1999 Fiscal Year Final Research Report Summary
Effects of long-term treatment with antidepressants on glucocorticoid receptor binding and gene expression in cultured rat hippocampal neurons.
| Project/Area Number |
10680725
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | Kansai Medical University |
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Principal Investigator |
OMORI Kyoko Kansai Medical University, Department of Pharmacology, Associate Professor, 医学部, 助教授 (90152256)
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| Project Period (FY) |
1998 – 1999
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| Keywords | glucocorticoid receptor / expression / antidepressants / hippocampal neuron / cell culture / glucocorticoid receptor binding |
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| Research Abstract |
The glucocorticoid receptor (GR) and/or mineralocorticoid receptor (MR) in the hippocampus have been implicated in cortisol feedback of the hypothalamus-pituitary-adrenal (HPA) axis, and abnormalities in those receptors might underlie the hyperactivity of the HPA axis described in patients with major depression. Animal studies have shown that long-term in vivo treatment with antidepressants up-regulates hippocampal GR and/or MR, but it is not clear whether this up-regulation is evoked through a direct action of antidepressants on these receptors. We therefore examined the direct effects of long-term antidepressant treatment on GR binding and the levels of GR messenger RNA (mRNA) in primary cultures of rat hippocampal neurons. The time course of the effects of the tricyclic antidepressants desipramine and amitriptyline on GR binding, as assessed by [ィイD13ィエD1H]dexamethasone binding using RU 28362, a specific agonist for GR, showed a biphasic mode of stimulation : desipramine significant
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ly increased the GR binding with 2-day exposure by 36% over that in controls and by 99% and 60% with 10-and 14-day exposures, respectively. Amitriptyline also led to a significant increase in GR binding, with peaks at 2 (by 60%) and 14 days of exposure (by 60%). The effects of 14-day treatment with desipramine required at least the first 4-day exposure, and the first 10-day exposure was required for the full effect. Northern blot analysis demonstrated that the GR mRNA level was significantly increased by 14-day treatment with desipramine (+142% over control), amitriptyline (+108%), mianserin (+124%), paroxetine (42%) and sulpiride (92%), but not with haloperidol. Immunocytochemistry for GR revealed that 2- or 14-day treatment with desipramine significantly increased the number of GR-positive cells with dominant immunoreactivity in the nuclei of granule cell-like neurons or in perikarya of pyramidal cell- and granule cell-like neurons. These findings suggest that tricyclic antidepressants directly increase hippocampal GR by short-term (2-day) and long-term (14-day) exposure, and that the increase by long-term exposure is evoked commonly with different classes of antidepressants through transcriptional up-regulation of GR expression. Less
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Research Products
(13 results)
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[Publications] Irie, T., Hara, M., Yasukura, T., Minamino, M., Omori, K., Matsuda, H., Inoue, K. and Inagaki, C.: "Chloride concentration in cultured hippocampal neurons increases during long-term exposure to ammonia through expression of anion exchanger."Brain Res.. 806. 246-256 (1998)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Zeng, X.-T., Higashida, T., Hara, M., Hattori, N., Kitagawa, K., Omori, K. and Inagaki, C.: "Antiserum against ClィイD1-ィエD1 pump complex recognized 51 kDa protein, a possible catalytic unit in the rat brain."Neurosci. Lett.. 258. 85-88 (1998)
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「研究成果報告書概要(欧文)」より
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[Publications] Fujiseki, Y., Omori, K., Omori, K., Mikami, Y., Suzukawa, J., Okugawa, G., Uyama, M. and Inagaki, C.: "Natriuretic peptide receptors, NPR-A and NPR-B, on cultured rabbit retinal pigment epithelial cells."Jpn. J. Pharmacol.. 79. 359-368 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Suzukawa, J., Omori, K., Okugawa, G., Fujiseki, Y., Heizmann, C. W. and Inagaki, C.: "Long-lasting c-fos and NGF mRNA expressions and loss of perikaryal parvalbumin immunoreactivity in the development of epileptogenesis after ethacrynic acid-induced seizure."Brain Res.. 834. 89-102 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Yagyu, K., Kitagawa, K., Irie, T., Hattori, N., Omori, K., Inagaki, C.: "Lithium decrease ClィイD1-ィエD1-ATPase activity and increases intracellular ClィイD1-ィエD1 concentration in cultured rat hippocampal neurons."Brain Res.. 821. 530-534 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Okugawa, G., Omori, K., Suzukawa, J., Fujiseki, Y., Kinoshita, T. and Inagaki, C.: "Long-term treatment with antidepressants increases glucocorticoid receptor binding and gene expression in cultured rat hippocampal neurons."J. Neuroendocrinol.. 11. 887-895 (1999)
Description
「研究成果報告書概要(欧文)」より
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