Background and Purpose: Cocaine addiction causes serious health problems and no effective treatment is available yet. We previously identified a genetic risk variant for cocaine addiction in the PLCB1 gene and found this gene upregulated in postmortem brains of cocaine abusers and in human dopaminergic neuron-like cells after an acute cocaine exposure. Here, we functionally tested the contribution of PLCB1 gene to cocaine addictive properties in mice. Experimental approach: We used heterozygous Plcb1 knockout mice (Plcb1+/-) and characterized their behavioral phenotype. Subsequently, mice were trained for operant conditioning and self-administered cocaine for 10 days. Plcb1+/- mice were assessed for cocaine motivation, followed by 26 days of extinction and finally evaluated for cue-induced reinstatement of cocaine seeking. Gene expression alterations after reinstatement were assessed in medial prefrontal cortex (mPFC) and hippocampus (HPC) by RNAseq. Key Results: Plcb1+/- mice showed normal behavior, although they had increased anxiety and impaired short-term memory. Importantly, after cocaine self-administration and extinction, we found a reduction in the cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/- mice. After reinstatement, we identified transcriptomic alterations in the medial prefrontal cortex of Plcb1+/- mice, mostly related to pathways relevant to addiction like the dopaminergic synapse and long-term potentiation. Conclusions and Implications: To conclude, we found that heterozygous deletion of the Plcb1 gene decreases cue-induced reinstatement of cocaine seeking, pointing at PLCB1 as a possible therapeutic target for preventing relapse and treating cocaine addiction.

中文翻译：

---

在Plcb1 +/-小鼠中降低提示诱导的可卡因寻找行为的恢复

背景与目的：可卡因成瘾会导致严重的健康问题，目前尚无有效的治疗方法。我们之前在PLCB1基因中发现了可卡因成瘾的遗传风险变异体，发现该基因在急性可卡因暴露后在可卡因滥用者的死后大脑和人多巴胺能神经元样细胞中上调。在这里，我们在功能上测试了PLCB1基因对小鼠可卡因成瘾性的贡献。实验方法：我们使用杂合的Plcb1基因敲除小鼠（Plcb1 +/-）并表征了它们的行为表型。随后，对小鼠进行操作条件训练和可卡因自用，持续10天。对Plcb1 +/-小鼠的可卡因动机进行了评估，然后灭绝了26天，最后对线索诱导的可卡因寻找的恢复进行了评估。恢复后的基因表达变化通过RNAseq在内侧前额叶皮层（mPFC）和海马（HPC）中进行评估。关键结果：Plcb1 +/-小鼠表现出正常行为，尽管它们增加了焦虑并损害了短期记忆。重要的是，在可卡因自我给药和灭绝后，我们发现在Plcb1 +/-小鼠中提示诱导的可卡因寻求行为的恢复降低。恢复后，我们确定了Plcb1 +/-小鼠内侧前额叶皮层的转录组变化，主要与成瘾有关的途径（如多巴胺能突触和长期增强作用）有关。结论和意义：总而言之，我们发现Plcb1基因的杂合缺失会降低线索诱导的可卡因寻找的恢复，