Recently, Zhao Yan, a researcher from the Institute of Biophysics of the Chinese Academy of Sciences, and his team and collaborators published the latest research results in Nature, providing important guiding information for the development of drugs to treat dopamine transporter (DAT) related mental diseases. Dopamine is a well-known "pleasure neurotransmitter" that plays an important regulatory role in biological processes such as cognition, movement, emotion, and reward. Many mental illnesses, such as depression, bipolar disorder, Parkinson's syndrome, and attention deficit hyperactivity disorder (ADHD), are associated with abnormal dopamine levels. One of the key substances that maintain the balance of dopamine homeostasis in the central nervous system is DAT. It acts like a courier, which can recycle dopamine released into the synaptic cleft to the presynaptic neurons, thereby terminating the continuous activation of downstream receptors by dopamine and waiting for the next nerve impulse signal to arrive. Due to its important role in regulating the spatial and temporal dynamics of dopamine neurotransmission, DAT has gradually become a key target for treating the aforementioned mental illnesses. In this study, the research team used single particle cryo electron microscopy technology to analyze five high-resolution structures of human DAT unbound substrate, bound substrate dopamine, bound ADHD drug methylphenidate, bound inhibitor GBR12909, and bound benzotropin. This study reveals for the first time the three conformations of extracellular, closed, and intracellular transport of human DAT, identifies substrate binding sites and ion binding sites, demonstrates the fine substrate recognition and conformational transition process of human DAT during dopamine reuptake, and reveals for the first time the different binding modes of DAT targeted psychostimulant drugs and antipsychotic drugs. (New Society)