In vitro neuronal and vascular responses to 5-hydroxytryptamine: modulation by 4-methylthioamphetamine, 4-methylthiomethamphetamine and 3,4-methylenedioxymethamphetamine

4-Methylthioamphetamine and 4-methylthiomethamphetamine are thioarylethylamines structurally related to 3,4-methylenedioxymethamphetamine (NMNIA, 'Ecstasy'). This study compared effects of these agents and MDMA on 5-hydroxytryptamine (5-HT) signalling systems in the brain and vasculature in vitro. Both 4-methylthioamphetamine and 4-methylthiomethamphetamine (100 muM) reduced the rate of specific high affinity [H-3]5-HT reuptake in isolated rat brain synaptosomes to 14% and 10% of control, respectively. The concentration required for half-maximal inhibition (IC50) of [H-3]5-HT reuptake by 4-methylthioamphetamine (0.27 muM) was significantly lower (P<0.005) than that for inhibition by MDMA (1.28 muM) and that for inhibition by 4-methylthiomethamphetamine (0.89 muM). Both 4-MTA and 4-MTMA caused a significant release of preloaded [H-3]5-HT from synaptosomes, but were significantly less effective than MDMA at the concentrations tested (1-100 muM). In isolated rat aorta, a 15-min preincubation with 4-methylthioamphetamine or 4-methylthiomethamphetamine significantly reduced the maximal contraction induced by 5-HT to 71% or 91% of control (P<0.05 in each case), respectively. In addition, 4-methylthiomethamphetamine (100 muM), but not 4-methylthioamphetamine, significantly increased the concentration of 5-HT required for half-maximal contraction (ECHO) from 4.13 to 20.08 muM (P<0.0001). In contrast, MDMA did not significantly alter the E-max or the EC50 of 5-HT-induced aortic contraction. It is concluded that both 4-methylthioamphetamine and 4-methylthiomethamphetamine are potent inhibitors of [H-3]5-HT reuptake in the brain, Furthermore, unlike MDMA, they both directly inhibit 5-HT-mediated vascular contraction. These results suggest that these compounds may be potentially more harmful than MDMA in the context of human misuse. (C) 2002 Elsevier Science B.V. All rights reserved.