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Biography

Jean Zwiller has completed his Ph.D in 1982 from the Université de Strasbourg, France. He is currently Directeur de Recherche at the CNRS, and head of a group entitled "Neuroadaptations to Psychostimulants" (UMR 7237, Strasbourg). Transcriptome studies together with the intravenous cocaine self-administration paradigm are used to describe mechanisms that are responsible for establishing long-term effects of the psychostimulant cocaine. During the six last years, he became increasingly interested in investigating epigenetic regulations induced by cocaine. Modifications of gene expression by these mechanisms are probably involved in drug dependence.

Abstract

Regulation of gene expression is known to contribute to the long-term adaptations taking place in brain structures in response to drugs of abuse. Recent studies highlight the regulation of gene transcription in neurons by chromatin remodeling, a process governed by the interplay of DNA methylation and post-translational modifications of histones, with histone acetylation being well documented. To test the involvement of epigenetic regulation on drug reinforcing properties, we submitted rats to the cocaine intravenous self-administration paradigm. Using the fixed-ratio 1 schedule, the histone deacetylase (HDAC) inhibitors trichostatin A (TsA) and phenylbutyrate were found to dose-dependently reduce cocaine self-administration. Under the progressive ratio schedule, they significantly reduced the breaking point, indicating that HDAC inhibition attenuated the motivation of rats for cocaine. Conversely, HDAC inhibition did not decrease self-administration for the natural reinforcer sucrose. The same HDAC inhibitors also 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 was carried out after a 3-week withdrawal period. We then studied gene regulation occurring in rats self-administering cocaine and treated with TsA. Additional epigenetic parameters were found to be involved. To fully characterize genes differentially expressed by TsA, we used the microarray technology. The data indicate that proteins encoded by some of these genes, such as those belonging to the reelin pathway, contribute to establish the neurobiological mechanisms underlying brain plasticity whereby TsA lowers the motivation for cocaine.