复旦大学刘星团队在研究中取得进展。他们报道了G蛋白依赖性多巴胺D2受体信号介导可卡因启动恢复。相关论文于2026年1月14日发表于国际顶尖学术期刊《中国药理学报》杂志上。

在本研究中，研究团队研究了G_αi蛋白和β-抑制蛋白依赖的D₂R信号通路在偏向配体处理的可卡因启动恢复主题可卡因自我给药（SA） motheme模型中的作用。该课题组发现，D₂R G_αi蛋白拮抗剂治疗，而不是β-抑制素拮抗剂治疗，可以显著减轻可卡因引发的药物寻求恢复，而不影响运动活动或焦虑水平。给予D₂R G_αi蛋白拮抗剂，而非β-抑制素拮抗剂，可增加伏隔核（NAc）中环磷酸腺苷（cAMP）的水平。

此外，D₂R G_αi蛋白拮抗剂而非β-抑制素拮抗剂可抑制可卡因诱导的NAc神经元活化。他们的研究结果表明，G_αi蛋白依赖的D₂R信号在可卡因引发的恢复中起着至关重要的作用，并表明D₂R G_αi蛋白偏向配体可能是治疗SUD的有希望的药物治疗靶点。

据悉，药物的高复发率是目前治疗物质主题障碍（SUD）的一个治疗难题。来自临床前动物模型的新证据表明，选择性多巴胺D₂受体（D₂R）拮抗剂预处理可防止药物寻找的恢复。然而，D₂R下游信号在调节复发行为中的作用尚不清楚。

附：英文原文

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

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

Issue&Volume: 2026-01-14

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.

DOI: 10.1038/s41401-025-01700-w

Source: https://www.nature.com/articles/s41401-025-01700-w