Targeting dopamine transporter for treating social transmission of depression-like behaviors in male mice

  • Nat Commun. 2026 Jun 16. doi: 10.1038/s41467-026-74206-6.
Kun Zhang  #  1  2 ,  Dake Song  #  2  3 ,  Yingying Zhang  #  1  2 ,  Le Yang  #  1 ,  Ruixia Liu  2 ,  Hengxin Gong  2 ,  Qi Yang  1 ,  Min Wang  2 ,  Xinshang Wang  3 ,  Yumei Wu  2 ,  Weiwei Hu  4 ,  Shuibing Liu  5  6 ,  Minggao Zhao  7
Affiliations
  • 1. Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 2. Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 3. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Pharmacy, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 4. Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, College of Pharmaceutical Sciences, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 5. Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].
  • 6. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Pharmacy, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].
  • 7. Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].
  • # Contributed equally.
PMID: 42303982 DOI: 10.1038/s41467-026-74206-6
Abstract

Mounting evidence has validated the social transmissibility of depression-like behaviors. This study identifies the essential roles of dopamine signaling and the olfactory system in mediating socially transmitted depression (STD) in male mice. Breath odors from defeated conspecifics induce approach behaviors through the main olfactory bulb-piriform cortex (MOB-PiC) pathway, whereas urine odors trigger avoidance via the accessory olfactory bulb-medial amygdala (AOB-MeA) pathway. Both chemosensory inputs ultimately converge in the medial prefrontal cortex (mPFC). Social interactions with defeated conspecifics markedly enhance dopamine release from the ventral tegmental area (VTA) to the mPFC. In STD-sensitive mice, upregulated Dopamine Transporter (DAT) expression in the mPFC reduces basal dopamine levels and facilitates depression-like phenotypes. The MOB-PiC-mPFC-VTA axis mediates social interaction-evoked dopamine elevation, and DAT modulates dopamine reduction. Elevated dopamine variability within the mPFC is sufficient to drive STD. Notably, DAT-targeted intervention confers superior therapeutic efficacy against STD compared with serotonin system modulation.

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