DAT terminates dopaminergic neurotransmission by reuptake of dopamine (DA) in presynaptic neurons and plays a key role in DA recycling. DAT can also provide reverse transport of DA under certain circumstances. Psychostimulants such as cocaine and amphetamines and drugs used for attention deficit hyperactivity disorder (ADHD) such as methylphenidate exert their actions via DAT Altered DAT function or density has been implicated in various types of psychopathology, including depression, BPAD, suicide, anxiety, aggression, and schizophrenia. Altered transport properties associated with some of the coding variants of DAT suggest that individuals with these DAT variants could display an altered DA system.17'20 Multiple human dopamine transporter (hDAT, SLC6A3) coding variants have been described, though to date they have been incompletely characterized. The antidepressant, bupropion (6) dose-dependently increases vesicular DA uptake; an effect also associated with VMAT-2 protein redistribution. Another purported antidepressant that weakly blocks DATs is radafaxine (7) ((2S,3S)-2-(3-chlorophenyl)-3,5,5,-trimethyl-2-morpholinol hydrochloride). NCEs that block DATs may have potential reinforcing effects and abuse liability, which needs to be addressed before clinical development.
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