HDAC3 is a negative regulator of cocaine-context-associated memory formation.

Cocaine-induced neuroplasticity mediated by histone acetylating and deacetylating enzymes may contribute to addiction-like behaviors. For example, overexpression of histone deacetylases (HDACs) 4 or 5 in the nucleus accumbens suppresses cocaine-induced conditioned place preference (CPP) acquisition in mice. HDAC4 and HDAC5 are known to interact with HDAC3, but the role of HDAC3 in cocaine-induced behaviors has never been examined. In this study, we address the hypothesis that HDAC3 is a negative regulator of cocaine-context-associated memory formation in mice. We examined the role of HDAC3 during the conditioning phase of CPP, when the mouse has the opportunity to form an associative memory between the cocaine-paired context and the subjective effects of cocaine. To address this hypothesis, Hdac3(flox/flox) and Hdac3(+/+) mice (generated from a C57BL/6 background) were infused into the nucleus accumbens with adeno-associated virus expressing Cre recombinase to create focal, homozygous Hdac3 deletions. Hdac3(flox/flox) mice exhibit significantly enhanced CPP acquisition, which is correlated with increased gene expression during the consolidation phase of acquisition. Increased gene expression of c-Fos and Nr4a2 is correlated with decreased HDAC3 occupancy and increased histone H4 lysine 8 acetylation at their promoters. The results from this study demonstrate that HDAC3 negatively regulates cocaine-induced CPP acquisition.