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  • 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 alter transcriptional regulation in the nucleus accumbens resulting in sex-specific responses to cocaine.

Cell reports (2023-10-01)
Devin Rocks, Ivana Jaric, Fabio Bellia, Heining Cham, John M Greally, Masako Suzuki, Marija Kundakovic
ABSTRACT

Early-life stress and ovarian hormones contribute to increased female vulnerability to cocaine addiction. Here, we reveal molecular substrates in the reward area, the nucleus accumbens, through which these female-specific factors affect immediate and conditioning responses to cocaine. We find shared involvement of X chromosome inactivation-related and estrogen signaling-related gene regulation in enhanced conditioning responses following early-life stress and during the low-estrogenic state in females. Low-estrogenic females respond to acute cocaine by opening neuronal chromatin enriched for the sites of ΔFosB, a transcription factor implicated in chronic cocaine response and addiction. Conversely, high-estrogenic females respond to cocaine by preferential chromatin closing, providing a mechanism for limiting cocaine-driven chromatin and synaptic plasticity. We find that physiological estrogen withdrawal, early-life stress, and absence of one X chromosome all nullify the protective effect of a high-estrogenic state on cocaine conditioning in females. Our findings offer a molecular framework to enable understanding of sex-specific neuronal mechanisms underlying cocaine use disorder.

MATERIALS
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Brand
Product Description

Sigma-Aldrich
Milli-Mark® Mouse IgG1-k, clone MOPC-21, Alexa Fluor 488 conjugate, Mouse IgG1-k Monoclonal Antibody control validated for use in Flow Cytometry.
Sigma-Aldrich
Anti-NeuN Antibody, clone A60, Alexa Fluor488 conjugated, clone A60, Chemicon®, from mouse