THE SITE OF ACTION OF NARCOTICS ON BRAIN METABOLISM

¹ From the Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee

Previous experiments have shown that the dehydrogenases and that part of the cytochrome system involved in the oxidation of succinate are relatively insensitive to narcotics. Two possible oxidation-reduction reactions on which narcotics might exert their effect in inhibiting the carbohydrate metabolism of brain, remain. They are

(1) The transfer of hydrogen from reduced cozymase to flavoprotein and

(2) the oxidation of flavoprotein by the cytochrome system by means of electron transfer.

These possibilities have been investigated here and it has been found that reduced cozymase did not accumulate during the carbohydrate metabolism of brain in the presence of nembutal; and that the reaction

[See equation in the PDF file]

was not affected by nembutal.

These results indicate that the block was not at the position suggested as the first possibility.

The oxidation of lactate by yeast was also found to be inhibited by nembutal. The fact that the yeast lactic enzyme, which unlike the enzyme in animal tissues does not require cozymase for activity, was inhibited, is further evidence that cozymase is not involved, and that the block occurs at cytochrome b or at some as yet unidentified step having properties similar to cytochrome b. We suggest that the narcotic may act by binding the reduced flavoprotein with cytochrome b (or other intermediate) and that the affinity of narcotic for this complex is greater than for the succinic dehydrogenase-cytochrome b complex which is not affected by low concentrations of narcotic.

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