Abstract
The dopamine transporter (DAT) is a sodium-coupled symporter protein responsible for modulating the concentration of extraneuronal dopamine in the brain. The DAT is a principle target of various psychostimulant, nootropic and antidepressant drugs, as well as certain drugs used recreationally, including the notoriously addictive stimulant cocaine. DAT ligands have traditionally been divided into two categories: cocaine-like inhibitors and amphetamine-like substrates. Whereas inhibitors block monoamine uptake by the DAT, but are not translocated across the membrane, substrates are actively translocated and trigger DAT-mediated release of dopamine by reversal of the translocation cycle. As both inhibitors and substrates increase extraneuronal dopamine levels, it is often assumed that all DAT ligands posses an addictive liability equivalent to cocaine. However, the recent development of novel 'atypical' inhibitors and 'partial substrate' ligands with reduced or even a complete lack of cocaine-like rewarding effects suggests that addictiveness is not a constant property of DAT-affecting compounds. These atypical ligands do not conform to the classical preconception that all DAT inhibitors (or substrates) are functionally and mechanistically alike. Instead, they suggest the possibility that the DAT exhibits some of the ligand-specific 'pleiotropic' functional qualities inherent to G-protein-coupled receptors. That is, ligands with different chemical structures induce specific conformational changes in the transporter protein, which can be differentially transduced by the cell, ultimately eliciting unique behavioral and psychical effects. The present overview discusses compounds with conformation-specific activity, useful not only as tools for studying the mechanics of dopamine transport, but also as leads for medication development in addictive disorders.
- The American Society for Pharmacology and Experimental Therapeutics