Department de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
Transl Psychiatry. 2021 Oct 11;11(1):521. doi: 10.1038/s41398-021-01396-6.
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 the PLCB1 gene to cocaine addictive properties using Plcb1+/- mice. First, we performed a general phenotypic characterization and found that Plcb1+/- mice showed normal behavior, although they had increased anxiety and impaired short-term memory. Subsequently, mice were trained for operant conditioning, self-administered cocaine for 10 days, and were tested for cocaine motivation. After 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. 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.
可卡因成瘾会导致严重的健康问题，但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，并且在可卡因滥用者的死后大脑和急性可卡因暴露后的人类多巴胺能神经元样细胞中发现该基因上调。在这里，我们使用 Plcb1+/- 小鼠对 PLCB1 基因对可卡因成瘾特性的贡献进行了功能测试。首先，我们进行了一般表型特征描述，发现 Plcb1+/- 小鼠表现出正常的行为，尽管它们表现出焦虑增加和短期记忆受损。随后，对小鼠进行操作性条件反射训练，让它们自行服用可卡因 10 天，并测试可卡因的动机。在消退后，我们发现 Plcb1+/- 小鼠的线索诱导可卡因寻求行为的复燃减少。复燃后，我们在 Plcb1+/- 小鼠的内侧前额叶皮层中发现了转录组改变，主要与成瘾相关的途径有关，如多巴胺能突触和长时程增强。总之，我们发现 Plcb1 基因的杂合缺失减少了线索诱导的可卡因寻求的复燃，这表明 PLCB1 可能是预防复发和治疗可卡因成瘾的潜在治疗靶点。
