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.
Highlights
Drug dependence is currently viewed as a chronic brain disease characterized primarily by a compulsive drugseeking and drug-taking behavior
We showed for instance that treatment with the histone deacetylase (HDAC) inhibitors trichostatin A (TsA) or phenylbutyrate (PhB) reduces the cocaine reinforcing properties under a fixed-ratio 1 (FR1) schedule of cocaine intravenous (i.v.) self-administration protocol [9]
Since we have previously reported that pretreatment with HDAC inhibitors reduces the cocaine reinforcing properties as well as the motivation of rats for cocaine [9], we investigated in the present study whether these pharmacological agents were able to affect the cocaine-seeking behavior
Summary
Drug dependence is currently viewed as a chronic brain disease characterized primarily by a compulsive drugseeking and drug-taking behavior. The development of dependence to drugs of abuse occurs over time and requires cellular adaptations. Characterization of long-term plasticity underlying addiction is currently an intensive research area and concerns mainly the characterization of changes in gene expression evoked by drugs of abuse [1]. Several studies have highlighted the importance of epigenetic regulations of gene transcription in diverse aspects of psychiatric disorders, including addiction [2,3,4]. Epigenetic regulations are complex mechanisms that control neuronal gene transcription by regulating the accessibility of genes to the transcriptional machinery [5]. Access to DNA in the nucleosome is achieved via complex associations of proteins in which posttranslational modifications of histones play a major role. Increased histone acetylation is associated with DNA relaxation and elevated transcriptional activity, whereas decreased acetylation brought about by histone deacetylases (HDACs) results in tighter DNA coiling and gene silencing [6,7,8]
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