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<p>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 D<sub>2</sub> receptor (D<sub>2</sub>R) antagonists prevents reinstatement of drug-seeking. However, the role of D<sub>2</sub>R downstream signaling in regulating relapse behavior remains unclear. In this study, we investigated the roles of G<sub><i>α</i>i</sub>-protein- and β-arrestin-dependent D<sub>2</sub>R signaling pathways in cocaine-primed reinstatement using cocaine self-administration (SA) mouse model treated with biased ligands. We found that treatment of D<sub>2</sub>R G<sub><i>α</i>i</sub>-protein antagonists, but not β-arrestin antagonists, significantly attenuated cocaine-primed reinstatement of drug seeking without affecting locomotor activity or anxiety levels. Administration of D<sub>2</sub>R G<sub><i>α</i>i</sub>-protein antagonists, but not β-arrestin antagonists, increased cyclic adenosine monophosphate (cAMP) levels in the nucleus accumbens (NAc). Furthermore, treatment of D<sub>2</sub>R G<sub><i>α</i>i</sub>-protein antagonists, but not β-arrestin antagonists, suppressed cocaine-induced neuronal activation in the NAc. Our results demonstrate that G<sub><i>α</i>i</sub>-protein-dependent D<sub>2</sub>R signaling plays a crucial role in cocaine-primed reinstatement and suggest that D<sub>2</sub>R G<sub><i>α</i>i</sub>-protein-biased ligands may be promising pharmacotherapeutic targets for SUD treatment.</p>

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

  • 期刊论文

  • 发表日期：

    2026年1月14日

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  • Hai-bo Li,
  • Yong-hui Liu,
  • Hai Liu,
  • Yuan Li,
  • Qiu-min Le,
  • Fei-fei Wang,
  • Lan Ma,
  • Xing Liu

摘要

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.