Neurotransmitter Transporters and Their Role in the Pharmacological Actions of Therapeutic and Abused Drugs

Neurotransmitter signaling is tightly controlled by transporters, which serve to terminate neurotransmission by high-affinity uptake of their cognate neurotransmitter from extracellular fluid into nerve terminals, and in some instances, into glia. Here we focus on five members of the solute carrier 6 (SLC6) family, the serotonin (5-HT), dopamine (DA), norepinephrine (NE), gamma-aminobutyric acid (GABA) and glycine transporters, SERT, DAT, NET, GAT and GlyT, respectively. Their crucial role in maintaining homeostasis of 5-HT, DA, NE, GABA and glycine signaling make them prime targets for therapeutics used to treat a broad spectrum of disorders ranging from major depression, anxiety, attention deficit hyperactivity disorder to obesity, epilepsy and pain. The monoamine transporters, SERT, DAT and NET, are also key sites of action for numerous drugs of abuse, including amphetamine, cocaine and their congeners. In addition, we discuss a subset of the SLC22 family of organic cation transporters (OCTs), OCT1, OCT2 and OCT3, as well as the SLC29 member, the plasma membrane monoamine transporter (PMAT). OCTs and PMAT are emerging as important players in monoaminergic signaling and are promising targets for development of novel therapeutics. We provide a general overview of these transporters, and then focus on their pharmacology and therapeutic applications.