The Inhibition of Histone Deacetylases Reduces the Reinstatement of Cocaine-Seeking Behavior in Rats

Pascal      Romieu; Elodie      Deschatrettes; Lionel      Host; Serge      Gobaille; Guy      Sandner; Jean      Zwiller

doi:10.2174/157015911795017317

Abstract

Drug addiction is a chronic brain disease characterized by a persistent risk of relapse, even after a long period of abstinence. A current hypothesis states that relapse results from lasting neuroadaptations that are induced in response to repeated drug administration. The adaptations require gene expression, some of which being under the control of stable epigenetic regulations. We have previously demonstrated that pretreatment with histone deacetylase (HDAC) inhibitors reduces the cocaine reinforcing properties as well as the motivation of rats for cocaine. We show here that the same HDAC inhibitors, trichostatin A and phenylbutyrate, significantly reduced the cocaine-seeking behavior induced by the combination of a cocaine injection together with the exposure to a light cue previously associated with cocaine taking. Reinstatement of drug-seeking behavior was carried out after a 3-week withdrawal period, which came after ten daily sessions of cocaine intravenous self-administration. Our results suggest that pharmacological treatment aimed at modulating epigenetic regulation, and particularly treatment that would inhibit HDAC activity, could reduce the risk of relapse, a major drawback in the treatment of drug addiction.

Keywords: Drug dependence, cocaine self-administration, cocaine-seeking behavior, epigenetic regulation, histone deacetylase, trichostatin A, phenylbutyrate, cocaine self - administration, ase, trichohistatin A, Phenyl burayte, DNA, psychiatric Disorders, Phenyl butyrate (phB)