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.
Original language | English (US) |
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Article number | 113187 |
Journal | Cell Reports |
Volume | 42 |
Issue number | 10 |
DOIs | |
State | Published - Oct 31 2023 |
Keywords
- CP: Neuroscience
- chromatin
- cocaine
- early life stress
- epigenetic regulation
- gene expression
- neuroplasticity
- nucleus accumbens
- ovarian hormones
- reward
- sex difference
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology