title: `Up-regulation of histone acetylation induced by social defeat mediates the conditioned rewarding effects of cocaine.
abstract: Social defeat (SD) induces a long-lasting increase in the rewarding effects of psychostimulants measured using the self-administration and conditioned place procedures (CPP). However, little is known about the epigenetic changes induced by social stress and about their role in the increased response to the rewarding effects of psychostimulants. Considering that histone acetylation regulates transcriptional activity and contributes to drug-induced behavioral changes, we addressed the hypothesis that SD induces transcriptional changes by histone modifications associated with the acquisition of place conditioning. After a fourth defeat, H3(K9) acetylation was decreased in the hippocampus, while there was an increase of HAT and a decrease of HDAC levels in the cortex. Three weeks after the last defeat, mice displayed an increase in histone H4(K12) acetylation and an upregulation of histone acetyl transferase (HAT) activity in the hippocampus. In addition, H3(K4)me3, which is closely associated with transcriptional initiation, was also augmented in the hippocampus three weeks after the last defeat. Inhibition of HAT by curcumin (100mg/kg) before each SD blocked the increase in the conditioned reinforcing effects of 1mg/kg of cocaine, while inhibition of HDAC by valproic acid (500mg/kg) before social stress potentiated cocaine-induced CPP. Preference was reinstated when animals received a priming dose of 0.5mg/kg of cocaine, an effect that was absent in untreated defeated mice. These results suggest that the experience of SD induces chromatin remodeling, alters histone acetylation and methylation, and modifies the effects of cocaine on place conditioning. They also point to epigenetic mechanisms as potential avenues leading to new treatments for the long-term effects of social stress on drug addiction.
authors.affiliation: Department of Psychobiology, Facultad de Psicología, Universitat de Valencia, Avda. Blasco Ibáñez, 21, 46010 Valencia, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Montagud-Romero
authors.affiliation: Department of Molecular and Cellular Pathology of Alcohol, Príncipe Felipe Research Center, C/Eduardo Primo Yúfera, 3, 46012 Valencia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Montesinos
authors.affiliation: Department of Molecular and Cellular Pathology of Alcohol, Príncipe Felipe Research Center, C/Eduardo Primo Yúfera, 3, 46012 Valencia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pascual
authors.affiliation: Department of Psychobiology, Facultad de Psicología, Universitat de Valencia, Avda. Blasco Ibáñez, 21, 46010 Valencia, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Aguilar
authors.affiliation: Department of Psychobiology, Facultad de Psicología, Universitat de Valencia, Avda. Blasco Ibáñez, 21, 46010 Valencia, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Roger-Sanchez
authors.affiliation: Department of Molecular and Cellular Pathology of Alcohol, Príncipe Felipe Research Center, C/Eduardo Primo Yúfera, 3, 46012 Valencia, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Guerri
authors.affiliation: Department of Psychobiology, Facultad de Psicología, Universitat de Valencia, Avda. Blasco Ibáñez, 21, 46010 Valencia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Miñarro
authors.affiliation: Department of Psychobiology, Facultad de Psicología, Universitat de Valencia, Avda. Blasco Ibáñez, 21, 46010 Valencia, Spain. Electronic address: marta.rodriguez@uv.es.
authors.forename: M
authors.initials: M
authors.lastname: Rodríguez-Arias
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004291:Dominance-Subordination; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D008297:Male; D051379:Mice; D012201:Reward; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology; D013315:Stress, Psychological / Q000378:metabolism*; D015854:Up-Regulation; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000697:Central Nervous System Stimulants; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D014635:Valproic Acid; D051548:Histone Acetyltransferases; D003042:Cocaine
keywords: Cocaine; Curcumin; Histone acetylation; Social defeat stress; Valproic acid