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Neurobiochemie, Wirkungsmechanismen

  • J. Fritze

Zusammenfassung

Aus der indischen Volksmedizin hervorgehend wurde als erstes antipsychotisches Medikament Reserpin durch Sen und Bose im Jahre 1931 entdeckt und 1954 durch Kline auch der westlichen Medizin bekannt gemacht (Ref. bei Hornykiewicz 1986). Delay und Deniker erkannten 1952 die antipsychotischen Wirkungen von Chlorpromazin, das eigentlich aus anästhesiologischem Interesse aus dem Antihistaminikum Promethazin für die Erzeugung eines künstlichen Winterschlafs entwickelt worden war. Sie prägten 1955 den Begriff „Neuroleptikum“. Als motorische Effekte beider Substanzen wurden bei der Ratte Katalepsie und beim Menschen von Forschern wie Haase im Jahre 1954 und Degwitz im Jahre 1960 Parkinsonoide beobachtet (Ref. bei Hornykiewicz 1986). Reserpin blockiert die Speicherung von Dopamin, Noradrenalin, Serotonin und auch Histamin in den synaptischen Vesikeln (Übersicht: Shore und Giachetti 1978). Auf der Suche nach neuen morphinartigen Analgetika beobachtete Janssen im Jahre 1961, daß bestimmte Butyrophenone wie Haloperidol beim Tier in der kataleptischen Wirkung dem Chlorpromazin ähneln. Carlsson et al. entdeckten im Jahre 1957, daß sich die Reserpin-induzierte Katalepsie durch 3,4-Dihydroxyphenylalanin (DOPA) antagonisieren lässt. Barbeau und Sourkes sowie Ehringer und Hornykiewicz bestätigten im Jahre 1960 die daraus abgeleitete Hypothese Carlsson’s eines Dopaminmangels bei Morbus Parkinson. Entsprechend konnten Birkmayer und Hornykiewicz 1961 die Wirksamkeit der Substitutionstherapie mit L-DOPA nachweisen (Ref. bei Hornykiewicz 1986). Carlsson und Lindquist beobachteten 1963 unter Chlorpromazin und Haloperidol einen Anstieg des Dopaminmetaboliten Methoxytyramin als Ausdruck einer erhöhten Aktivität dopaminerger Neuronen; daraus leiteten sie die Hypothese ab, daß Neuroleptika Dopaminrezeptoren blockieren. In Verbindung mit den psychotogenen Wirkungen chronisch konsumierten Amphetamins, das u. a. die dopaminerge Neurotransmission fördert, führte die Blockade dopaminerger Rezeptoren durch Neuroleptika zur Formulierung der Dopaminhypothese der Schizophrenien (Carlsson 1978, Snyder et al. 1974).

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