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

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 beh...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757768/
https://www.ncbi.nlm.nih.gov/pubmed/26879809
http://dx.doi.org/10.1038/ncomms10652
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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.
author_facet 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.
author_sort Freyberg, Zachary
collection PubMed
description 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.
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spelling pubmed-47577682016-03-04 Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain 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. Nat Commun Article 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. Nature Publishing Group 2016-02-16 /pmc/articles/PMC4757768/ /pubmed/26879809 http://dx.doi.org/10.1038/ncomms10652 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ 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/
spellingShingle Article
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.
Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain
title Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain
title_full Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain
title_fullStr Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain
title_full_unstemmed Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain
title_short Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain
title_sort mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in drosophila brain
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757768/
https://www.ncbi.nlm.nih.gov/pubmed/26879809
http://dx.doi.org/10.1038/ncomms10652
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