Dopamine Transporter - Pharmacology

Pharmacology

DAT is also the target of several "DAT-releasers" & “DAT-blockers” including amphetamines and cocaine. These chemicals inhibit the action of DAT and, to a lesser extent, the other monoamine transporters, but their effects are mediated by separate mechanisms.

Cocaine blocks DAT by binding directly to the transporter and reducing the rate of transport. In contrast, amphetamines trigger a signal cascade thought to involve PKC or MAPK that leads to the internalization of DAT molecules, which are normally expressed on the neuron’s surface.

Amphetamine on DAT also has a direct effect in the increased levels of secreted dopamine. Lipophilic AMPH diffuses into the cytoplasm and into the dopamine secretory vesicles disrupting the proton gradient established across the vesicle wall. This induces a leaky channel and DA diffuses out into the cytoplasm. Additionally, AMPH causes a reversal of normal DA flow at the DAT. Instead of DA reuptake, in the presence of AMPH, a reversal in the mechanism of DAT occurs causing an outflow of dopamine released into the cytoplasm into the synaptic space changing it from a symporter to an antiporter-like functionality.

Both of these mechanisms result in less removal of dopamine from the synapse and increased signaling, which is thought to underlie the pleasurable feelings elicited by these substances.