Mechanism of action of psychostimulants

Mechanism of action of psychostimulants

Amphetamines’ psychostimulant effects are generally thought to result from increased extracellular dopamine mediated by efflux of cytoplasmic dopamine through the dopamine transporter (DAT). How amphetamines mobilize dopamine from vesicles to the cytoplasm for subsequent efflux is less clear.

Dopamine is synthesized in the cytosol and concentrated into synaptic vesicles ~105-fold (~0.1M intraluminal dopamine) relative to cytoplasmic dopamine (~1μM) by the vesicular monoamine transporter (VMAT). Whether amphetamines also act directly on VMAT to redistribute dopamine from vesicles into the cytoplasm has been debated, and numerous mechanisms have been proposed.

Researchers show in rodents that acute pharmacological inhibition of the vesicular monoamine transporter (VMAT) blocks amphetamine-induced locomotion and self-administration without impacting cocaine-induced behaviors.

To study VMAT’s role in mediating amphetamine action in dopamine neurons, authors 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, authors find that at pharmacologically relevant concentrations, amphetamines must be actively transported by DAT and VMAT in tandem to produce psychostimulant effects.