Early-life stress and ovarian hormones alter transcriptional regulation in the nucleus accumbens resulting in sex-specific responses to cocaine Institutional Repository Document uri icon


  • AbstractEarly-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 FosB, 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.

altmetric score

  • 18.95

author list (cited authors)

  • Rocks, D., Jaric, I., Bellia, F., Cham, H., Greally, J. M., Suzuki, M., & Kundakovic, M.

citation count

  • 0

complete list of authors

  • Rocks, Devin||Jaric, Ivana||Bellia, Fabio||Cham, Heining||Greally, John M||Suzuki, Masako||Kundakovic, Marija

Book Title

  • bioRxiv

publication date

  • April 2023