Activation of glucocorticoid receptors increases 5-HT2A receptor levels
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Activation of glucocorticoid receptors increases 5-HT2A receptor levels. / Trajkovska, Viktorija; Kirkegaard, Lisbeth; Krey, Gesa; Marcussen, Anders Bue; Thomsen, Morten Skøtt; Chourbaji, Sabine; Brandwein, Christiane; Ridder, Stephanie; Halldin, Christer; Gass, Peter; Knudsen, Gitte M; Aznar, Susana.
In: Experimental Neurology, Vol. 218, No. 1, 2009, p. 83-91.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Activation of glucocorticoid receptors increases 5-HT2A receptor levels
AU - Trajkovska, Viktorija
AU - Kirkegaard, Lisbeth
AU - Krey, Gesa
AU - Marcussen, Anders Bue
AU - Thomsen, Morten Skøtt
AU - Chourbaji, Sabine
AU - Brandwein, Christiane
AU - Ridder, Stephanie
AU - Halldin, Christer
AU - Gass, Peter
AU - Knudsen, Gitte M
AU - Aznar, Susana
N1 - Keywords: Aldosterone Antagonists; Analysis of Variance; Animals; Autoradiography; Corticosterone; Fluorobenzenes; Gene Expression Regulation; Hippocampus; Hormone Antagonists; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mifepristone; Piperidines; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Glucocorticoid; Serotonin Plasma Membrane Transport Proteins; Spironolactone; Tissue Culture Techniques; Tritium
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
U2 - 10.1016/j.expneurol.2009.04.008
DO - 10.1016/j.expneurol.2009.04.008
M3 - Journal article
C2 - 19379741
VL - 218
SP - 83
EP - 91
JO - Experimental Neurology
JF - Experimental Neurology
SN - 0014-4886
IS - 1
ER -
ID: 19978224