Abstract
Dopamine (DA) is an important modulatory neurotransmitter that is involved in daily activities such as movement, memory, and reward-oriented learning of essential behaviors and needs. DA signaling is initiated by the release of DA into the synaptic cleft that will bind to dopamine receptors to mediate the physiological response. To terminate the DA response, the DA is taken up by the dopamine transporter (DAT), a surface membrane protein. Psychostimulants, like cocaine and amphetamine, both target DAT and interfere with the DA uptake process, resulting in an increased amount of DA in the synaptic cleft. Continuous use of psychostimulants can lead to psychostimulant use disorders (PUDs), which are marked by uncontrollable psychostimulant craving and misuse. Because of the unmet need for treatment options for PUDs, novel strategies for discovering therapies are essential. Over the years, DAT-targeting ligands have been identified with atypical properties such as reduced abuse liability compared to cocaine. These compounds have been proposed to bind to different sites from cocaine and/or prefer and stabilize specific conformations of DAT. In addition, some of these compounds can interfere with psychostimulant-DAT binding and may have therapeutic potential in treating PUDs. This chapter introduces the role of DAT in PUDs, presents the mechanism of action of novel DAT-binding ligands, and discusses the therapeutic potential of atypical DAT-binding ligands for PUDs.