1991 Fiscal Year Final Research Report Summary
Biochemical and pharmacolotical pathogenesis of dyskinesia in the IDPN-treated rat model
| Project/Area Number |
01570449
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Neurology
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| Research Institution | Okayama University |
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Principal Investigator |
OGAWA Norio Okayama University Medical School, Associate Professor, 医学部, 助教授 (90033208)
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| Project Period (FY) |
1989 – 1991
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| Keywords | Dyskinesia / IDPN / Serotonergic Mechanism / Dopaminergic Mechanis / Aged-rat / Receptors / Ceruletide / Messenger RNA |
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| Research Abstract |
Chronic administration of iminodipropionitrile(IDPN). a neurotoxine, to rats produces a persistent behavioral syndrome characterized by lateral and vertical head twitching. Conventionally. this IDPN-induced dyskinesia has been considered to be due to abnormalities in the serotonin neuronal system. However, the present srudy also demonstrated marked alterations in the dopamine(DA)and acetylcholine(ACh)neuronal systems. Receptor alterations in the DA and ACh neuronal systems may be secondary due to abnormalities in these neurotransmetter systems. Assays of monoaminergic neurotransmitters and their metabolites in various brain regions-indicate that an imbalance between dopaminergic and serotonergic neuronal systems play a major role in the pathogenesis of the IDPN-induced dyskinesia, i. e. the ratio of(DOPAC+HVA)/5HIAA was significantly greater in the striatum but significantly smaller in the hippocampus of the IDPN-treated vs normal animals. IDPN-induced dyskinasia was enhanced by admini
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stration of levodopa, which increases dopamine concentration, but was completely inhibited by ceruletide, which inhibits dopamine release. After repeated daily dose of cedruletide for 6 days, the number of head swiches was reduced to low levels and remained significantly below pretreatment levels until the 4th posttreatment day. These results indicate that the inhibition of dyskinesia by ceruletide was long-lasting. Initially abnormal ratio of(DOPAC+HVA)/5-HIAA in the striatum and hippocampus of IDPN-treated animals returned to normal following treatment with ceruletide, corresponding with the reduction of head twitching. Ceruletide also exerted a marked effect on dopaminergic receptors and their messenger RNA expressions in the IDPN-treated rats, in contrast to only a slight effect in normal animals. The obsered beneficial effect of ceruletide on impaired neuronal pathways indicates that it acts as a neuro-normalizer in the animal model of IDPN-induced dyskinesia. Thus, ceruletide may useful in the treatment of dyskinesia, and the IDPN-treated rat model is useful for clarifing the biochemical pathophysiology of dyskinesia and developing drugs for its treatment. Less
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