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.
Department of Biochemistry, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, 4, Dublin, Ireland.
James
J
Murphy
James J
JJ
Flynn
Dara M
DM
Cannon
Patrick J
PJ
Guiry
Peter
P
McCormack
Alan W
AW
Baird
Gethin J
GJ
McBean
Alan K
AK
Keenan
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