In vivo monoamine oxidase inhibition by d-amphetamine

In vitro, d- and l-amphetamine (AMPH) are reversible monoamine oxidase (MAO) type A inhibitors, the d-form being approximately five times more potent. Experiments were conducted in rats to determine whether MAO inhibition occurs in vivo. d-AMPH was more effective than l-AMPH at decreasing striatal 3,4-dihydroxyphenylacetic acid (DOPAC). However, assays of striatal MAO activity following administration of AMPH in vivo failed to show MAO inhibition. In other experiments, rats were treated with d-AMPH (zero time) followed by phcnelzine (1 hr), an irreversible MAO inhibitor, and were killed at 25 hr. MAO activity was determined in vitro for the striatum and the rest of the brain using serotonin (MAO-A) and phenylethylaminc (MAO-B) as substrates. d-AMPH provided significant protection against MAO-A inhibition by phenelzine, whereas l-AMPH and cocaine (used instead of AMPH) were without effect. d-AMPH failed to protect against MAO-B inhibition by phenelzine. Thus, d-AMPH appears to inhibit reversibly MAO type A in vivo. However, using the same ‘protection protocol’, d-AMPH failed to oppose phenelzine-induced lowering of striatal DOPAC. Experiments were undertaken to determine whether the protective effect of d-AMPH on MAO type A would influence striatal dopamine depletion by RO4-1284, a rapidly acting reserpine-like agent. RO4-1284-induced depletion of dopamine was inhibited by phenelzine. Prior treatment with d-AMPH reduced significantly the protective effect of phenelzine, suggesting reversible, intraneuronal MAO inhibition by d-AMPH in vivo. The possible neuronal mechanisms for these events are discussed.