There is a sex-based disparity associated with substance use disorders (SUDs) as demonstrated by clinical and preclinical studies. Females are known to escalate from initial drug use to compulsive drug-taking behavior (telescoping) more rapidly, and experience greater negative withdrawal effects than males. Although these biological differences have largely been attributed to sex hormones, there is evidence for non-hormonal factors, such as the influence of the sex chromosome, which underlie sex disparities in addiction behavior. However, genetic and epigenetic mechanisms underlying sex chromosome influences on substance abuse behavior are not completely understood. In this review, we discuss the role that escape from X-chromosome inactivation (XCI) in females plays in sex-associated differences in addiction behavior. Females have two X chromosomes (XX), and during XCI, one X chromosome is randomly chosen to be transcriptionally silenced. However, some X-linked genes escape XCI and display biallelic gene expression. We generated a mouse model using an X-linked gene specific bicistronic dual reporter mouse as a tool to visualize allelic usage and measure XCI escape in a cell specific manner. Our results revealed a previously undiscovered X-linked gene XCI escaper (CXCR3), which is variable and cell type dependent. This illustrates the highly complex and context dependent nature of XCI escape which is largely understudied in the context of SUD. Novel approaches such as single cell RNA sequencing will provide a global molecular landscape and impact of XCI escape in addiction and facilitate our understanding of the contribution of XCI escape to sex disparities in SUD.

临床和临床前研究表明，物质使用障碍 (SUD) 存在性别差异。众所周知，女性从最初的吸毒行为升级为强迫性吸毒行为（伸缩）的速度比男性更快，并且经历比男性更大的负面戒断效应。尽管这些生物学差异很大程度上归因于性激素，但有证据表明非激素因素，例如性染色体的影响，它是成瘾行为性别差异的基础。然而，性染色体影响药物滥用行为的遗传和表观遗传机制尚不完全清楚。在这篇综述中，我们讨论了女性逃避 X 染色体失活 (XCI) 在成瘾行为的性别相关差异中所扮演的角色。女性有两条 X 染色体 (XX)，在 XCI 过程中，随机选择一条 X 染色体进行转录沉默。然而，一些 X 连锁基因逃避 XCI 并显示双等位基因表达。我们使用 X 连锁基因特异性双顺反子双报告小鼠作为工具来生成小鼠模型，以可视化等位基因的使用并以细胞特异性方式测量 XCI 逃逸。我们的结果揭示了一个先前未被发现的 X 连锁基因 XCI escaper (CXCR3)，它是可变的且依赖于细胞类型。这说明了 XCI 转义的高度复杂性和上下文相关性，而在 SUD 的上下文中，XCI 转义在很大程度上没有得到充分研究。