Cocaine addiction is a chronic and relapsing disorder with an important genetic component. Human candidate gene association studies showed that the single nucleotide polymorphism (SNP) rs16969968 in the α5 subunit (α5SNP) of nicotinic acetylcholine receptors (nAChRs), previously associated with increased tobacco dependence, was linked to a lower prevalence of cocaine use disorder (CUD). Three additional SNPs in the α5 subunit, previously shown to modify α5 mRNA levels, were also associated with CUD, suggesting an important role of the subunit in this pathology. To investigate the link between this subunit and CUD, we submitted rats knockout for the α5 subunit gene (α5KO), or carrying the α5SNP, to cocaine self-administration (SA) and showed that the acquisition of cocaine-SA was impaired in α5SNP rats while α5KO rats exhibited enhanced cocaine-induced relapse associated with altered neuronal activity in the nucleus accumbens. In addition, we observed in a human cohort of patients with CUD that the α5SNP was associated with a slower transition from first cocaine use to CUD. We also identified a novel SNP in the β4 nAChR subunit, part of the same gene cluster in the human genome and potentially altering CHRNA5 expression, associated with shorter time to relapse to cocaine use in patients.

In conclusion, the α5SNP is protective against CUD by influencing early stages of cocaine exposure while CHRNA5 expression levels may represent a biomarker for the risk to relapse to cocaine use. Drugs modulating α5 containing nAChR activity may thus represent a novel therapeutic strategy against CUD.

可卡因成瘾是一种具有重要遗传成分的慢性复发性疾病。人类候选基因关联研究表明，烟碱乙酰胆碱受体 (nAChR) α5 亚基 (α5SNP) 中的单核苷酸多态性 (SNP) rs16969968 以前与烟草依赖增加有关，但与可卡因使用障碍 (CUD) 的患病率降低有关. α5 亚基中的三个额外 SNP，先前显示可改变 α5 mRNA 水平，也与 CUD 相关，表明该亚基在该病理学中起重要作用。为了研究该亚基和 CUD 之间的联系，我们提交了敲除 α5 亚基基因 (α5KO) 或携带 α5SNP 的大鼠，可卡因自我给药 (SA) 并表明可卡因-SA 的获得在 α5SNP 大鼠中受损，而 α5KO 大鼠表现出增强的可卡因诱导的复发，与伏核中神经元活动的改变有关。此外，我们在一组 CUD 患者中观察到，α5SNP 与从首次使用可卡因到 CUD 的过渡较慢有关。我们还在 β4 nAChR 亚基中发现了一个新的 SNP，它是人类基因组中相同基因簇的一部分，可能会改变CHRNA5表达，与患者使用可卡因的复发时间较短有关。

总之，α5SNP 通过影响可卡因暴露的早期阶段来预防 CUD，而CHRNA5表达水平可能代表可卡因使用复发风险的生物标志物。因此，调节含有 nAChR 活性的 α5 的药物可能代表一种针对 CUD 的新治疗策略。