Sex chromosome genes contribute to cocaine vulnerability in a strain-dependent manner

Objective We used wild-type C57BL/6J (B6) mice and four core genotype (FCG) mice on two strain backgrounds (B6 and MF1) to examine the role of SCC, estradiol, and genetic background in vulnerability to cocaine use. Results In wild-type B6 mice, no effects of sex, gonadectomy, or estradiol treatment were observed during acquisition or progressive-ratio testing. In contrast, in gonadectomized B6 FCG mice, vulnerability was driven by SCC, with XY mice showing greater acquisition and responding than XX mice. SCC effects were not observed in MF1 FCG mice, indicating strain dependence. Whole-genome sequencing identified a missense single nucleotide polymorphism in Zfy2 , consistent with Y-chromosome variation in the B6 FCG line. Anogenital distance was reduced in FCG B6 mice, suggesting altered early androgen exposure. Expression of toll-like receptor genes ( Tlr7, Tlr8 ), and their association with cocaine self-administration behavior, differed by SCC and strain. Conclusion SCC can influence cocaine vulnerability in a strain- and hormone-dependent manner; however, these effects are not generalizable across FCG models and may reflect interactions with strain-specific genetic features, including the X-to-Y chromosome translocation present in the B6 FCG line. Candidate mechanisms include Y-linked variation, developmental androgen exposure, and immune signaling; however, their functional relevance remains to be established.