We investigated the role of histone H3 phosphoacetylation in the nucleus accumbens (NAc) in heroin-conditioned place preference paradigm. Heroin could dose-dependently increase histone H3 phosphoacetylation specifically in the NAc and could enhance heroin place preference. Injection of trichostatin A into the NAc significantly augmented heroin-induced histone H3 phosphoacetylation and enhanced heroin place preference. Conversely, injection of MK-801 into the NAc attenuated histone H3 phosphoacetylation and reduced heroin place preference. These data suggest that histone H3 phosphoacetylation in the NAc may play a critical role in heroin addiction.