Previous studies demonstrated that histone acetylation modulated the transcription of associated gene expression and thus contributed to the persistence of addictive behaviors and neuroplasticity. Nonetheless, the roles of histone acetylation in distinct phases of methamphetamine (METH)-induced conditioned place preference (CPP) remain unclear. The current study examines the effects of the histone deacetylases (HDACs) inhibitor sodium butyrate (NaB) on the acquisition, extinction, and reinstatement of METH-induced CPP in mice. Our results showed that 1mg/kg METH induced CPP in mice after four conditioning sessions. METH-induced CPP was extinguished after three extinction training sessions and could be triggered by the same dose (1mg/kg) of METH on the reinstatement test day. Meanwhile, NaB (400mg/kg) per se had no effect on the natural preference of mice, but injections of NaB during the conditioning and extinction phases facilitated the acquisition and extinction of METH-induced CPP, respectively. Additionally, although the effect of a single NaB injection prior to the trigger of CPP reinstatement was not observed, repeated NaB injections during the extinction phase totally blocked the reinstatement of METH-induced CPP. Taken together, our results suggested a specific effect of histone acetylation on modulating distinct phases of METH-induced CPP and that treatment of NaB during the extinction phase not only produced beneficial effects on eliminating already established CPP but also blocked the reinstatement of METH-induced CPP. (C) 2016 Wiley Periodicals, Inc.