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

Nature Communications
Z FreybergJ A Javitch

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.

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Citations

Feb 7, 2017·Journal of Chemical Neuroanatomy·Aparna ShekarAurelio Galli
Dec 1, 2017·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·David M HedgesScott C Steffensen
Jan 18, 2018·The Journal of Clinical Investigation·Thomas SteinkellnerThomas S Hnasko
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Jan 10, 2021·Neuroscience and Biobehavioral Reviews·Jiří Dvořáček, Dalibor Kodrík
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Methods Mentioned

BETA
gene knockdown
biosensor
biosensors
transgenic
Assay

Software Mentioned

Prairie View
MATLAB
ImageJ
GraphPad
Choreography
VMAT
Fiji
Multi
SPSS
Worm Tracker

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