@article{68abaf3d8a9546a2b5e03bda27073b86,
title = "Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain",
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.",
author = "Zachary Freyberg and Sonders, {Mark S.} and Aguilar, {Jenny I.} and Takato Hiranita and Karam, {Caline S.} and Jorge Flores and Pizzo, {Andrea B.} and Yuchao Zhang and Farino, {Zachary J.} and Audrey Chen and Martin, {Ciara A.} and Kopajtic, {Theresa A.} and Hao Fei and Gang Hu and Lin, {Yi Ying} and Mosharov, {Eugene V.} and McCabe, {Brian D.} and Robin Freyberg and Kandatege Wimalasena and Hsin, {Ling Wei} and Dalibor Sames and Krantz, {David E.} and Katz, {Jonathan L.} and David Sulzer and Javitch, {Jonathan A.}",
note = "Funding Information: We are grateful to Richard Axel, Arthur Cho, Lynnette Daws, Erik Floor, Martin Heisenberg, Adam Henke, N. Markiavelli, Stephen Rayport and Leslie Vosshall for helpful discussion and comments on the manuscript as well as to Maryann Carrigan and Patty Ballerstadt for administrative assistance (J.L.K.). We also gratefully acknowledge the contributions of Dawn French-Evans in conducting both catalepsy and locomotor activity studies in mice and of Eve Vagg for assistance with figures. This work was financially supported by K08 DA031241 (Z.F.), Louis V. Gerstner, Jr, Scholars Program (Z.F.), Leon Levy Foundation (Z.F.), NARSAD Young Investigator Award (C.S.K.), K05 DA022413, (J.A.J.), P01 DA12408 (J.A.J.), Lieber Center for Schizophrenia Research and Treatment award (J.A.J.), R01 DA007418 (D. Sulzer), PO1 DA0 10154 (D. Su.), JPB and Parkinson{\textquoteright}s Disease Foundations (D. Su.), R01 MH086545 (D. Sames), G. Harold & Leila Y. Mathers Charitable Foundation (D. Sa.), NS075572 (B.D.M.), AG08702 (B.D.M.), the Dana Foundation (B.D.M.), the Gatsby Initiative in Brain Circuitry (B.D.M.), New York Presbyterian Seizure Disorders Fund (B.D.M.), R01 MH076900 (D.E.K.), R01 ES015747 (D.E.K.), P01 ES016732 (D.E.K.), Brain and behaviour Research Foundation (D.E.K.), UCLA Brain Research Institute (D.E.K.), UCLA Molecular Toxicology Program, Ruth L. Kirschstein T32 ES015457 (C.A.M.), Ruth L. Kirschstein GM07185 (A.C.), R01 NS075222 (E.M.), and the Intramural Research Program of NIDA (J.L.K.).",
year = "2016",
month = feb,
day = "16",
doi = "10.1038/ncomms10652",
language = "English (US)",
volume = "7",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Research",
}