Amantadine increases the extracellular dopamine levels in the striatum by re-uptake inhibition and by N-methyl-D-aspartate antagonism.

This study was performed to investigate the mechanism how amantadine increases the extracellular dopamine (DA) levels in the striatum in vivo. Local application of amantadine (1 mM, 40 min) to the striatum through the dialysis membrane significantly increased the extracellular DA levels. Coadministration of nomifensine (10 mM, 120 min), an inhibitor of neuronal DA uptake, into the perfusion fluid attenuated the amantadine-induced increase in DA outflow. The amantadine-induced increases in the extracellular DA levels were also inhibited by co-perfusion with Ringer containing high Mg2+ (15 mM, 120 min) or with MK-801 (1 microM, 80 min). These findings suggest that amantadine increases the extracellular DA levels in the striatum by inhibiting the re-uptake of DA and/or by blocking the channel in the N-methyl-D-aspartate (NMDA) receptor, which results in antagonism of NMDA receptor function.