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Creating and Validating Rat Models for Cognitive Deficits of Schizophrenia

Research Project

Project/Area Number 08457251
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Psychiatric science
Research InstitutionFukushima Medical Univ. School of Medicine

Principal Investigator

NIWA Sin-ichi  Fukushima Medical Univ., School of Medicine, Professor, 医学部, 教授 (30110703)

Co-Investigator(Kenkyū-buntansha) 竹内 賢  福島県立医科大学, 医学部, 助手 (90285023)
Project Period (FY) 1996 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 1998: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1997: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1996: ¥2,700,000 (Direct Cost: ¥2,700,000)
Keywordsschizophrenia / rats / neonatal hippocampla lesion / phencyclidine / cognitive deficit / P3-like potential / nucleus accumbence / dopamine release / ドパミン / 海馬 / 興奮性アミノ酸 / メタンフェタミン / フェンサクリジン
Research Abstract

In the present study, two experiments were conducted in order to clarify biological mechanisms leading to a fundamental impairment in schizophrenia, cognitive deficit. First, we carried out a trial of replicating in rats a significant evidence for cognitive deficit of schizophrenia, amplitude reduction and latency prolongation of P3 which is a component of event-related potentials reflecting the cognitive function. In the first experiment, repeated MAP administration and PCP administration models were employed as rat models of schizophrenia. Second, we attempted to record P3-like potentials in neonatal hippocampal lesioned rat, a new rat model of schizophrenia. The neonatal hippocampal lesion model was first introduced as an animal model of schizophrenia by Lipska and her colleagues who made lesion by administering the ibotenic acid in the ventral hippocampus of rats.
1)In the first experiment, male SD rats were trained to discriminate two different tones pressing a response lever to on … More e designated tone. Electrical stimulation to the medial forebrain bundle(MFB)was delivered to correct responses as rewards to facilitate the require3d discrimination learning. After rats were trained in the discrimination task, constantly yielding good performance levels of more than 85% hit rates, P3-like potentials were begun to be recorded. The rats displayed P3-like potentials to rare tones in the discrimination task markedly similar to human P3 potentials.
The P3-like potentials in rats were remarkably attenuated after repeated administration of MAP as well as PCP. Because MAP and PCP psychosis are thought to be models of schizophrenia, the P3-like potential reduction in rats receiving repeated administration of MAP and PCP is expected to provide a clue for elucidating neurochemical and neuroanatomical bases for P3 reduction in schizophrenia. Although P3 amplitude reduction was replicated, P3 latency prolongation was not replicated in these rats. This result may indicate that P3 latency prolongation is caused by different reasons from those for P3 amplitude reduction in schizophrenia.
2)In the second experiment, the neonatal hippocampal lesioned rats displayed excessive behavioral responses (hyperlocomotion) to PCP and MAP at the postnatal day 56 (PD56) but not at PD35. PD56 is post-pubertal, while PD 35 is in the pre-pubertal period. This result is intriguing in terms of the well-known fact that schizophrenia mainly starts after puberty. This result indicates the validity of the neonatal hippocampal lesion model of schizophrenia. We measured the extracellular concentrations of dopamine (DA) and its metabolites in the nucleus accumbens (NAc) by means of mycrodialysis from the lesioned and sham-operated rats before and after repeated administration of PCP. Repeated administration of PCP increased DA and its metabolites concentrations in both hippocampal lesioned and sham-operated rats ; however, the extents of increase were greater in the sham-operated rats than the lesioned rats, which was inconsistent with the result for behavioral responses after PCP. Taking these results into account, it is suggested that the mechanisms for hyperlocomotion includes not only increased DA release but also decreased GABAergic inhibition due to NMDA receptor blockade as well ad increased signal transmission in the DA system exclusively at the intracellular processes.
3)The neonatal hippocampal lesioned rats had difficulties in learning so that the performance levels for the two-tone discrimination task were markedly delayed in improving. When the P3-like potentials were recorded in the lesioned rats, they failed to display distinct P3-like potentials. At this moment, the reason for extremely attenuated P3-like potentials in the lesioned rats remains to be clarified in further research particularly employing larger number of lesioned rats with exceeding performance levels over the designated criteria. Less

Report

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

    (39 results)

All Other

All Publications (39 results)

  • [Publications] Ito,Mitsuhiro: "Social cue perception in Japanese schizophrenic patients"Schizophrenia Research. 34. 113-119 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 高野佳寿子: "精神病と記憶障害"Clinical Neuroscience. 16. 174-177 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 丹羽真一: "分裂病の認知障害、陰性症状、生活障害"精神医学レビュー. 27. 56-65 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 丹羽真一: "精神分裂病の認知障害、その生理学的基盤"作業療法ジャーナル. 32. 997-1004 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 丹羽真一: "幻覚の発生機構と神経生理学"臨床精神医学. 27. 747-752 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Takeuchi,Satoshi: "Effects of repeated administration of methamphetamine on P3-like potentials in rats"International Journal of Psychophysology. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 加藤光三: "幼若期海馬傷害ラットの成熟後のphencyclidine反応性と側坐核におけるdopamineおよびその代謝産物の変化"精神薬療基金研究年報. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Suzuki,Yoshiaki: "Repeated administration of phencyclidne attenuates P3b-like potential in rats"International Journal of Psychophysology. 30. 124-124 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 丹羽真一: "臨床精神医学講座2 精神分裂病I(松下正明 編集)神経生理学"中山書店. 30

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Niwa, S., Takeuchi, S., Suzuki, Y., Hoshino, K. and Matsuki, T.,: "Implications of catecholaminergic dysfunction in P300 reduction of schizophrenia."Ogura, C., Koga, Y., Shimokochi, M. (eds.), Recent advances in event-related brain potential research. Elsevier, Amsterdam. 911-915 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Niwa, S., Takeuchi, S., Suzuki, Y., Hoshino, K. and Matsuki, T.: "Clinical and experimental observations on the relationship between P300 and catecholamines for schizophrenia research."Kimura, J., Shibazaki, H. (eds.), Recent Advances in Clinical Neurophysiology, Elsevier, Amsterdam. 723-726 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Takeuchi, S., Hoshino, K., Kurosu, S., Mori, Y., Honda, K., Suzuki, H. and Niwa, S.: "Serial Changes of P300, p-HVA and p-MHPG in the cuurse of treatment of schizophrenia"Ogura, C., Koga, Y., Shimokochi, M. (eds.), Recent advances in eventrelated brain potential research. Elesevier, Amsterdam. 984-989 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shishido, T., Watanabe, Y., Matsuoka, I., Nakanishi, H. and Niwa, S.: "Acute methampetamine administration increases tyrosine hydroxylase mRNA levels in rat locus coeruleus."Molecular Brain Res. 52. 146-150 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shishido, T., Watanabe, Y., Suzuki, H., Kato, K., Newa, S., Hanoune, J. and Matsuoka, I.: "Effects of repeated methamphetamine administration on dopamine D1 receptor, D2 receptor and adenylate cyclase type V mRNA levels in the rat striatum."Neuroscience Letters. 222. 175-178 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ito, M., Kanno, M., Mori, Y. and Niwa, S.: "Attention deficits assessed by Continuous Performance Test and Span of Apprehension Test in Japanese schizophrenic patients."Schizophrenia Res.. 23. 205-211 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Fukuda, M., Niwa, S., Hiramatsu, K., Hata, A., Saitoh, O., Hayashida, S., Nakagome, K., Iwanami, A., Sasaki, T., Honda, H. and Itoh, k.: "Behavioral and P3 amplitude enhancement in schizophrenia following feedback training."Schizophrenia Res.. 25. 31-242 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ito , M., Shiragata, M., Kanno, M., Mori, Y., Hoshino, K. and Niwa, S.: "Social cue perception in Japanese schizophrenic patients."Schizophrenia Res. 34. 113-119 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Suzuki, Y., Jodo, E., Takeuchi, S., Kayama, Y. and Niwa, S.: "Repeated administration of phencyclidine attenuates P3b-like potential in rats."Int J Psychophysiol.. 30. 124 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Takeuchi, S., Jodo, E., Suzuki, Y., Matsuki, T., Kayama, Y. and Niwa, S.: "Effects of repeated administration of methamphetamine on P3-like potentials in rats."Int J Psychophysiol. 32. 183-192 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ito, Mitsuhiro: "Social cue perception in Japnese schizophrenic patients" Schizophrenia Research. 34. 113-119 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 高野佳寿子: "精神病と記憶障害" Clinical Neuroscience. 16(2). 174-177 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 丹羽真一: "分裂病の認知障害、陰性症状、生活障害" 精神医学レビュー. 27. 56-65 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 丹羽真一: "精神分裂病の認知障害、その生理学的基盤" 作業療法ジャーナル. 32. 997-1004 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 丹羽真一: "幻覚の発生機構と神経生理学" 臨床精神医学. 27(7). 747-752 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takeuchi, Satoshi: "Effects of repeated administration of methamphetamine on P3-like potentials in rats" International Journal of Psychophysology. in press.

    • Related Report
      1998 Annual Research Report
  • [Publications] 加藤光三: "幼若期海馬障害ラットの成熟後のphencyclidine反応性と側坐核におけるdopamineおよびその代謝産物の変化" 精神薬療基金研究年報. in press.

    • Related Report
      1998 Annual Research Report
  • [Publications] Suzuki, Yoshiaki: "Repeated administration of phencyclidne attenuates P3b-loke potential in rats" International Journal of Psychophysology. 30. 124-124 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 丹羽真一: "臨床精神医学講座2 精神分裂病I(松下正明 編集)神経生理学" 中山書店, 169-199(30) (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] 伊藤光宏: "精神分裂病の認知障害" 精神病治療の最新情報. 3(3). 10-12 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ito,M: "Attention dificits assessed by Continuous Performance Test and Span of Apprehension Test in Japanese schizophrenic patients." Schizophrenia Research. 23. 205-211 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 丹羽真一: "分裂病の認知障害" こころの科学. 73. 2-6 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 丹羽真一: "分裂病の臨床(1)-診断・治療の進歩" 日本医事新報. 3816. 19-32 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 丹羽真一: "分裂病の臨床(2)-診断・治療の進歩" 日本医事新報. 3817. 18-25 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 丹羽真一: "発症予防の観点から見た精神分裂病の病態" 日本社会精神医学会雑誌. 5(2). 224-227 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 丹羽真一: "認知科学から見た分裂病の症状" 臨床精神病理. 18(2). 106-109 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 丹羽真一: "「分裂病と分裂病型人格障害の臨床的研究」の概要" 精神分裂病研究の進歩. 6(1). 104 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Fukuda,M: "Behavioral and P3 amplitude enhancement in schizophrenia following feedback training" Schizophrenia Research. 25. 231-242 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 斎藤薫: "精神分裂病患者の思考障害に対するHarrow思考障害スケール(日本語版)の有用性の検討" 臨床精神医学. 26(11). 1443-1451 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 宍戸壽明: "Methamphetamine単回 ラット脳におけるtyrosine hydroxylase mRNAの経時的変化" 精神薬療基金研究年報. 28. 184-189 (1997)

    • Related Report
      1997 Annual Research Report

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

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