Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain

Zachary Freyberg, Mark S. Sonders, Jenny I. Aguilar, Takato Hiranita, Caline S. Karam, Jorge Flores, Andrea B. Pizzo, Yuchao Zhang, Zachary J. Farino, Audrey Chen, Ciara A. Martin, Theresa A. Kopajtic, Hao Fei, Gang Hu, Yi Ying Lin, Eugene V. Mosharov, Brian D. McCabe, Robin Freyberg, Kandatege Wimalasena, Ling Wei HsinDalibor Sames, David E. Krantz, Jonathan L. Katz, David Sulzer, Jonathan A. Javitch

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

Amphetamines elevate extracellular dopamine, but the underlying mechanisms remain uncertain. Here we show in rodents that acute pharmacological inhibition of the vesicular monoamine transporter (VMAT) blocks amphetamine-induced locomotion and self-administration without impacting cocaine-induced behaviours. To study VMATa's role in mediating amphetamine action in dopamine neurons, we have used novel genetic, pharmacological and optical approaches in Drosophila melanogaster. In an ex vivo whole-brain preparation, fluorescent reporters of vesicular cargo and of vesicular pH reveal that amphetamine redistributes vesicle contents and diminishes the vesicle pH-gradient responsible for dopamine uptake and retention. This amphetamine-induced deacidification requires VMAT function and results from net H + antiport by VMAT out of the vesicle lumen coupled to inward amphetamine transport. Amphetamine-induced vesicle deacidification also requires functional dopamine transporter (DAT) at the plasma membrane. Thus, we find that at pharmacologically relevant concentrations, amphetamines must be actively transported by DAT and VMAT in tandem to produce psychostimulant effects.

Original languageEnglish (US)
Article number10652
JournalNature communications
Volume7
DOIs
StatePublished - Feb 16 2016
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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