Carrier‐Mediated Release of Serotonin by 3,4‐Methylenedioxymethamphetamine: Implications for Serotonin‐Dopamine Interactions

MDMA (ecstasy) increases serotonin levels in the brain by directly causing serotonin transporters to release the neurotransmitter, rather than by triggering nerve cell firing. Blocking serotonin transporters with fluoxetine prevents both the serotonin and the dopamine surges normally caused by MDMA. When serotonin production is boosted beforehand with carbidopa and L-5-hydroxytryptophan, MDMA produces an even larger, synergistic increase in serotonin and also amplifies dopamine release. These findings support a model in which serotonin actively stimulates dopamine release, and they clarify the chemical mechanism behind MDMA's effects on mood and behavior.

Study at a glance

Abstract

Abstract: In vivo microdialysis was used to determine whether the 3,4‐methylenedioxymethamphetamine (MDMA)‐induced release of serotonin (5‐HT) in vivo involves a carrier‐mediated process and to investigate further the state‐dependent interaction between 5‐HT and dopamine. MDMA produced a dose‐dependent increase in the extracellular concentration of 5‐HT in the striatum and prefrontal cortex that was attenuated by treatment with fluoxetine but not by tetrodotoxin. Suppression by fluoxetine of the MDMA‐induced release of 5‐HT was accompanied by a suppression of the MDMA‐induced release of dopamine. Administration of MDMA to rats treated with carbidopa and l ‐5‐hydroxytryptophan resulted in a synergistic elevation of the extracellular concentration of 5‐HT that was much greater than that produced by either treatment alone. The MDMA‐induced release of dopamine by MDMA also was potentiated in 5‐hydroxytryptophan‐treated rats. These data are consistent with the view that MDMA increases the extracellular concentration of 5‐HT by facilitating carrier‐mediated 5‐HT release, which can be enhanced greatly under conditions in which 5‐HT synthesis is stimulated. Moreover, these data are supportive of a state‐dependent, stimulatory role of 5‐HT in the regulation of dopamine release.