OBJECTIVE To investigate the role and possible mechanisms of deep brain stimulation (DBS)treatment for the two sub-regions (dorsal and ventral) of medial prefrontal cortex (mPFC) in the extinction and reinstatement of heroin seeking behavior.METHODS The rats were implanted with electrodes in the dmPFC, vmPFC and trained to self-administer heroin (0.05 mg/kg/infusion) under a FR1 schedule in daily 4 h sessions.Then,extinction session (2 h) were conducted for 10 d, DBS (130 Hz or 10 Hz, 0.1 ms, 0.2 mA) were conducted 1 h before each extinction session.Cue-induced heroin seeking reinstatement test was conducted 24 h after the last extinction training.RESULTS In the DBS treatment with dmPFC, two-factor repeated ANOVA revealed that the HDBS group had significantly lower active pokes in cue-induced reinstatement of heroin seeking compared with those of sham stimulation group, while there was no difference in active pokes between sham stimulation and L-DBS group in cue-induced reinstatement of heroin seeking.There was also no difference in active nose-pokes between stimulated and sham control groups during the extinction sessions.In the DBS treatment with vmPFC, two-factor repeated ANONA found the number of active pokes in HDBS group were significantly higher than the sham control group in cue-induced reinstatement of heroin seeking or during day 4-7 extinction sessions.But low-frequency DBS in vmPFC had no effect on both extinction and cue-induced heroin-seeking.We also explored the effects of long-term high frequency stimulation of dmPFC on p-CREB , p-AKT and p-ERK expression in the NAc core and NAc shell.Western blot and immunohistochemical analysis showed that the level of p-CREB in the NAc core significantly increased in the rats treated with H-DBS compared with the sham control.In contrast, the level of p-ERK and p-AKt in the NAc core significantly decreased in the rats treated with H-DBS compared with the sham control.However, both pCREB and p-ERK in the NAc shell did not change significantly, but could significantly down-regulate the p-AKt expression.We conclude that the high frequency stimulation of dmPFC can inhibit the reinstatement of heroin-seeking induced by conditioned cues, and its regulation of phosphorylated CREB, phosphorylated ERK and phosphorylated AKt expression in NAc core may contribute to the behavioral inhibition in cue-induced reinstatement.High frequency stimulation of the vmPFC can impair the extinction of heroin seeking and facilitate the reinstatement of heroinseeking induced by conditioned cues; Low frequency stimulation of either dmPFC or vmPFC have no influence on heroin seeking behavior during extinction and cue-induced reinstatement.CONCLUSION The present studies demonstrated that chronic DBS treatment with mPFC may represent a useful treatment method for heroin addiction.