MDMA causes a redistribution of serotonin transporter from the cell surface to the intracellular compartment by a mechanism independent of phospho-p38-mitogen activated protein kinase activation

3,4-methylenedioxymethamphetamine (MDMA) causes long-term serotonin depletion and reduced serotonin transporter (SERT) function in humans and in animal models. Using quantitative Western blotting and real-time PCR, we have shown that total SERT protein in the striatum and nucleus accumbens and mRNA levels in the dorsal raphe nucleus were not significantly changed following MDMA exposure in rats (4×2 h i.p. injections, 10 mg/kg each). In mouse neuroblastoma (N2A) cells transiently expressing green fluorescent protein-tagged human SERT (GFP-hSERT), we have shown redistribution of SERT from the cell surface to intracellular vesicles on exposure to MDMA using cell surface biotinylation, total internal reflection fluorescence microscopy (TIRFM) and live-cell confocal microscopy. To investigate the mechanism responsible for SERT redistribution, we used specific antibodies to phospho-p38-mitogen activated protein kinase (p38 MAPK), a known signalling pathway involved in SERT membrane expression. We found that p38 MAPK activation was not involved in the MDMA-induced redistribution of SERT from the cell-surface to the cell interior. A loss of SERT from the cell surface on acute exposure to MDMA may contribute to the decreased SERT function seen in rats exposed to MDMA.