Distinguishing the brain mechanisms affected by distinct addictive drugs may inform targeted therapies against specific substance use disorders (SUDs). Here, we explore the function of a drug-associated, transcriptionally repressive transcription factor (TF), ZFP189, whose expression in the nucleus accumbens (NAc) facilitates cocaine-induced molecular and behavioral adaptations. To uncover the necessity of ZFP189-mediated transcriptional control in driving cocaine-induced behaviors, we created synthetic ZFP189 TFs of distinct transcriptional function, including ZFP189^VPR, which activates the expression of target genes and exerts opposite transcriptional control to the endogenously repressive ZFP189. By virally delivering synthetic ZFP189 TFs to the NAc of mice, we discover that the transcriptional control exerted by synthetic or endogenous ZFP189 solely alters behavioral adaptations to cocaine but not morphine, saline, or sucrose. Further, these synthetic ZFP189 TFs are only capable of producing gene-expression changes in rodents exposed to cocaine, but not morphine or saline. In these cocaine exposed mice, the gene-expression profile produced by ZFP189^VPR is inversely related to the cocaine-induced transcriptional response, as characterized by Upstream Regulator Analysis in Ingenuity Pathway Analysis. Lastly, we demonstrate that NAc ZFP189^WT increases vulnerability to cocaine reinforcement through selective sensitization to the reinforcing effects of small cocaine doses. In contrast, ZFP189^VPR treated mice do not experience changes in cocaine sensitivity and had lower rates of cocaine self-administration. Collectively, this research describes the brain mechanisms by which a TF specifically coordinates the molecular adaptations that produce increased cocaine addiction-like behaviors. The use of synthetic ZFP189^VPR uncovers novel strategies for therapeutic interventions to potentially halt these cocaine-induced transcriptional processes.

区分受不同成瘾药物影响的大脑机制可能为针对特定物质使用障碍 （SUD） 的靶向治疗提供信息。在这里，我们探讨了药物相关的转录抑制转录因子 （TF） ZFP189 的功能，其在伏隔核 （NAc） 中的表达促进了可卡因诱导的分子和行为适应。为了揭示 ZFP189 介导的转录控制在驱动可卡因诱导行为中的必要性，我们创造了具有不同转录功能的合成 ZFP189 TFs，包括 ZFP189^VPR，它激活靶基因的表达并施加与内源性抑制性 ZFP189 相反的转录控制。通过病毒将合成的 ZFP189 TFs 递送到小鼠的 NAc，我们发现合成或内源性 ZFP189 施加的转录控制仅改变对可卡因的行为适应，而不改变吗啡、盐水或蔗糖的行为适应。此外，这些合成的 ZFP189 TFs 只能在暴露于可卡因的啮齿动物中产生基因表达变化，而不能在吗啡或盐水中产生基因表达变化。在这些可卡因暴露的小鼠中，ZFP189^VPR 产生的基因表达谱与可卡因诱导的转录反应呈负相关，如 Ingenuity Pathway Analysis 中的上游调节因子分析所表征。最后，我们证明 NAc ZFP189^WT 通过对小剂量可卡因的强化作用选择性敏感，增加了对可卡因强化的脆弱性。相比之下，ZFP189^VPR 处理的小鼠可卡因敏感性没有变化，并且可卡因自我给药率较低。 总的来说，这项研究描述了 TF 特异性协调产生增加可卡因成瘾样行为的分子适应的大脑机制。合成 ZFP189^VPR 的使用揭示了治疗干预的新策略，以潜在地阻止这些可卡因诱导的转录过程。