MDMA (ECSTASY) INHIBITION OF MAO TYPE-A AND TYPE-B - COMPARISONS WITHFENFLURAMINE AND FLUOXETINE (PROZAC)

3,-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 norma lly be degraded by monoamine oxidase (MAO). The effects of both enanti omers of MDMA were examined on MAO-A and monoamine oxidase-B (MAO-B) a ctivity in rat brain homogenates. Both enantiomers competitively inhib ited 5-HT catabolism by rat brain MAO-A. The K-i of MDMA for MAO-A was 22 mu mol/L. A mixed type of inhibition by MDMA was observed for phen ethylamine 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 IC50 of 44 mu mol/L for inhibition of MAO-A by MDMA . The IC50 value of MDMA inhibition of MAO-B was 370 mu mol/L, showing a selective potency for MAO-A inhibition. The MAO inhibitory properti es of fenfluramine (FEN) and fluoxetine (FLUOX) were compared to those of MDMA. The rank order potency of these drugs for MAO-A inhibition w as MDMA>FLUOX>FEN, whereas for MAO-B inhibition, FLUOX>MDMA>FEN. A com bination of FLUOX and MDMA at their respective IC50 did not inhibit MA O activity more than either drug alone at equivalent concentrations. T hese results indicate that the actions of FEN do not appear to involve MAO inhibition. MDMA (ecstasy) produced a preferential inhibition of MAO-A (IC50 = 44 mu mol/L), which should increase extracellular 5-HT. This may explain ifs high toxicity potential. Finally, FLUOX (Prozac) showed an inhibition of MAO-B (IC50 = 80 mu mol/L, which may increase the intracellular content of 5-HT. This may contribute to its therapeu tic potential. In contrast, FEN appears to be a poor inhibitor of both MAO-A and MAO-B.