Paradoxical abatement of striatal dopaminergic transmission by cocaine and methylphenidate

Mauro Federici, Emanuele Claudio Latagliata, Ada Ledonne, Francesca R. Rizzo, Marco Feligioni, Dave Sulzer, Matthew Dunn, Dalibor Sames, Howard Gu, Robert Nisticò, Stefano Puglisi-Allegra, Nicola B. Mercuri

Research output: Contribution to journalArticlepeer-review


We combined in vitro amperometric, optical analysis of fluorescent false neurotransmitters and microdialysis techniques to unveil that cocaine and methylphenidate induced a marked depression of the synaptic release of dopamine (DA) in mouse striatum. In contrast to the classical dopamine transporter (DAT)-dependent enhancement of the dopaminergic signal observed at concentrations of cocaine lower than 3 μM, the inhibitory effect of cocaine was found at concentrations higher than 3 μM. The paradoxical inhibitory effect of cocaine and methylphenidate was associated with a decrease in synapsin phosphorylation. Interestingly, a cocaine-induced depression of DA release was only present in cocaine-insensitive animals (DAT-CI). Similar effects of cocaine were produced by methylphenidate in both wild-type and DAT-CI mice. On the other hand, nomifensine only enhanced the dopaminergic signal either in wild-type or in DAT-CI mice. Overall, these results indicate that cocaine and methylphenidate can increase or decrease DA neurotransmission by blocking reuptake and reducing the exocytotic release, respectively. The biphasic reshaping of DA neurotransmission could contribute to different behavioral effects of psychostimulants, including the calming ones, in attention deficit hyperactivity disorder.

Original languageEnglish
Pages (from-to)264-274
Number of pages11
JournalJournal of Biological Chemistry
Issue number1
Publication statusPublished - Jan 3 2014

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)


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