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 (MDMA, '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 micro M) reduced the rate of specific high affinity [3H]5-HT reuptake in isolated rat brain synaptosomes to 14% and 10% of control, respectively. The concentration required for half-maximal inhibition (IC(50)) of [3H]5-HT reuptake by 4-methylthioamphetamine (0.27 micro M) was significantly lower (P<0.005) than that for inhibition by MDMA (1.28 micro M) and that for inhibition by 4-methylthiomethamphetamine (0.89 micro M). Both 4-MTA and 4-MTMA caused a significant release of preloaded [3H]5-HT from synaptosomes, but were significantly less effective than MDMA at the concentrations tested (1-100 micro M). In isolated rat aorta, a 15-min preincubation with 4-methylthioamphetamine or 4-methylthiomethamphetamine significantly reduced the maximal contraction (E(max)) induced by 5-HT to 71% or 91% of control (P<0.05 in each case), respectively. In addition, 4-methylthiomethamphetamine (100 micro M), but not 4-methylthioamphetamine, significantly increased the concentration of 5-HT required for half-maximal contraction (EC(50)) from 4.13 to 20.08 micro M (P<0.0001). In contrast, MDMA did not significantly alter the E(max) or the EC(50) of 5-HT-induced aortic contraction. It is concluded that both 4-methylthioamphetamine and 4-methylthiomethamphetamine are potent inhibitors of [3H]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.
Murphy
James
J
Department of Biochemistry, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, 4, Dublin, Ireland.
Flynn
James J
JJ
Cannon
Dara M
DM
Guiry
Patrick J
PJ
McCormack
Peter
P
Baird
Alan W
AW
McBean
Gethin J
GJ
Keenan
Alan K
AK
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects*
D000662:Amphetamines; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C078956:4-methylthioamphetamine