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Do atypical antipsychotic drugs improve symptoms of schizophrenia by influencing noradrenergic neurons?

Research Project

Project/Area Number 13671039
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Psychiatric science
Research InstitutionUniversity of Occupational and Environmental Health

Principal Investigator

NAKAMURA Jun  School of Medicine Psychiatry Professor (Chairman), 医学部, 教授 (40148804)

Co-Investigator(Kenkyū-buntansha) YOSHIMURA Reiji  School of Medicine Psychiatry Assistant Professor, 医学部, 講師 (90248568)
TERAO Takeshi  School of Medicine Psychiatry Associate Professor, 医学部, 助教授 (80217413)
YANAGIHARA Nobuyuki  School of Medicine Pharmacology Professor (Chairman), 医学部, 教授 (80140896)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥1,700,000 (Direct Cost: ¥1,700,000)
Keywordsatypical antipsychotic drugs / noradrenaline transporter / clozapine / risperidone / adrenal medullary cells / MHPG / HVA / catecholamine / ノルアドレナリン取り込み / デシプラミン結合 / 阻害 / clozapine / zotepine
Research Abstract

The effects of long-term treatment with clozapine on functional activity, synthesis and mRNA of noradrenaline transorter (NAT) were examined in bovine adrenal medullary cells in culture. Treatment of cells with clozapine at 0.1-3.0 μM concentrations produced dual phases of changes in [^3H]noradrenaline(NA) uptake, i.e. the first phase showed a decrease in [^3H]NA uptake at 2-48h, and the following phase showed an increase in uptake at 72-168h. Treatment with clozapine for 6h decreased V_<max> to 40% of the control without changing the K_m value for [^3H]NA uptake. However, treatment with clozapine for 96h increased V_<max> by 56% over the control without a change in K_m. Scatchard plot analysis of [^3H]desipramine(DMI) binding to membranes isolated from cells treated with clozapine for 6h revealed a decrease in B_<max> without any change in K_d ; in contrast, treatment with clozapine for 96h caused an increase in B_<max> without any change in K_d. Both actinomycin D and cycloheximide, which are inhibitors of protein synthesis, suppressed the clozapine (96h)-induced increase in [^3H]NA uptake. Treatment of cells with clozapine for 12-96h increased the level of NAT mRNA in a concentration-dependent manner (0.1-3.0 μM). These findings suggest that treatment with clozapine results in the down-regulation and subsequent up-regulation of NAT. In addition, we examined the relationship among the clinical efficacies of risperidone, plasma free 3-methoxy-4-hydroxyphenylglycol (pMHPG) and plasma homovanillic acid (pHVA) in 34 schizophrenic patients. Clinical improvement in negative symptoms of schizophrenia treated with risperidone has been associated with increased pMHPG and pHVA levels in the responders to risperidone were higher than those of nonresponders before risperidone administration. These results suggest that risperidone might improve positive and negative symptoms in schizophrenia by influencing dopaminergic and noradrenergic neurons, respectively.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] Yoshimura R et al.: "Plasma levels of homovanillic acid and the response to risperidone in first episode untreated acute schizophrenia"International Clinical Psychopharmacology. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ueda N, et al.: "Fluvoxamine improves some depressive symptoms by influencing noradrenergic neurons"Psychiatry Research. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshimura R et al.: "Interaction between fluvoxamine and cotinine or caffeine"Neuropsychobiology. 45. 32-35 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ueda N, et al.: "Plasma levels of catecholamine metabolites predict the response to sulpiride or fluvoxamine in major depression"Pharmacopsychiatry. 35. 175-181 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shinkai K, et al.: "Pretreatment plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) may predict response to milnacipral or paroxetine"International Journal of Neuropsychopharmacology. 5. 204-205 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 吉村玲児他: "抗うつ薬、抗精神病薬と反応性予測"臨床精神薬理. 6. 313-319 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 中村 純: "臨床精神薬理ハンドブック"医学書院(印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshimura R, et al.: "Plasma levels of homovanillic acid and response to risperidone in first episode untreated acute schizophrenia"International Clinical Psychopharmacology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ueda N, et al.: "Fluvoxamine improves some depressive symptoms by influencing noradrenergic neurons"Psychiatry Research. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshimura R, et al.: "Interaction between fluvoxamine and cotinine or caffeine"Neuropsychobiology. 45. 32-35 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ueda N, et al.: "Plasma levels of catecholamine metabolites predict the response to sulpiride or fluvoxamine in major"Pharmacopsychiatry. 35. 175-181 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shinkai K, et al.: "Pretreatment plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) may predict response to milnacipran or paroxetine"International Journal of Neuropsychopharmacology. 5. 204-205 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshimura R, et al.: "Prediction of response to antidepressants and antipsychotics : view from plasma levels of monoamine metabolites (in Japanese)"Japanese Journal of Clinical Psychopharmacology. 6. 313-319 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] "Phamacology of sleepdisorders/Hypnotics, Handbook of Clinical Psychopharmacology (in Japanese), (in press)"Igakushoin.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshimura R et al.: "Plasma levels of homovanillic acid and the response to risperidone in first episode untreated acute schizophrenia"International Clinical Psychopharmacology. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Ueda N, et al.: "Fluvoxamine improves some depressive symptoms by influencing noradrenergic neurons"Psychiatry Research. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshimura R et al.: "Interaction between fluvoxamine and cotinine or caffeine"Neuropsychobiology. 45. 32-35 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ueda N, et al.: "Plasma levels of catecholamine metabolites predict the response to sulpiride or fluvoxamine in major depression"Pharmacopsychiatry. 35. 175-181 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shinkai K, et al.: "Pretreatment plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) may predict response to milnacipral or paroxetine"International Journal of Neuropsychopharmaclolgy. 5. 204-205 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 吉村玲児他: "抗うつ薬、抗精神病薬と反応性予測"臨床精神薬理. 6. 313-319 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 中村 純: "臨床精神薬理ハンドブック"医学書院(印刷中).

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshimura, R. et al.: "Dual Phases of functional charge in norepirephrine transporter in cultured bovine adrenal medullary cells"by long-term treatment with clozapine Journal of Neurochemistry. 77. 1018-1026 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Terao, T. et al.: "High serum cholesteral and suicide risk"American Journal of Psychiatry. 158. 824 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 上田展久 他: "非定型抗精神病薬の長期有害事象"臨床精神薬理. 4. 881-888 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 吉村玲児 他: "海外におけるolanzapineの臨床成績"臨床精神薬理. 4. 939-944 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nakamura J. et al.: "Treds in prescription of antipychotic drugs for schizophrenic inpatients in Japan"International Clinical Psychopharmacology. 16. 300-301 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yoshimura, R. et al.: "Possible relationship between combined plasma concert-rations of risperidoneplus 9-hydroxyrisperidone and"extrapynamidol Symptons Neuropsychobioloty. 44. 129-133 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 中村 純: "症状性精神障害と化学物質中毒などによる精神障害-標準精神医学"医学書院. 15 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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