The effect of various doses of tranylcypromine on the degree of inhibition of rat brain monoamine oxidase (MAO) using 5‐hydroxytryptamine (5‐HT), dopamine and phenylethylamine as substrates has been examined 120 min after injection of the inhibitor. The concentration of brain 5‐HT was also examined both after tranylcypromine alone and also when L‐tryptophan (100 mg/kg) had been given 30 min after the tranylcypromine.

All doses of tranylcypromine greater than 2.5 mg/kg totally inhibited MAO oxidation of 5‐HT, phenylethylamine and dopamine as measured in vitro and produced a similar rise of brain 5‐HT in vivo. When tryptophan was also given, there was a further rise of brain 5‐HT, which was comparable after all doses of tranylcypromine above 2.5 mg/kg and the characteristic syndrome of hyperactivity made its appearance.

Clorgyline (a ‘Type A’ MAO inhibitor), in doses up to 10 mg/kg, did not totally inhibit MAO activity towards phenylethylamine although it did inhibit 5‐HT oxidation by 100%. Deprenil (a ‘Type B’ MAO inhibitor) at doses up to 10 mg/kg did not fully inhibit 5‐HT oxidation although phenylethylamine oxidation was inhibited almost completely. Administration of either compound alone did not produce as great an accumulation of brain 5‐HT as that seen after tranylcypromine (2.5 mg/kg) and subsequent administration of tryptophan did not cause hyperactivity or the rise of brain 5‐HT seen after tranylcypromine (2.5 mg/kg) plus tryptophan.

Administration of clorgyline plus deprenil (2.5 mg/kg of each) almost totally inhibited oxidation of both 5‐HT and phenylethylamine; subsequent tryptophan administration resulted in a rise of brain 5‐HT nearly as great as that seen following tranylcypromine (2.5 mg/kg) plus tryptophan and the animals became hyperactive.

No evidence was found pointing to the formation of any other 5‐substituted indole in the brain following tranylcypromine plus L‐tryptophan administration as suggested by others.

It is concluded that while 5‐HT may normally be metabolized in the brain by ‘Type A’ MAO in vivo, when this form is inhibited, 5‐HT can still be metabolized by ‘Type B’ enzyme. It is only when both forms are almost totally inhibited that the largest rise of brain 5‐HT is seen and subsequent tryptophan administration produces the hyperactivity syndrome.