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Die Wirkung von Antipsychotika auf glutamaterge Neurotransmission im Tiermodell

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Zusammenfassung

Post-mortem-Untersuchungen bestätigten, dass glutamaterge NMDA-, AMPA- und Kainatrezeptoren an der Pathophysiologie der Schizophrenie beteiligt sind. Ob die veränderten Rezeptorzahlen dabei krankheits- oder medikamentenbedingt sind, ist bislang unklar. Im Tiermodell wurde deshalb der Einfluss von antipsychotischer Medikation nach bis zu 6-monatiger Behandlung untersucht und hier zusammengefasst.

Übereinstimmend ergab sich eine erhöhte NMDA-Rezeptor-Bindung nach Haloperidol im Striatum und Nucleus accumbens, nach Clozapin nur im Nucleus accumbens. Die AMPA-Rezeptorzahl war nach Haloperidol im Gyrus cinguli, Striatum, insulären Kortex sowie Nucleus accumbens, nach Clozapin im anterioren Gyrus cinguli und infralimbischen Kortex erhöht. Die Kainatrezeptorbindung wurde im Hippokampus von beiden Antipsychotika erhöht, jedoch in größerem Ausmaß von Clozapin.

Die Ergebnisse zeigen einen differenziellen Effekt zwischen dem Neuroleptikum Haloperidol und dem Atypikum Clozapin. Ein Teil der post-mortem erhobenen Befunde im glutamatergen System bei Patienten mit langjähriger Schizophrenie lassen sich auf auf Medikamenteneffekte zurückführen und sind Ausdruck plastischer Veränderungen durch die Langzeitmedikation mit Antipsychotika.

Summary

Post-mortem investigations have confirmed that glutamatergic NMDA, AMPA, and kainate receptors are involved in the pathophysiology of schizophrenia. It is still unclear, however, whether the altered number of receptors is caused by the disease itself or the medication. Therefore, animal models were investigated for effects of antipsychotic medication after treatment periods of up to 6 months, the results of which are summarized here.

Generally, NMDA receptor binding was found to be increased in striatum and nucleus accumbens after therapy with haloperidol, whereas clozapine only increased the number of receptors in nucleus accumbens. While haloperidol led to an increase in AMPA receptors in the posterior cingulate gyrus, striatum, insular cortex, and n. accumbens, clozapine was found to elevate ligand binding in the anterior cingulate gyrus and infralimbic cortex. Although kainate receptor binding was increased in hippocampus by both antipsychotics, clozapine was significantly more effective.

In conclusion, data reveal different effects from the typical neuroleptic haloperidol and the atypical antipsychotic clozapine. The results suggest that post-mortem findings in patients with schizophrenia may at least partially be explained by drug effects and plasticity changes induced by long-term medication with antipsychotics.

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  1. Zentralinstitut für Seelische Gesundheit, Universität Mannheim

    A. Schmitt, B. May, B. Müller, M. Zink, D. F. Braus & F. A. Henn

  2. Zentralinstitut für Seelische Gesundheit, Universität Mannheim, J5, 68159 , Mannheim

    A. Schmitt

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Schmitt, A., May, B., Müller, B. et al. Die Wirkung von Antipsychotika auf glutamaterge Neurotransmission im Tiermodell. Nervenarzt 75, 16–22 (2004). https://doi.org/10.1007/s00115-003-1593-3

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