1988 Fiscal Year Final Research Report Summary
The Biochemical Study on Central monoaminergic Receptors・membrane associated Substances and a Mode of Action of Antidepressants
| Project/Area Number |
61480244
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Psychiatric science
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| Research Institution | St. Marianna University School of Medicine |
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Principal Investigator |
ASAKURA Mikio St. Marianna University School of Medicine, Associate Professor, 医学部, 教授 (70103504)
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| Co-Investigator(Kenkyū-buntansha) |
TSUKAMOTO Tohru St. Marianna University School of Medicine, Assistant Professor, 医学部, 講師 (30171979)
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| Project Period (FY) |
1986 – 1988
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| Keywords | Antidepressants / -Receptor down-regulation / Serotonin / Protein Kinase C / Inositol-phospholipid turnover / Phorbol-12 / 13-dibutyrate(IPDBu) |
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| Research Abstract |
We examined the effects of long-term treatment with antidepressants on the binding characteristics of [^3H]phorbol 12, 13-dibutyrate (PDBu), which binds to a regulatory domain of Ca^<2+>-phospholipid dependent protein kinase (protein kinase C) in several brain regions of the rat. Treatment with either clomipramine, imipramine or mianserin but not desipramine for 14 days but not 7 days produced a significant increase in [^3H]PDBu binding sites in amygdaloid particulates prepared with Ca^<2+>-containing buffer, while no significant change in the binding was observed in any other brain regions. There was also a significant increase in the PDBu-stimulated activity of protein kinase C in the amygdaloid cytosolic fraction prepared without Ca^<2+> 14 days after treatment with clomipramine whereas fluoxetine had little influence, indicating an increase in the cytosolic protein kinase C but not the membrane-bound protein kinase C. T ne (PCPA) for 7 days caused an increase in [^3H]PDBu binding sites in amygdaloid membranes but 5-hydroxy-tryptophan (5-HTP) abolished the increase in the binding sites induced by PCPA. Furthermore, treatment with either ritanserin, a selective 5-HT_2 antagonist, or methysergide, a both 5-HT_<1C> and 5-HT_2 antagonist, mimicked the effect of PCPA in amygdala, leading to the suggestion that the reduction in synaptic 5-HT availability may contribute to the increase in [^3H]PDBu binding sites induced by long-term effect of the specific agents. Since both 5-HT_2 and 5-HT_<1C>-receptors are coupled to the inositol phospholipid turnover system, these results suggest that the increase in the [^3H]PDBu binding sites might reflect an "up-regulation" of protein kinase C in response to the reduction in the turnover of inositol phospholipids.
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