THE MECHANISMS BY WHICH AMPHETAMINE INHIBITS OXIDATIVE DEAMINATION OF NOREPINEPHRINE IN BRAIN

¹ Department of Pharmacology, University of Colorado School of Medicine, Denver, Colorado

pre-treatment of rabbits with d-amphetamine sulfate, 1 to 10 mg/kg, results in a decrease in the oxidative deamination of norepinephrine in brain cortex tissue slices. This effect is dose-related and is of short duration. The maximal effect occurs one-half hour after an i.p. injection of the drug. Inhibition of monoamine oxidase activity after pretreatment with amphetamine is also observed in isolated synaptosomes in which mitochondria containing monoamine oxidase are localized within a neuronal membrane. Amphetamine pretreatment does not reduce monoamine oxidase activity in synaptosomes which are osmotically lysed or in ``free'' mitochondria. When amphetamine is incubated in vitro with synaptosomes and ``free'' mitochondria, it is observed that: 1) uptake of norepinephrine into synaptosomes is most sensitive to amphetamine (50% inhibition at 2.7 x 10^-6 M); 2) deamination of norepinephrine in the synaptosomal fraction is less readily inhibited by amphetamine (50% inhibition at 1.4 x 10^-6 M) and 3) deamination of norepinephrine in the mitochondrial fraction is affected least by amphetamine (50% inhibition at 8.9 x 10^-6 M). These results suggest that amphetamine administration leads to an inhibition of oxidative deamination of norepinephrine primarily by inhibition of the uptake of the amine into the neuron thus limiting access of norepinephrine to intraneuronal monoamine oxidase.