Abstract Cocaine abuse represents a worldwide significant issue because it is one of the most dangerous commonly used illicit drugs. Both psychiatric and neurological symptoms are usual manifestations of cocaine toxicity. A few reports mention that certain transcripts of the central nervous system are changed by cocaine administration. Differential display (DD) detects mRNA variations among many different kinds of tissues and cells and is more highly sensitive. We analysed the transcriptome in the brain of murine models following cocaine administration using a fluorescence differential display (FDD). Seventeen differentially expressed genes were found with FDD, and confirmed by nucleotide sequence and real time PCR. Of these genes, four genes including silencer of death domain (SODD) and Mpv 17-like protein (M-LP) increased. Of the remaining 13 genes containing A20 binding inhibitor of NF-κB activation-2 (ABIN-2) decreased. Increased SODD may inhibit signal-transduction following TNF stimulation for apoptosis. Raised M-LP might suppress apoptosis to reduce ROS via SOD production. The decrease of ABIN-2, which meant the increase of NF-κB activation via the reducing of the A-20 and ABIN02 complex, might enable apoptosis suppression. Therefore, the expressions of all genes identified in this study might lead to the prevention of neuronal apoptosis. In this study, we found the specific alteration of transcripts following the administration of cocaine. The results of this study may contribute to revealing the pathophysiology of cocaine in the brain.