In the NAc, endogenous HDAC5 also plays a key role in regulating gene expression in response to chronic, but not acute, cocaine exposure. Only repeated exposure to cocaine induces phosphorylation and nuclear export of HDAC5, thus reducing histone deacetylation and increasing gene expression of certain HDAC5 target genes [54]. Consistent with its regulation only by chronic cocaine exposure, drug-naïve HDAC5 knockout mice display normal cocaine reward. After a prior cocaine exposure, however, HDAC5 knockout mice hypersensitize to the rewarding effects of cocaine [54]. These findings raise the possibility that HDAC5 is involved in the behavioral transitions which occur between acute and chronic cocaine exposure (e.g., experimental drug use to compulsive drug use). The receptor for substance P, NK1, is one relevant target gene for HDAC5: its expression is induced to a greater extent by chronic cocaine in HDAC5 knockout mice and this induction appears to contribute to enhanced behavioral responses to the drug [45].
