title: A role for repressive histone methylation in cocaine-induced vulnerability to stress.
abstract: Substance abuse increases an individual's vulnerability to stress-related illnesses, which is presumably mediated by drug-induced neural adaptations that alter subsequent responses to stress. Here, we identify repressive histone methylation in nucleus accumbens (NAc), an important brain reward region, as a key mechanism linking cocaine exposure to increased stress vulnerability. Repeated cocaine administration prior to subchronic social defeat stress potentiated depressive-like behaviors in mice through decreased levels of histone H3 lysine 9 dimethylation in NAc. Cre-mediated reduction of the histone methyltransferase, G9a, in NAc promoted increased susceptibility to social stress, similar to that observed with repeated cocaine. Conversely, G9a overexpression in NAc after repeated cocaine protected mice from the consequences of subsequent stress. This resilience was mediated, in part, through repression of BDNF-TrkB-CREB signaling, which was induced after repeated cocaine or stress. Identifying such common regulatory mechanisms may aid in the development of new therapies for addiction and depression.
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1065, New York, NY 10029, USA.
authors.forename: Herbert E
authors.initials: HE
authors.lastname: Covington
authors.forename: Ian
authors.initials: I
authors.lastname: Maze
authors.forename: HaoSheng
authors.initials: H
authors.lastname: Sun
authors.forename: Howard M
authors.initials: HM
authors.lastname: Bomze
authors.forename: Kristine D
authors.initials: KD
authors.lastname: DeMaio
authors.forename: Emma Y
authors.initials: EY
authors.lastname: Wu
authors.forename: David M
authors.initials: DM
authors.lastname: Dietz
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Lobo
authors.forename: Subroto
authors.initials: S
authors.lastname: Ghose
authors.forename: Ezekiel
authors.initials: E
authors.lastname: Mouzon
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Carol A
authors.initials: CA
authors.lastname: Tamminga
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000503:physiopathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003863:Depression / Q000503:physiopathology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012919:Social Behavior; D013315:Stress, Psychological
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D018765:Dopamine Uptake Inhibitors; D006657:Histones; D020813:Receptor, trkB; D003042:Cocaine