Objective To investigate the changes of P38 MAPK, PKC and CaMK II expression and involvement of P2X7 receptors in the prefrontal cortex of rats after cerebral 5-HT depletion. Methods Rats were randomly divided into normal group, sham-operated group (control group), PCPA group, P2X7 receptor antagonist group and P2X7 receptor agonist group. 5-HT depletion was induced by intraperitoneal injection of PCPA. Immunohistochemistry, western blot and real-time fluorescence quantitative PCR were performed to analyze the protein and mRNA expression of P38 MAPK, PKC and CaMK II in the prefrontal cortex. Results Expression of P38 MAPK in the PCPA group increased while PKC and CaMK expression decreased significantly compared with those in control group. Treatment of P2X7 receptor antagonist induced decrease of P38 MAPK expression and increase of PKC and CaMK II expression dramatically when compared with the PCPA group. As supposed, P2X7 receptor agonist worked the opposite way compared with P2X7 receptor antagonist. Conclusions P2X7 receptors play an important role in modulating P38 MAPK, PKC and CaMK II expression in the prefrontal cortex in rat model of cerebral 5-HT depletion.