Psychostimulants induce stable changes in neural plasticity and behavior in a transcription-dependent manner. Further, stable cellular changes require transcription that is regulated by epigenetic mechanisms that alter chromatin structure, such as histone acetylation. This mechanism is typically catalyzed by enzymes with histone acetyltransferase or histone deacetylase (HDAC) activity. Class Ila HDAC5 are notable for their high expression in important regions of the brain reward circuitry and their neural activity-dependent shuttling in and out of the cell nucleus. In particular, HDAC5 has an important modulatory function in cocaine-induced behaviors and social defeat stress-induced effects. Although a mutation in HDAC5 has been shown to cause hypersensitive responses to chronic cocaine use whether this response worsens during chronic early life stress has not been examined yet. In this study, we exposed mouse pups to two different early life stress paradigms (social isolation, ESI, and social threat, EST) to determine whether the heterozygous null mutation in HDAC5 (HDAC5+/) moderated the effects of exposure to stress in early life on adult cocaine-induced conditioned place preference (CPP). Notably, HDAC5+/ mice that had been exposed to ESI were more susceptible to developing cocaine-induced CPP and more resistant to extinguishing this behavior. The same effect was not observed for HDAC5+/ mice experiencing EST, suggesting that only ESI induces behavioral changes by acting precisely through HDAC5-related biological pathways. Finally, an analysis of c-Fos expression performed to discover the neurobiological substrates that Mediated this phenotype, identified the dorsolateral striatum as an important structure that mediates the interaction between HDAC5 mutation and ESL Our data demonstrate that decreased HDAC5 function is able to exacerbate the long-term behavioral effects of adverse rearing environment in mouse. (C) 2016 Elsevier Inc. All rights reserved.