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. © 1969 Springer-Verlag.