ANKS1B in the Nucleus Accumbens regulate long-access cocaine self-administration and cocaine-seeking behavior

Ankyrin repeat domain-containing protein 1B (ANKS1B) has been implicated in the pathogenesis of multiple neuropsychiatric disorders, with common variants identified as shared risk factors for drug dependence. Cocaine addiction, as a disorder of neuroplasticity, is driven by epigenetic modulation and chromatin dynamics. However, the potential involvement of ANKS1B in this process remains unexplored. Here, we found that prolonged cocaine exposure downregulates ANKS1B expression in the Nucleus Accumbens (NAc). Mechanistically, ANKS1B constrains CREB-binding protein (CBP)-dependent H3K27 acetylation, whereas its overexpression counteracts cocaine-induced epigenetic activation. This ANKS1B-CBP interaction epigenetically represses the transcription factor FoxO3; its upregulation is both necessary and sufficient to mediate ANKS1B's influence on addiction-related behaviors. Collectively, these results establish ANKS1B as a central epigenetic determinant of cocaine addiction and highlight the ANKS1B-CBP-FoxO3 axis as a promising therapeutic target.