Discovering how amphetamine works in the brain

2014

Challenge

Amphetamines have long been known to increase dopamine levels and regulate the activity of glutamate—two important neurotransmitters. However, doctors still did not understand exactly what happens in the brain to cause amphetamines’ stimulating effects.

Advance

Working with cultured mouse neurons, a team led by Susan Amara, Ph.D., identified a series of chemical events that underlie amphetamines’ stimulating effects. They showed that amphetamine enters dopamine neurons through specific entry proteins on the cell surface. Once inside the cells, the drug triggers the internalization of a glutamate transporter from the cell surface, which enhances the excitatory actions of amphetamine.

Impact

With knowledge of the specific chain of events amphetamines set in motion in the brain, it is now possible to target the cascade of molecules—from outside the cell, to cell membrane, to inside the cell—in the development of better drug therapies in, for example, ADHD.

Publications

Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG. (2014). Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons. Neuron. 83(2), 404-16.

Comment: Ferrarelli LK. (2014). Synaptic transmission on speed. Science Signaling. 7(336), ec200.