3, 4-Methylenedioxymethamphetamine (MDMA), a serotonin (5-HT) neurotoxin, has been shown to promote the release of serotonin (5-HT) and block its reuptake. The increased buildup of extracellular 5-HT should normally be degraded by monoamine oxidase (MAO). The effects of both enantiomers of MDMA were examined on MAO-A and monoamine oxidase-B (MAO-B) activity in rat brain homogenates. Both enantiomers competitively inhibited 5-HT catabolism by rat brain MAO-A. The Ki of MDMA for MAO-A was 22 μmol/L. A mixed type of inhibition by MDMA was observed for phenethylamine catabolism by MAO-B for both optical antipodes. Logistical analysis of concentration response curves for MDMA inhibition of MAO-A and MAO-B show an 1C50 of 44 μmol/L for inhibition of MAO-A by MDMA. The 1C50 value of MDMA inhibition of MAO-B was 370 μmol/L, showing a selective potency for MAO-A inhibition. The MAO inhibitory properties of fenfluramine (FEN) and fluoxetine (FLUOX) were compared to those of MDMA. The rank order potency of these drugs for MAO-A inhibition was MDMA>FLUOX>FEN, whereas for MAO-B inhibition, FLUOX>MDMA>FEN. A combination of FLUOX and MDMA at their respective 1C50 did not inhibit MAO activity more than either drug alone at equivalent concentrations. These results indicate that the actions of FEN do not appear to involve MAO inhibition. MDMA (ecstasy) produced a preferential inhibition of MAO-A (1C50 = 44 μmol/L), which should increase extracellular 5-HT. This may explain its high toxicity potential. Finally, FLUOX (Prozac) showed an inhibition of MAO-B (IC50 = 80 μmol/L, which may increase the intracellular content of 5-HT. This may contribute to its therapeutic potential. In contrast, FEN appears to be a poor inhibitor of both MAO-A and MAO-B.
ASJC Scopus subject areas
- Psychiatry and Mental health