Abstract:
BACKGROUND:Addiction relies on persistent alterations of neuronal properties, which depends on gene regulation. Activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that modulates neuronal plasticity underlying learning and memory. Its role in cocaine-induced neuronal and behavioral adaptations remains elusive. METHODS:Acute cocaine-treated mice were used for quantitative reverse-transcriptase polymerase chain reaction, immunocytochemistry, and confocal imaging from striatum. Live imaging and transfection assays for Arc overexpression were performed from primary cultures. Molecular and behavioral adaptations to cocaine were studied from Arc-deficient mice and their wild-type littermates. RESULTS:Arc messenger RNA and proteins are rapidly induced in the striatum after acute cocaine administration, via an extracellular-signal regulated kinase-dependent de novo protein synthesis. Although detected in dendrites, Arc accumulates in the nucleus in active zones of transcription, where it colocalizes with phospho-Ser10-histone H3, an important component of nucleosomal response. In vitro, Arc overexpression downregulates phospho-Ser10-histone H3 without modifying extracellular-signal regulated kinase phosphorylation in the nucleus. In vivo, Arc-deficient mice display decreased heterochromatin domains, a high RNA-polymerase II activity and enhanced c-Fos expression. These mice presented an exacerbated psychomotor sensitization and conditioned place preference induced by low doses of cocaine. CONCLUSIONS:Cocaine induces the rapid induction of Arc and its nuclear accumulation in striatal neurons. Locally, it alters the nucleosomal response, and acts as a brake on chromatin remodeling and gene regulation. These original observations posit Arc as a major homeostatic modulator of molecular and behavioral responses to cocaine. Thus, modulating Arc levels may provide promising therapeutic approaches in drug addiction.
journal_name
Biol Psychiatryjournal_title
Biological psychiatryauthors
Salery M,Dos Santos M,Saint-Jour E,Moumné L,Pagès C,Kappès V,Parnaudeau S,Caboche J,Vanhoutte Pdoi
10.1016/j.biopsych.2016.05.025subject
Has Abstractpub_date
2017-04-01 00:00:00pages
573-584issue
7eissn
0006-3223issn
1873-2402pii
S0006-3223(16)32473-8journal_volume
81pub_type
杂志文章abstract:BACKGROUND:Childhood-onset schizophrenia (COS), defined as onset of psychotic symptoms by age 12 years, is a rare and severe form of the disorder that seems to be clinically and neurobiologically continuous with the adult disorder. METHODS:We studied a rare cohort consisting of 98 probands; 71 of these probands receiv...
journal_title:Biological psychiatry
pub_type: 杂志文章
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更新日期:2012-11-15 00:00:00
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pub_type: 临床试验,杂志文章
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更新日期:1995-06-15 00:00:00
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journal_title:Biological psychiatry
pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:Biological psychiatry
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更新日期:2017-10-15 00:00:00
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更新日期:1990-02-01 00:00:00
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更新日期:2015-07-15 00:00:00
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journal_title:Biological psychiatry
pub_type: 杂志文章
doi:
更新日期:1980-02-01 00:00:00
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更新日期:1999-08-01 00:00:00
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更新日期:1987-01-01 00:00:00
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更新日期:2007-01-01 00:00:00
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更新日期:2014-06-15 00:00:00
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journal_title:Biological psychiatry
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更新日期:2005-11-01 00:00:00
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journal_title:Biological psychiatry
pub_type: 杂志文章
doi:
更新日期:1977-06-01 00:00:00
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pub_type: 杂志文章,多中心研究,随机对照试验
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更新日期:2007-06-15 00:00:00
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journal_title:Biological psychiatry
pub_type: 杂志文章
doi:10.1016/j.biopsych.2011.03.005
更新日期:2011-09-01 00:00:00
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journal_title:Biological psychiatry
pub_type: 杂志文章
doi:10.1016/s0006-3223(98)00082-1
更新日期:1999-02-15 00:00:00
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journal_title:Biological psychiatry
pub_type: 杂志文章
doi:10.1016/j.biopsych.2013.03.027
更新日期:2013-10-15 00:00:00