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Role of sigma receptors in the animal models for neuropsychological diseases.

Research Project

Project/Area Number 08457027
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionNagoya University

Principal Investigator

NABESHIMA Toshitaka  School of Medicine, Nagoya University, Professor, 医学部, 教授 (70076751)

Co-Investigator(Kenkyū-buntansha) HASEGAWA Takaaki  School of Medicine, Associate Professor, 医学部, 教授 (80198720)
Project Period (FY) 1996 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥7,400,000 (Direct Cost: ¥7,400,000)
Fiscal Year 1998: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1997: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1996: ¥3,400,000 (Direct Cost: ¥3,400,000)
KeywordsSigma receptors / Neurostereoids / Stress / Schizophrenia / Drug dependence / Learning and memory / ストレス疾病モデル / 一酸化窒素(NO) / NO合成阻害薬 / 依存 / phenytoin感受性シグマ1受容体 / ドパミン作動性神経系 / cyclic GMP
Research Abstract

9-1. We examined the effects of sigma receptor-related agents on conditioned fear stress (CFS) response that could not be attenuated by typical antidepressants and anxiolytics in mice. The activation of phenytoin-sensitive sigma1 receptors which are closely connected to the meso-limbic dopaminergic systems was demonstrated to be involved in the ameliorating effects of (+) -SKF-10,047 and dextromethorphan, sigma1 receptor agonists on the CFS response. Dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate, neurosteroids that have an affinity for sigma1 receptors, also attenuated the CFS response. The DHEAS concentration in the serum of mice showing CFS response was lower than that in the non-stressed mice. These findings suggested that neurosteroids play an important role in the expression of CFS response.
9-2. We developed the animal model for negative symptom in schizophrenia using phencyclidine (POP), which produces schizophrenic-like symptom in human, and examined the effect … More s of sigma receptor-related agents on PCP-induced negative symptom-like action. (+) -SKF-10,047 as well as PCP induced negative symptom-like action in mice. Sigma receptor antagonists did not attenuate the PCP-induced negative symptom-like action. Although sigma receptors may be involved in expression of PCP-induced negative symptom-like action, it is unlikely that sigma receptor antagonists are candidates of potential therapeutic drug for negative symptoms in schizophrenia.
9-3. We examined the effects of sigma receptor-related agents on the discriminative stimulus effects of PCP in rats using drug discrimination test. Sigma receptor agonists did not produce PCP-like discriminative stimulus effects in rats trained to discriminate PCP from saline. The discriminative stimulus effects of PCP were not attenuated by sigma receptor antagonists. These findings suggested that sigma receptors were not involved in the discriminative stimulus effects of PCP.
9-4. N^G-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor and dizocilpine, non-competitive NMDA receptor antagonist, impaired the spatial working memory in mice and rats, respectively. These impairments were ameliorated by (+) -SKF-10,047, the ameliorating effect being antagonized by NE-lO0. These findings suggested that sigma receptors were involved in the regulation of processes required for spatial memory formation. Less

Report

(4 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] Kiyofumi Yamada: "Role of nitric oxide and cyclic GMP in the dizocilpine-induced impairment of spontaneous alternation behavior in mice." Neuroscience. 74. 365-374 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hiroyuki Kamei: "(+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress through the activation of phenytoin-regulated σ1 sites." European Journal Pharmacology. 299. 21-28 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kiyofumi Yamada: "Simultaneous measurement of nitrite and nitrate levels as indices of nitric oxide release in the cerebellum of conscious rats." Journal of Neurochemistry. 68. 1234-1243 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kiyofumi Yamada: "Two pathways of nitric oxide production through glutamate receptors in the rat cerebellum in vivo." Neuroscience Research. 28. 93-102 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yukihiro Noda: "Involvement of dopaminergic system in phencyclidine-induced place preference in mice pretreated with phencyclidine repeatedly." Journal of Pharmacology and Experimental Therapeutics. 286. 44-51 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Li-Bo Zou: "σ Receptor ligands (+)-SKF10,047 and SA4503 improve dizocilpine-induced spatial memory deficits in rats." European Journal Pharmacology. 355. 1-10 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kiyofumi Yamada: "Role of nitric oxide and cyclic GMP in the dizocilpine-induced impairment of spontaneous alternation behavior in mice." Neuroscience. 74. 365-374 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hiroyuki Kamei: "(+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress through the activaion of phenytoin-regulated sigma_1 sites." European Journal Pharmacology. 299. 21-28 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kiyofumi Yamada: "Simultaneous measurement of nitrite and nitrate levels as indices of nitric oxide release in the cerebellum of conscious rats." Journal of Neurochemistry. 68. 1234-1243 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kiyofumi Yamada: "Two pathways of nitric oxide production through glutamate receptors in the rat cerebellum in vivo." Neuroscience Research. 28. 93-102 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yukihiro Noda: "Involvement of dopaminergic system in phencyclidine-induced place preference in mice pretreated with phencyclidine repeatedly." Journal of Pharmacology and Experimental Therapeutics. 286. 44-51 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Li-Bo Zou: "sigma Receptor ligands (+)-SKF10,047 and SA4503 improve dizocilpine-induced spatial memory deficits in rats." European Journal Pharmacology. 355. 1-10 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yukihiro Noda: "Involvement of dopaminergic systen in phencyclidine-induced place preference in mice pretreated with phencyclidine repeatedly." Journal of Pharmacology and Experimental Therapeutics. 286. 44-51 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Li-Bo Zou: "σ Receptor ligands (+)-SKF10,047 and SA4503 improve dizocilpine-induced spatial memory deficits in rats." European Journal Pharmacology. 355. 1-10 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Masayuki Hiramatsu: "Effects of U-50,488H on scopolamine-,mecamylamine- and dizocilpine-induced learning and memory impairment in rats." Journal of Pharmacology and Experimental Therapeutics. 284. 858-867 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Li-Bo Zou: "Nitric oxide synthase inhibitors impair reference memory formation in a radial arm maze task in rats." Neuropharmacology. 37. 323-330 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kiyofumi Yamada: "Simultaneous measurement of nitrite and nitrate levels as indices of nitric oxide release in the cerebellum of conscious rats" J.Neurochem. 68. 1234-1243 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kiyofumi Yamada: "Two pathways of nitric oxide production through glutamate receptors in the rat cerebellum in vivo" Neurosci.Res.28. 93-102 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hiroyuki Kamei: "Role of (+)-SKF-10,047-sensitive sub-population of ^σ1 receptors in amelioration of conditioned fear stress in rats: association with mesolimbic dopaminergic systems" Eur.J.Pharmacol.319. 165-172 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] シュウ リハ: "Dizocilpine(MK-801)により輸発されるラットの空間記憶障害に対するσligand(+)-SKF-10,047の改善作用" 日本神経精神薬理学雑誌. (印刷中). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] 亀井雪江: "恐怖条件付ストレス反応に対するニューロステロイドの作用" 日本薬理学雑誌. (印刷中). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yukihiro Noda: "Role of nitric oxide in the phenclidine-indiced place preference in mice" The Biology of Nitre Oxide. Part 6. (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kiyofumi Yamada: "Role of nitric oxide and cyclic GMP in the dizocilpine-induced impairment of spontaneous alternation behavior in mice" Neuroscience. 74 : 2. 365-374 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiroyuki Kamei: "(+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress through the activation of phenytoin-regulated σ 1 sites" European Journal of Pharmacology. 299. 21-28 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiroyuki Kamei: "(+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress via dopaminergic systems linked to phenytoin-regulated σ 1 sites" European Journal of Pharmacology. 309. 149-158 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiroyuki Kamei: "Role of (+)-SKF-10,047-sensitive sub-population σ 1 receptors in amelioration of conditioned fear stress in rats : association with mesolimbic dopaminergic systems" European Journal of Pharmacology. 319. 165-172 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kiyoyuki Kitaichi: "In vivo functional interaction between phencyclidine binding sites and σ receptors to produce head-weaving behavior in rats" European Journal of Pharmacology. 318. 205-211 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Takayoshi Mamiya: "Effects of sigma receptor ligands on nitric oxide synthase inhibitor-induced impairment of alternation behavior in mice" Japanese Journal of Pharmacology. 71 : Suppl.I. 93P (1996)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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