Activation of glucocorticoid receptors increases 5-HT2A receptor levels

Viktorija Trajkovska; Lisbeth Kirkegaard; Gesa Krey; Anders Bue Marcussen; Morten Skøtt Thomsen; Sabine Chourbaji; Christiane Brandwein; Stephanie Ridder; Christer Halldin; Peter Gass; Gitte M Knudsen; Susana Aznar

doi:10.1016/j.expneurol.2009.04.008

Activation of glucocorticoid receptors increases 5-HT2A receptor levels

Viktorija Trajkovska, Lisbeth Kirkegaard, Gesa Krey, Anders Bue Marcussen, Morten Skøtt Thomsen, Sabine Chourbaji, Christiane Brandwein, Stephanie Ridder, Christer Halldin, Peter Gass, Gitte M Knudsen, Susana Aznar

Department of Clinical Medicine

23 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Experimental Neurology
Volume	218
Issue number	1
Pages (from-to)	83-91
Number of pages	8
ISSN	0014-4886
DOIs	https://doi.org/10.1016/j.expneurol.2009.04.008
Publication status	Published - 2009

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10.1016/j.expneurol.2009.04.008

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@article{8af4a77068ab11df928f000ea68e967b,

title = "Activation of glucocorticoid receptors increases 5-HT2A receptor levels",

abstract = "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.",

author = "Viktorija Trajkovska and Lisbeth Kirkegaard and Gesa Krey and Marcussen, {Anders Bue} and Thomsen, {Morten Sk{\o}tt} and Sabine Chourbaji and Christiane Brandwein and Stephanie Ridder and Christer Halldin and Peter Gass and Knudsen, {Gitte M} and Susana Aznar",

note = "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",

year = "2009",

doi = "10.1016/j.expneurol.2009.04.008",

language = "English",

volume = "218",

pages = "83--91",

journal = "Experimental Neurology",

issn = "0014-4886",

publisher = "Academic Press",

number = "1",

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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

SN - 0014-4886

VL - 218

SP - 83

EP - 91

JO - Experimental Neurology

JF - Experimental Neurology

IS - 1

ER -

Activation of glucocorticoid receptors increases 5-HT2A receptor levels

Abstract

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