Elsevier

Brain Research

Volume 695, Issue 1, 9 October 1995, Pages 10-18
Brain Research

Research report
Release of serotonin induced by 3,4-methylenedioxymethamphetamine (MDMA) and other substituted amphetamines in cultured fetal raphe neurons: further evidence for calcium-independent mechanisms of release

https://doi.org/10.1016/0006-8993(95)00774-KGet rights and content

Abstract

The substituted amphetamines 3,4-methylenedioxyamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), p-chloroamphetamine (PCA) and fenfluramine (FEN) all exert their effects by releasing serotonin (5-HT) from presynaptic nerve terminals. In the current study, we examined the ability of these agents to induce the release of 5-HT in cultured fetal raphe neurons. The data indicate that the rank order of release potencies for these agents was (±)PCA > (+)MDMA = (+)MDA = (±)FEN. Studies examining the role of calcium in 5-HT release demonstrate that preventing calcium influx with L- and N-type calcium channel blockers inhibits potassium-stimulated release of [3H]5-HT but has no effect on release induced by the substituted amphetamines. Furthermore, omitting calcium from the extracellular media or depleting the vesicular pool of neurotransmitter with continual potassium stimulation did not affect the release of [3H]5-HT induced by these compounds. Administration of fluoxetine prior to the substituted amphetamines significantly attenuated the releasing effects of these agents, while producing no effect on potassium-stimulated release. These results are consistent with the notion that the amphetamines induce release of cytoplasmic 5-HT via the plasma membrane transporter.

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      It is not clear why there is circadian variability in the response to MDMA, but one possible explanation is that the ability of MDMA to provoke 5-HT release varies over the light/dark cycle. MDMA preferentially releases 5-HT from the newly synthesized cytoplasmic pool (Wichems et al., 1995), and the neurochemical and electrophysiological effects of MDMA are potentiated by administration of the 5-HT precursor l-tryptophan, which increases 5-HT synthesis (Bradberry et al., 1990; Sprouse et al., 1990; Evans et al., 2008). As the rate of 5-HT synthesis increases during the light phase (Héry et al., 1972), it is likely that the ability of MDMA to induce 5-HT release peaks during the light phase of the diurnal cycle.

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