Propofol exerts anti-anhedonia effects via inhibiting the dopamine transporter

Xiao-Na Zhu; Jie Li; Gao-Lin Qiu; Lin Wang; Chen Lu; Yi-Ge Guo; Ke-Xin Yang; Fang Cai; Tao Xu; Ti-Fei Yuan; Ji Hu

doi:10.1016/j.neuron.2023.02.017

Propofol exerts anti-anhedonia effects via inhibiting the dopamine transporter

Neuron. 2023 May 17;111(10):1626-1636.e6. doi: 10.1016/j.neuron.2023.02.017. Epub 2023 Mar 13.

Authors

Xiao-Na Zhu¹, Jie Li², Gao-Lin Qiu³, Lin Wang¹, Chen Lu¹, Yi-Ge Guo¹, Ke-Xin Yang¹, Fang Cai¹, Tao Xu⁴, Ti-Fei Yuan⁵, Ji Hu⁶

Affiliations

¹ School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
² Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
³ Department of Anesthesiology, First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
⁴ Department of Anesthesiology, Affiliated Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China. Electronic address: balor@sjtu.edu.cn.
⁵ Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. Electronic address: tifei.yuan@smhc.org.cn.
⁶ School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: huji@shanghaitech.edu.cn.

PMID: 36917979
DOI: 10.1016/j.neuron.2023.02.017

Abstract

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 [¹⁸F] 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.

Keywords: D1-MSNs; anti-anhedonia; dopamine transporter; nucleus accumbens; propofol.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anhedonia
Animals
Dopamine Plasma Membrane Transport Proteins / metabolism
Dopamine* / metabolism
Mice
Mice, Inbred C57BL
Molecular Docking Simulation
Nucleus Accumbens / physiology
Propofol* / metabolism
Propofol* / pharmacology
Receptors, Dopamine D1 / metabolism

Substances

Dopamine
Propofol
Dopamine Plasma Membrane Transport Proteins
Receptors, Dopamine D1