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Lasker's award-winning drug propofol is widely used in general anesthesia. The recreational use of propofol is reported to produce a well-rested feeling and euphoric state; yet, the neural mechanisms underlying such pleasant effects remain unelucidated. Here, we report that propofol actively and directly binds to the dopamine transporter (DAT), but not the serotonin transporter (SERT), which contributes to the rapid relief of anhedonia. Then, we predict the binding mode of propofol by molecular docking and mutation of critical binding residues on the DAT. Fiber photometry recording on awake freely moving mice and [ 18 F] FP-CIT-PET scanning further establishes that propofol administration evokes rapid and lasting dopamine accumulation in nucleus accumbens (NAc). The enhanced dopaminergic tone drives biased activation of dopamine-receptor-1-expressing medium spiny neurons (D1-MSNs) in NAc and reverses anhedonia in chronically stressed animals. Collectively, these findings suggest the therapeutic potential of propofol against anhedonia, which warrants future clinical investigations., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)