Sex differences in susceptibility to substance use disorder: Role for X chromosome inactivation and escape?

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.