Non-neurotoxic amphetamine derivatives release serotonin through serotonin transporters

3,4-Methylenedioxymethamphetamine (MDMA) and several other amphetamine derivatives cause degeneration of serotonergic nerve terminals. These drugs also release serotonin from nerve terminals both in vivo and in vitro. Two non-neurotoxic derivatives of MDMA were tested in membrane vesicle model systems to determine whether they also lacked the ability to release serotonin. 3-Methoxy-4-methylamphetamine (MMA) and 5-methoxy-6-methyl-2-aminoindan (MMAI) both inhibited imipramine binding to serotonin transporters in platelet plasma membrane vesicles and both inhibited Na+ gradient-driven serotonin transport into those vesicles. Significantly, both MMA and MMAI released [3H]serotonin from plasma membrane vesicles, apparently by a process of exchange. The half-maximal concentrations for this effect were comparable to that reported for MDMA. In addition to their effects on plasma membrane transporters, MMA and MMAI both inhibited serotonin transport into chromaffin granule membrane vesicles catalyzed by the vesicular biogenic amine transporter. At higher concentrations, these compounds also caused release of [3H]serotonin from chromaffin granule membrane vesicles and dissipated the transmembrane pH difference (delta pH). Although MMAI effects on the serotonin transporter were similar to those of MDMA, the two compounds had different effects on dopamine transporters. MDMA and methamphetamine inhibited binding of a cocaine analog to the dopamine transporter and released dopamine accumulated by cells expressing dopamine transporters, but similar concentrations of MMAI were inactive.