[1][2][6] When these transporters operate in reverse, they produce neurotransmitter efflux (i.e., the movement of neurotransmitters from the cytosol to the extracellular space via transporter-mediated release, as opposed to exocytotic release).
[1][2] In neurons, transporter reversal facilitates the release of neurotransmitters into the synaptic cleft, resulting in a higher concentration of synaptic neurotransmitters and increased signaling through the corresponding neurotransmitter receptors.
For example, monoamine releasing agents, such as amphetamines, cause monoamine neurotransmitter efflux (i.e., the release of monoamine neurotransmitters from neurons into the synaptic cleft via monoamine transporter-mediated release) by triggering reverse transport at vesicular monoamine transporters (specifically, VMAT1 and VMAT2) and other monoamine transporters that are located along the plasma membrane of neurons (specifically, DAT, NET, and SERT).
[1][2][7] The exact mechanisms by which amphetamines and other monoamine releasing agents mediate induction of reverse transport are poorly understood.
[8][9][10] However, the process may involve intracellular calcium ion (Ca2+) elevation, protein kinase C (PKC) activation, and Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) activation.