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 Hsin, Dalibor Sames, David E. Krantz, Jonathan L. Katz, David Sulzer and Jonathan A. Javitch ()
Additional contact information
Zachary Freyberg: College of Physicians & Surgeons, Columbia University
Mark S. Sonders: College of Physicians & Surgeons, Columbia University
Jenny I. Aguilar: College of Physicians & Surgeons, Columbia University
Takato Hiranita: Psychobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health
Caline S. Karam: College of Physicians & Surgeons, Columbia University
Jorge Flores: Howard Hughes Medical Institute, College of Physicians & Surgeons, Columbia University
Andrea B. Pizzo: College of Physicians & Surgeons, Columbia University
Yuchao Zhang: College of Physicians & Surgeons, Columbia University
Zachary J. Farino: College of Physicians & Surgeons, Columbia University
Audrey Chen: Hatos Center for Neuropharmacology, David Geffen School of Medicine University of California
Ciara A. Martin: University of California
Theresa A. Kopajtic: Psychobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health
Hao Fei: Hatos Center for Neuropharmacology, David Geffen School of Medicine University of California
Gang Hu: Columbia University
Yi-Ying Lin: School of Pharmacy, College of Medicine, National Taiwan University
Eugene V. Mosharov: College of Physicians & Surgeons, Columbia University
Brian D. McCabe: Center for Motor Neuron Biology and Disease, College of Physicians & Surgeons, Columbia University
Robin Freyberg: Stern College for Women, Yeshiva University
Kandatege Wimalasena: Wichita State University
Ling-Wei Hsin: School of Pharmacy, College of Medicine, National Taiwan University
Dalibor Sames: Columbia University
David E. Krantz: Hatos Center for Neuropharmacology, David Geffen School of Medicine University of California
Jonathan L. Katz: Psychobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health
David Sulzer: College of Physicians & Surgeons, Columbia University
Jonathan A. Javitch: College of Physicians & Surgeons, Columbia University

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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 VMAT’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.

Date: 2016
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DOI: 10.1038/ncomms10652

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