these phenomena are linked to each other, and whether a low 5-HT2A receptor level is a state or a trait marker of depression is unknown. In mice with altered glucocorticoid receptor (GR) expression we investigated 5-HT2A receptor levels by Western blot and 3H-MDL100907 receptor binding. Serotonin fibre density was analyzed by stereological quantification of serotonin transporter immunopositive fibers. To establish an effect of GR activation on 5-HT2A levels, mature organotypic hippocampal cultures were exposed to corticosterone with or without GR antagonist mifepristone and mineralocorticoid receptor (MR) antagonist spironolactone. In GR under-expressing mice, hippocampal 5-HT2A receptor protein levels were decreased (26.3 +/- 1.6%, p < 0.05) and frontal 5-HT2A receptor binding was decreased (20 +/- 15%, p < 0.01) as compared to wild-type mice. Conversely, in over-expressing GR mice hippocampal 5-HT2A receptor protein levels were increased (60.8 +/- 4.0%, p = 0.0001) and 5-HT2A receptor binding was increased in dorsal hippocampus (77 +/- 35%, p < 0.05) as compared to wild-type mice. No difference in serotonin fibre density was observed in the GR over-expressing mice, while the GR under-expressing mice showed lower serotonergic innervation in the frontal cortex area. An effect of GR activation on 5-HT2A receptor levels was further corroborated by the culture studies as long-term exposure of 3 microM corticosterone to organotypic hippocampal cultures increased 5-HT2A receptor levels (p < 0.05). The corticosterone-induced 5-HT2A receptor up-regulation was blocked by addition of either spironolactone or mifepristone.
Trajkovska
Viktorija
V
Neurobiology Research Unit and Centre for Integrated Molecular Brain Imaging (CIMBI), Copenhagen University Hospital, Unit 9201, Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark.
Kirkegaard
Lisbeth
L
Krey
Gesa
G
Marcussen
Anders B
AB
Thomsen
Morten S
MS
Chourbaji
Sabine
S
Brandwein
Christiane
C
Ridder
Stephanie
S
Halldin
Christer
C
Gass
Peter
P
Knudsen
Gitte M
GM
Aznar
Susana
S
D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography / Q000379:methods; D003345:Corticosterone / Q000494:pharmacology; D005464:Fluorobenzenes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015735:Mifepristone / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013148:Spironolactone / Q000494:pharmacology; D046509:Tissue Culture Techniques; D014316:Tritium / Q000378:metabolism
D005464:Fluorobenzenes; D006727:Hormone Antagonists; D000451:Mineralocorticoid Receptor Antagonists; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D011965:Receptors, Glucocorticoid; D050486:Serotonin Plasma Membrane Transport Proteins; D014316:Tritium; D013148:Spironolactone; D015735:Mifepristone; C079049:volinanserin; D003345:Corticosterone