Effects of Monoamine Oxidase Inhibition by Clorgyline, Deprenil or Tranylcypromine on 5‐hydroxytryptamine Concentrations in Rat Brain and Hyperactivity Following Subsequent Tryptophan Administration

Abstract

1 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. 2 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. 3 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. 4 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 fQllowing tranylcypromine (2.5 mg/kg) plus tryptophan and the animals became hyperactive. 5 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. 6 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.

In vivo, noradrenaline is a substrate for rat brain monoamine oxidase A and B

“…After administration of tranylcypromnine, the non-selective MAO inhibitor, the brain NA level also rises to the concentrations seen after the combination of clorgyline and (-)-deprenyl, with a further increase after L-DOPA. These results are very similar to those obtained for the in vivo deamination of 5-HT and dopamine in the rat brain (Green & Youdim, 1975;Green et al, 1977 The present study thus indicates that while in vitro noradrenaline may be deaminated exclusively by MAO A Suzuki et al, 1979;Kinemuchi et al, 1979), when this enzyme form is fully inhibited in vivo, MAO B can continue to act on noradrenaline, albeit at a slower rate, indicating that the affinity of MAO B as compared to MAO A for NA is much lower. These results are not in agreement with the studies of Neff, Yang & Goridis (1973) and others (Goridis & Neff, 1971;Neff & Fuentes, 1976) who reported that noradrenaline was a specific substrate for MAO A alone in the rat brain.…”

“…Previously, Green & Youdim (1975), observed that, while in vitro 5-hydroxytryptamine (5-HT) was deaminated exclusively by brain monoamine oxidase (MAO) type A (Johnston, 1968), nevertheless when the latter enzyme form is selectively inhibited in vivo by clorgyline, MAO type B can continue to deaminate the amine. These results have been confirmed by the in vitro studies of Ekstedt (1976) and Fowler & Tipton (1982) using liver and brain mitochondrial preparations respectively.…”

Tyramine Antagonistic Properties of Agn 1135, an Irreversible Inhibitor of Monoamine Oxidase Type B

“…Since the inhibitory effects on uptake of (-)-deprenyl are only apparent at doses far above those that cause complete inhibition of MAO type B (1.0 mg/kg in the rat, see Green & Youdim, 1975), such an action does not apparently play a role in the non-potentiation of tyramine responses at selective MAO-B inhibitory clinical doses of (-)-deprenyl. In addition, since selective inhibition of MAO-B by AGN 1135 also did not result in potentiation of tyramine pressor responses, it may be that complete inhibition of MAO-B is not accompanied by potentiation of indirectly acting amines.…”

“…(-)-Deprenyl has been shown to possess amphetamine-like actions on rat locomotor activity (Green & Youdim, 1975) and cat cardiovascular system (Simpson, 1978a) in higher doses than those that selectively inhibit MAO type B. Deprenyl is metabolized to amphetamine and methamphetamine in man (Reynolds, Elsworth, Blau, Sandler, Lees & Stem, 1978), although it is not clear whether deprenyl itself or its metabolites are responsible for this effect. However, AGN 1135 does not possess such intrinsic sympathomimetic activity (Finberg et al, 1979).…”

“…Indeed, the (+)-isomer of deprenyl is more potent as an inhibitor of [:H]-noradrenaline uptake than the (-)-isomer, although, the latter is more potent in antagonizing tyramine effects . In addition to these actions, deprenyl also possesses intrinsic amphetamine-like activity (Green & Youdim, 1975;Simpson, 1978a).…”