Summary
It is biochemically shown that optimal and lower dosages of oxypertine produce a differential depletion in norepinephrine and dopamine concentration in rat brain, and a slight, if any, effect on 5-HT concentration. Only after toxic doses (35 and 70 mg/kg) does the effect include also a fall in 5-HT concentration; it is quantitatively similar for all three amines, in the first few hours at least. The serotonin is restored earlier than noradrenaline.
Electron microscopic studies were carried out in order to determine the precise action of the drug. At various dosages, ultrastructural alterations of norepinephrine-binding vesicles in the hypothalamic region and in the pineal gland occur with loss of dense core material from the norepinephrine-binding vesicles. However, in the substantia nigra the alteration of the monoamine-binding vesicles is much less. This differential effect of oxypertine on the catecholamine-binding vesicles in the hypothalamic and nigral regions provides in accordance with chemical determinations some evidence that the latter may contain not norepinephrine, but rather dopamine.
The releasing mechanism of oxypertine may be due to the interference of monoamine binding at the different storage vesicles. However, toxic doses result in disruption of the vesicular membrane of granulated storage vesicles.
Zusammenfassung
Biochemisch wird gezeigt, daß optimale und schwache Dosen von Oxypertin die Konzentrati on von Noradrenalin am stärksten, diejenige von Dopamin nur halb so stark und diejenige von Serotonin — wenn überhaupt — nur ganz gering, für kurze Zeit senken. Nur durch sehr hohe, toxische Dosierung von Oxypertin (35 und 70 mg/kg) werden Noradrenalin, Dopamin und Serotonin anfänglich etwa gleich stark aus dem Rattenhirn ausgetrieben, wonach aber die Serotonin-Depots viel schneller wieder aufgefüllt werden als diejenigen des Noradrenalins.
Beim Versuch, den subcellulären Wirkungsort verschiedener Dosierungen des Oxypertins zu bestimmen, zeigen sich substrukturelle Veränderungen der noradrenalinhaltigen Granula im caudalen Hypothalamus und in der Epiphyse, wobei das elektronendichte Material der noradrenalinbindenden Vesikel verloren geht. Die Wirkung der Substanz auf die granulierten Vesikel in der Substantia nigra ist dagegen viel geringer oder fehlt sogar. Dieser unterschiedliche Effekt des Oxypertins auf die katecholaminhaltigen Vesikel im hinteren Hypothalamus und in der Substantia nigra weist in Übereinstimmung mit chemischen Bestimmungen darauf hin, daß die Substantia nigra kein Noradrenalin, sondern überwiegend Dopamin in den Speichervesikeln enthält.
Der Freisetzungsmechanismus der Katecholamine durch Oxypertin kann auf einer Störung der Monoaminbindung in den Speichergranula beruhen. Toxische Dosen von Oxypertin dagegen zerstören die Membran der Monoaminspeichervesikel, so daß diese fast unterschiedslos auslaufen.
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Bak, I.J., Hassler, R. & Kim, J.S. Differential monoamine depletion by oxypertine in nerve terminals. Z. Zellforsch. 101, 448–462 (1969). https://doi.org/10.1007/BF00335580
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DOI: https://doi.org/10.1007/BF00335580