Repeated exposure to psychostimulants such as cocaine, leads to long term alterations to both the brain and the behavior. Although, there are plenty of researches devoted to depict such plasticity changes of the brain, molecular mechanisms underlying such structural alterations are not very clear. Studies focused on nucleus accumbens (NAc) have discovered many genes and signal pathways are involved in these plastic changes. Even though studies from both human and rodents have shown that PFC have an important role in mediating the long term effects of cocaine. There are very few molecular studies dedicated to it. In search of such molecular mechanisms, we used the sequencing method RNA-Seq, at three time points after chronic cocaine injections, to check the dynamic changes of mRNAs in PFC on the transcriptome level. Different numbers of differentially expressed genes (DGEs) were discovered at three withdrawal time points: 463 (2H), 14 (24H), 535 (7D). DEGs from all three time points were then pooled together to analyze the correlation of their dynamic expression changes along the time line, as a result of which, five time-serielly correlated clusters were obtained. Further analysis of DEGs from individual time points and clusters revealed several dynamically changed pathways. To be specific, both the circadian and MAPK signaling pathways were up-regulated from 2H-24H, with ERK pathway from MAPK still altered at time point 7D, implying a role in mediating the acute effects of cocaine by both circadian and MAPK signaling pathways and ERK pathway’s involvement in the long term brain and behavior changes. Other than that, we also found a decline tendency in the metabolism (both energy and protein) pathways, which reached a significant low level at withdrawal time day 7, supporting a role of metabolism pathways in the long term cocaine effects. This is also the first report of such a role at the systematic molecular level. At last, to our surprise, no alternative splicing event were discovered in any of the three time points, in contrast to the previous study reporting chronic cocaine exposure has led to many alternative splicing events in the nucleus accumbens, suggesting the regional specificity of splicing regulation by cocaine.