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

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    Freyberg_2016.pdf (1.787Mb)
    Date
    2016-02-16
    Author
    Freyberg, Zachary
    Sonders, Mark S.
    Aguilar, Jenny I.
    Hiranita, Takato
    Karam, Caline S.
    Flores, Jorge
    Pizzo, Andrea B.
    Zhang, Yuchao
    Farino, Zachary J.
    Chen, Audrey
    Martin, Ciara A.
    Kopajtic, Theresa A.
    Fei, Hao
    Hu, Gang
    Lin, Yi-Ying
    Mosharov, Eugene V.
    McCabe, Brian D.
    Freyberg, Robin
    Wimalasena, Kandatege
    Hsin, Ling-Wei
    Sames, Dalibor
    Krantz, David E.
    Katz, Jonathan L.
    Sulzer, David
    Javitch, Jonathan A
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    Citation
    Freyberg, Z. et al. Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain. Nat. Commun. 7:10652 doi: 10.1038/ncomms10652 (2016).
    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.
    Description
    This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
    URI
    http://dx.doi.org/10.1038/ncomms10652
    http://hdl.handle.net/10057/11973
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