Injection of the histone deacetylases inhibitor trichostatin A to rats has been shown to decrease the reinforcing properties of cocaine. In the present study, we investigated alterations in gene expression patterns in the anterior cingulate cortex, caudate-putamen and nucleus accumbens of rats self-administering cocaine and treated with trichostatin A. As recent studies highlighted the importance of chromatin remodelling in the regulation of gene transcription in neurons, we studied the expression of Mecp2 and of several histone deacetylases. Cocaine self-administration was accompanied by an increased synthesis of Mecp2, HDAC2 and HDAC11 and by a decreased nuclear localization of HDAC5 and of the phospho-form of HDAC5, suggesting a nuclear export of this protein in response to the drug. The latter mechanism was further addressed by the demonstration of an enhanced expression of MEF2C transcription factor. Among the genes we examined, treatment with trichostatin A before each cocaine self-administration session was found to mostly affect Mecp2 and HDAC11 expression. A correlation was found between the modification of Mecp2 and MEF2C gene expression and the reinforcing property of cocaine. The two factors known to regulate gene transcription are likely to play a role in the neurobiological mechanism underlying a decrease in the reinforcing properties of cocaine.