Early-Life Stress and Ovarian Hormones Alter Transcriptional Regulation in the Nucleus Accumbens Resulting in Sex-Specific Responses to Cocaine

Early-life stress and ovarian hormones contribute to increased female vulnerability to cocaine addiction. Here we reveal molecular substrates in the key reward area, the nucleus accumbens, through which these female-specific factors affect immediate and conditioning responses to cocaine in mice. We find shared involvement of X chromosome and estrogen signaling gene regulation in enhanced conditioning responses seen after early-life stress and during the low-estrogenic state in females. During the low-estrogenic state, females respond to acute cocaine exposure by increasing the accessibility of neuronal chromatin enriched for the binding sites of ΔFosB, a transcription factor implicated in chronic cocaine response and addiction. Conversely, high-estrogenic females respond to cocaine by preferential closing of neuronal chromatin, providing a mechanism for limiting cocaine-driven chromatin and synaptic plasticity. We find that physiological estrogen withdrawal, exposure to early-life stress, and absence of the second X chromosome all nullify the protective effect of high-estrogenic state on cocaine conditioning in females. Our findings offer a molecular framework to understand sex-specific neuronal mechanisms underlying cocaine use disorder. ### Competing Interest Statement The authors have declared no competing interest.