Electroencephalographic analysis of the 6-azauridine action on the central nervous system

The intravenous administration of 6-azauridine, an antimetabolite of pyrimidine nucleotides, causes no apparent changes in the EEG of the conscious rabbit and the catence´phale isole´ preparation. Its administration into the lateral cerebral ventricle in theence´phale isole´ cat caused an initial shift of the record to higher frequencies followed by a period of EEG synchrony. Similar changes were also seen after the intraventricular administration of 6-azauracil and the antimetabolically inactive 5-ethyl-6-azauracil. Excitability of the hippocampus, measured as the threshold for afterdischarges, was decreased after intravenous administration of higher doses of 6-azauridine in the rabbit and after intraventricular administration in the catence´phale isole´ preparation. Also, the threshold for cortical desynchronization elicited by electrical stimulation of the midbrain reticular formation was higher and its duration shortened after intraventricular administration of 6-azauridine in the cat. The duration of cortical desynchronization elicited by intravenous administration of nicotine was shortened after intravenous and intraventricular injection of 6-azauridine in the same preparation; the higher doses given intraventricularly blocking the reaction completely. Cortical desynchronization elicited by acetylcholine was influenced to the same degree but that elicited by arecoline only slightly affected. From this interaction with cholinergic agents it is concluded that 6-azauridine has an anticholinergic component in its central action, which is more antinicotinic than antimuscarinic. 6-Azauracil and cancerostatically ineffective 5-ethyl-6-azauracil failed to show any antinicotinic action. The relation between antimetabolic activity and the central nervous system effects is discussed. The initial EEG changes observed after intraventricular administration of these three derivatives are not related to antimetabolic activity and are probably due to the direct action of the compoundsper se. The anticholinergic component, on the other hand, was seen only after antimetabolically active 6-azauridine. It is suggested that the central anticholinergic and cancerostatic activities might be based on the same biochemical mechanism—the inhibition of orotidylic acid decarboxylase.