2. Academic Validation
  3. G protein-dependent dopamine D2 receptor signaling mediates cocaine-primed reinstatement

G protein-dependent dopamine D2 receptor signaling mediates cocaine-primed reinstatement

  • Acta Pharmacol Sin. 2026 Jan 14. doi: 10.1038/s41401-025-01700-w.
Hai-Bo Li # 1 2,  Yong-Hui Liu # 1 2,  Hai Liu 1 2,  Yuan Li 1 2,  Qiu-Min Le 1 2,  Fei-Fei Wang 1 2,  Lan Ma 3 4,  Xing Liu 5 6
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Pharmacology Research Center, Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200032, China.
  • 2 Research Unit of Addiction Memory, Chinese Academy of Medical Sciences (2021RU009), Shanghai, 200032, China.
  • 3 School of Basic Medical Sciences, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Pharmacology Research Center, Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200032, China. [email protected].
  • 4 Research Unit of Addiction Memory, Chinese Academy of Medical Sciences (2021RU009), Shanghai, 200032, China. [email protected].
  • 5 School of Basic Medical Sciences, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Pharmacology Research Center, Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200032, China. [email protected].
  • 6 Research Unit of Addiction Memory, Chinese Academy of Medical Sciences (2021RU009), Shanghai, 200032, China. [email protected].
  • # Contributed equally.
PMID: 41535707 DOI: 10.1038/s41401-025-01700-w
Abstract

The high relapse rate of drugs is currently a therapeutic dilemma in the treatment of substance use disorder (SUD). Emerging evidence from preclinical animal models demonstrates that pretreatment with selective dopamine D2 receptor (D2R) antagonists prevents reinstatement of drug-seeking. However, the role of D2R downstream signaling in regulating relapse behavior remains unclear. In this study, we investigated the roles of Gαi-protein- and β-arrestin-dependent D2R signaling pathways in cocaine-primed reinstatement using cocaine self-administration (SA) mouse model treated with biased ligands. We found that treatment of D2R Gαi-protein antagonists, but not β-arrestin antagonists, significantly attenuated cocaine-primed reinstatement of drug seeking without affecting locomotor activity or anxiety levels. Administration of D2R Gαi-protein antagonists, but not β-arrestin antagonists, increased cyclic adenosine monophosphate (cAMP) levels in the nucleus accumbens (NAc). Furthermore, treatment of D2R Gαi-protein antagonists, but not β-arrestin antagonists, suppressed cocaine-induced neuronal activation in the NAc. Our results demonstrate that Gαi-protein-dependent D2R signaling plays a crucial role in cocaine-primed reinstatement and suggest that D2R Gαi-protein-biased ligands may be promising pharmacotherapeutic targets for SUD treatment.

Keywords

biased signaling; cocaine; dopamine D2 receptor; nucleus accumbens; reinstatement.

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