Objective    To investigate the role of prelimbic cortex (Prl) in methamphetamine (METH) induced conditioned place preference (CPP) in mice, and further identify the regulatory mechanism of Kv7.3 in Prl cortex.     Methods    In this study, C57BJ/6J mice were intraperitoneally injected with METH (2mg/kg) to establish animal model of CPP. Through chemical genetic manipulation, hM4di-mcherry virus was injected into Prl, by Clozapine N-oxide (CNO),s activation of small G protein signaling, to analyze the role of Prl in METH induced CPP. Then, qPCR and Western blot were used to detect the expression of Kv7.3 in METH addiction mice. Finally, cannulas were implanted stereotactically into Prl to observe the resulting effect of Kv7 channel agonist retigabine on CPP score.   Results   METH activated neurons in Prl and decreased the expression level of Kv7.3 significantly. CPP score was obviously reduced after specific inhibition of Prl neurons by chemical genetics. Also, Kv7.3 channel agonist retigabine decreased CPP score evidently.  Conclusions     Prl takes part in the regulation of METH induced CPP and Kv7.3 channel plays a crucial role in it.