The effect of drugs on the “metabolic pattern” of the brain. The effect of isoniazid, iproniazide, and phenylcyclopropyl amine on the utilation of endogenous sources of the brain in the production of respiratory CO2

Abstract The effects of isoniazid, iproniazide, phenylcyclopropylamine, 5-HTP, and DOPA on the “metabolic pattern” of the brain have been investigated in brain-perfusion experiments in vivo , under conditions as near normal as possible. The expression “metabolic pattern” is intended to indicate the relative rates at which exogenous glucose and other endogenous substrates participate in the various metabolic processes of the brain, or in the production of various intermediary metabolites. When, under “resting” conditions, uniformily labeled C 14 glucose was the only substrate offered in the perfusion blood to the brain, all pre-existing glucose and its glycolytic and tricar☐ylic cycle metabolites in the brain were exchanged for the incoming glucose and its derivatives within a perfusion period of 30–70 min. During this initial period, the respiratory CO 2 , the lactate, glutamate, and aspartate of the brain attained their highest specific activities, which remained practically constant for hours. Only about 50 per cent of the lactate carbon, 32 per cent of the carbon of the respiratory CO 2 , about 34 per cent of the free glutamate carbons, and 24 per cent of the free aspartate carbons of the cat's brain were derived directly from glucose. The remaining carbons were contributed by endogenous material of the brain which, in the course of 3–4 hrd did not acquire enough radioactivity to contribute appreciably to the radioactivity of the glycolytic and tricar☐ylic cycle metabolites. When isoniazid, iproniazide, and phenycylopropylamine were added to the perfusion blood, the carbon derived from glucose in the respiratory CO 2 rose linearly to about twice the figures found in untreated animals. The specific activity of the brain lactate also reached a correspondingly high level in the brains of the iproniazide and isoniazid-treated animals. An inhibition of transminations by these two drugs is indicated by the relatively low specific activities of the free brain glutamate and aspartate even though the specific activity of the respiratory CO 2 is high. Phenylcylopropylamine, however, did not increase the relative specific activity of the lactate, nor did it significantly inhibit transaminations. Nevertheless, the specific activity of the respiratory CO 2 of these animals was high, indicating a blocking of the influx of “cold” carbon into the tricar☐ylic cycle. The serotonin content of the brain was increased over the normal by adding comparatively large amounts of 5-hydroxytryptophan to the perfusion blood. The metabolic patten of the brain did not change and the relative specific activity of its metabolites was not different from those of untreated animals. Nor did the addition of DOPA to the perfusion blood change the relative specific activity of the metabolites. It is concluded that shifts in the “metabolic pattern” of the brain in the presence of iproniazide and of cyclopropylamine in pharmacologically active doses represent hitherto unknown biochemical effects of these drugs, independent from their MAO-inhibitory action.