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Thus, we find that at pharmacologically relevant concentrations, amphetamines must be actively transported by DAT and VMAT in tandem to produce psychostimulant effects. Amphetamine-induced vesicle deacidification also requires functional dopamine transporter (DAT) at the plasma membrane. 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. 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. To study VMAT’s role in mediating amphetamine action in dopamine neurons, we have used novel genetic, pharmacological and optical approaches in Drosophila melanogaster.
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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. Amphetamines elevate extracellular dopamine, but the underlying mechanisms remain uncertain.