| Co-Investigator(Kenkyū-buntansha) |
FURUKAWA Nobuya Yokohama City Univ.Sch.Med., Dept.Pharmacol., Res. Assoc., 医学部, 助手 (90285114)
FUKUSHIMA Nobuyuki Yokohama City Univ.Sch.Med., Dept.Pharmacol., Res. Assoc.(U.C.S.D., Dept.Pharmac, サンディエゴ校・医学部, 助手 (10254161)
MIYAMAE Takeaki Yokohama City Univ.Sch.Med., Dept.Pharmacol., Res.Assoc., 医学部, 助手 (00239435)
GOSHIMA Yoshio Yokohama City Univ.Sch.Med., Dept.Pharmacol., Assoc.Prof., 医学部, 助教授 (00153750)
UEDA Hiroshi Yokohama City Univ.Sch.Med., Dept.Pharmacol.Assoc.Prof.(nagasaki Univ.Sch.Pharma, 薬学部, 教授 (00145674)
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| Budget Amount *help |
¥33,300,000 (Direct Cost: ¥33,300,000)
Fiscal Year 1997: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 1996: ¥5,700,000 (Direct Cost: ¥5,700,000)
Fiscal Year 1995: ¥23,700,000 (Direct Cost: ¥23,700,000)
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| Research Abstract |
1 Rat lower brainstem : (1) DOPA is a transmitter of the primary baroreceptor afferents terminating in the nucleus tractus solitarii (NTS). (2) DOP Aergic transmission in NTS is inhibited pre- and post-synaptically via GABAA receptors by endogenously released GABA,while DOPA microinjected releases neuronal GABA.(3) There exists baroreceptor-aortic and carotid sinus nerves-NTS-caudal ventrolateral medulla (CVLM) DOP Aergic neuronal pathway. (4) In comparison with age-matched Wistar Kyoto rats, respective sttenuation, abolition and augmentation of neuronal DOPA release in NTS,CVLM and rostral VLM (RVLM), decrease in AADC activities and increase in pressor responses to DOPA in RVLM of adult spontaneously hypertensive rats are involved in maintenance of hypertension. (5) Newly developed DOPA cyclohexyl ester (CHE) is a potent and stable competitive antagonist for DOPA,as compared to DOPA methyl ester (ME). Further development of high affinity iode-labelled antagonist ligand is now in progr
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ess. (6) In patch-clamp whole cell recordings of NTS single neurons isolated from young rats, DOPA elicits ME-sensitive increase in high voltage-activated Ca^<2+> channel currents. (7) In Xenopus laevis oocytes injected with poly (A)^+ RNA from pooled NTS of rats received aortic nerve denervation, DOPA elicited inward currents, but currents were too small to continue cDNA cloning of DOPA receptors. 2 Striatum : (1) Endogenously released DOPA potentiates activities of postsynaptic D2 receptors relating to locomotor activities. (2) During microdialysis in Parkinson's model rats received 6-OHDA injections in medial forebrain bundle, DOPA (nM) inhibits by itself acetylcholine release.(3) In the model membrane preparations, DOPA (pM) slightly inhibits GTPase activities. 3 DOPA-glutamate-interactions : (1) After simultaneous injections of poly (A)^+ RNA from the model striatum and cRNA from mGlu-R1 in oocytes, DOPA (pM) elicited ME-sensitive modifications of mGlu-R1 currents. This approach, however, was not suitable, because a DOPA recognition site was endogenously expressed in some oocytes. (2) The DOPA recognition site differs from glutamate receptors : in brain membrane preparations, DOPA displaces selective binding of ^3H-AMPA with a low affinity (IC50,260muM), but elicits no displacement against ^3H-kainate, -CGP39653, -MK-801 and -DCKA,while ME and CHE displace only binding of ^3H-MK-801 with a low affinity (IC50,1.00 and 0.68 mM). (3) We reported that during striatal microdialysis of conscious rats, DOPA (nM) releases neuronal glutamate, the non-effecive dose markedly sensitizes glutamate release in rats pretreated with i.c.v.6-OHDA injections. But, some problems were found in measurement system of glutamate release. Reconfirmation experiments are now in progress. (4) In 10 days in culture of fetal striatal neurons, 100 muM DOPA surely releases glutamate and elicits delayd neuronal cell death in a glutamate antagonists-sensitive, stereoselective and autoxidation-ir Less
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