Integrative transporter-mediated release from cytoplasmic and vesicular 5-hydroxytryptamine stores in cultured neurons

The direct effects of 3,4-methylenedioxymethamphetamine (MDMA) and p-chloroamphetamine (PCA) were studied in microculture of fetal 5-hydroxytryptamine (5-HT) neurons. Both MDMA and PCA released 5-HT with the potency of PCA > MDMA by a mechanism inhibited by fluoxetine, an inhibitor of the 5-HT transporter. The transporter-mediated release by MDMA and PCA reduced intracellular stores of 5-HT. Both MDMA and PCA inhibit MAO-A activities, which also contributes to the increase of extracellular 5-HT levels. Deprenyl (10^-7 M) increased the amount of intracellular 5-HT and potentiated the MDMA- or PCA-induced release of 5-HT. Conversely, reserpine (10^-9 M) reduced the intracellular 5-HT level and attenuated the transporter-mediated release. In addition, MDMA- or PCA-mediated release was attenuated by nimodipine (10^-8 M), an L-type Ca²⁺ channel antagonist. Our results indicate that MDMA- or PCA-induced release of 5-HT occurs from the cytoplasm to the media through the 5-HT transporter, and that the release may incorporate 5-HT from the vesicular stores.