| Co-Investigator(Kenkyū-buntansha) |
MOTOHASHI Noburaka NCNP,Musashi Hsp.Section Chief, 神経センター・武蔵病院, 医長 (30166342)
MURAOKA Mitsutaro Hiroshima Univ.Schl.Medicine Research Assrociate, 医学部, 助手 (40229951)
HAYAKAWA Hiroshi Hiroshima Univ.Schl.Medicine Research Associate, 医学部, 助手 (80243559)
UCHITOMI Yosuke Hiroshima Univ.Schl.Medicine Assistant Professor, 医学部, 講師 (60243565)
長田 昌士 広島大学, 医学部, 助手 (50233507)
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| Budget Amount *help |
¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 1994: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1993: ¥3,700,000 (Direct Cost: ¥3,700,000)
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| Research Abstract |
We have investigated intracellular Ca^<2+> signaling systems to understand the pathophysiology of affective disorders.
1.Platelets form bipolar manic patients were prepared for intracellular Ca^<2+> measurement. 5-HT-induced intracellular Ca^<2+> mobilization in platelets from manic patients was significantly greater than that of control subjects. Moreover, plateau phase after the peak was also enhanced in manic patients.
2.The intracellular signaling system following Ca^<2+> rise mediated by 5-HT-2A receptors was investigated, and we have found that an activation of 5-HT-2A receptors facilitates calcium-sensitive NO synthase-like activity, producing cGMP in the cells of glial origin.
3.Lithium, which is the most popular mood stabilizer, is proved to be effective on Ca^<2+> exchanging system in the CNS.Lithium inhibited ouabain-induced intracellular Ca^<2+> rise in rat hippocampal slice. Thus, lithium appears to affect intracellular rather than receptors on the cell surface.
4.Amitriptylin
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e, imipramine, desipramine and mianserin at high concentrations increased Ca^<2+> in primary cultured rat cortical neurons. The antidepressants also increased IP_3 formation up to 150 % of basal levels. These results indicate that antidepressant drugs directly activate intracellular signaling pathways, resulting in an increase in Ca^<2+>. Furthermore, 30 muM imipramine reduces depolarization-induced Ca^<2+> rise in cultured cortical neurons. Imipramine and amitriptyline, at the concentrations of 10-50 muM,inhibited spontaneous oscillations in cultured neuronal cells. Tricyclic antidepressants are amphiphilic so that they can easily penetrate cell membrane, regulating most of intracellular responses including Ca^<2+> signaling system.
5.GABA,as well as NMDA,increased Ca^<2+> in primary cultured rat cortical neurons, and these response was modulated by pregnenolone sulfate, a neurosteoroid.
Thus, it is important to investigate intracellular Ca^<2+> signaling system to understand the pathophysiology of affective disorders. Less
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