3,4-Methylenedioxymethamphetamine (MDMA) Alters Synaptic Dopamine Release in the Dorsal Striatum Through Nicotinic Receptors and DAT Inhibition

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Abstract

An increase of extracellular dopamine (DA) has been implicated in the psychostimulant properties of 3,4-methylenedioxymethamphetamine (MDMA). Although this drug has been reported to affect the DA uptake transporter (DAT), it might activate other mechanisms to regulate the outflow of DA in the brain. Our aim was to examine the overall effects of MDMA on the release of DA in the striatum. We studied the effect of MDMA on stimulus-evoked synaptic DA release in dorsal striatal slices of mice using in vitro amperometric techniques. We also tested the effects of MDMA on the nicotine-induced responses in substantia nigra pars compacta (SNpc) neurons using intracellular electrophysiological recordings. MDMA (1–30 µM) depressed the amplitude and prolonged the decay-time of synaptic DA release in the striatum. Interestingly, in the presence of the broad nicotinic receptor antagonist mecamylamine, and the more selective α4β2 antagonist dihydroβerythroidine (DHβE), MDMA enhanced both peak and duration of DA release. A similar effect was found on cocaine-insensitive (DAT-CI) mice slices. Concentrations of MDMA higher than 100 µM enhanced striatal DA outflow that was in turn, reduced by cocaine. Electrophysiological recordings of dopaminergic neurons in SNpc showed that MDMA depressed the effects of nicotine. Our data are consistent with a prevalent MDMA-induced inhibition of the synaptic release of DA in the dorsal striatum mediated by an interaction with nicotinic receptors. This drug also blocks DAT acting on a different site from cocaine and, at higher concentrations, has amphetamine-like releasing properties.

Original languageEnglish
Pages (from-to)69-76
Number of pages8
JournalNeuroscience
Volume377
DOIs
Publication statusPublished - May 1 2018

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Keywords

  • 3,4-methylenedioxymethamphetamine (MDMA)
  • cocaine
  • DA transporter
  • dopamine
  • nicotinic cholinergic receptors

ASJC Scopus subject areas

  • Neuroscience(all)

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