Amphetamine enters the presynaptic neuron across the neuronal membrane or through
DAT.
[1] Once inside, it binds to
TAAR1 or enters synaptic vesicles through
VMAT2.
[1][2] When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into the
cytosol (light tan-colored area) through VMAT2.
[2][3] When amphetamine binds to TAAR1, it reduces the
firing rate of the dopamine neuron via
G protein-coupled inwardly rectifying potassium channels (GIRKs) and activates
protein kinase A (PKA) and
protein kinase C (PKC), which subsequently phosphorylate DAT.
[1][4][5] PKA phosphorylation causes DAT to withdraw into the presynaptic neuron (
internalize) and cease transport.
[1] PKC-phosphorylated DAT may either operate in reverse or, like
PKA-phosphorylated DAT, internalize and cease transport.
[1] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a
CAMKIIα-dependent pathway, in turn producing dopamine efflux.
[6][7]