title: Histone deacetylase inhibitors decrease cocaine but not sucrose self-administration in rats.
abstract: Regulation of gene expression is known to contribute to the long-term adaptations taking place in response to drugs of abuse. Recent studies highlighted the regulation of gene transcription in neurons by chromatin remodeling, a process in which posttranslational modifications of histones play a major role. To test the involvement of epigenetic regulation on drug-reinforcing properties, we submitted rats to the cocaine operant self-administration paradigm. Using the fixed ratio 1 schedule, we found that the histone deacetylase (HDAC) inhibitors trichostatin A and phenylbutyrate dose-dependently reduced cocaine self-administration. Under the progressive ratio schedule, both trichostatin A and depudecin 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. This observation was correlated with measurements of HDAC activity in the frontal cortex, which was inhibited in response to cocaine, but not to sucrose self-administration. Control experiments showed that the decrease in the motivation for the drug was not attributable to a general motivational dysfunction because trichostatin A had no adverse effect on locomotion during the habituation session or on cocaine-induced hyperlocomotion. It was not attributable to anhedonia because the inhibitor had no effect on the sucrose preference test. In contrast, trichostatin A completely blocked the cocaine-induced behavioral sensitization. Together, the data show that epigenetic regulation of gene transcription in adult brain is able to influence a motivated behavior and suggest that HDAC inhibition may counteract the neural sensitization leading to drug dependence.
authors.affiliation: Inserm, U575, Centre de Neurochimie, 67084 Strasbourg, France, Institut Fédératif de Recherche 37 Neurosciences, 67085 Strasbourg, France. romieu@neurochem.u-strasbg.fr
authors.forename: Pascal
authors.initials: P
authors.lastname: Romieu
authors.forename: Lionel
authors.initials: L
authors.lastname: Host
authors.forename: Serge
authors.initials: S
authors.lastname: Gobaille
authors.forename: Guy
authors.initials: G
authors.lastname: Sandner
authors.forename: Dominique
authors.initials: D
authors.lastname: Aunis
authors.forename: Jean
authors.initials: J
authors.lastname: Zwiller
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D003216:Conditioning, Operant; D019175:DNA Methylation / Q000187:drug effects; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008297:Male; D010654:Phenylbutyrates / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration; D013395:Sucrose / Q000494:pharmacology
chemical_list: D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D010654:Phenylbutyrates; C012589:trichostatin A; D013395:Sucrose; D006655:Histone Deacetylases; D003042:Cocaine
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