Activity-Regulated Cytoskeleton-Associated Protein Accumulates in the Nucleus in Response to Cocaine and Acts as a Brake on Chromatin Remodeling and Long-Term Behavioral Alterations

International audienceBackgroundAddiction 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.MethodsAcute cocaine-treated mice were used for Q-RT-PCR, 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.ResultsArc mRNA and proteins are rapidly induced in the striatum after acute cocaine administration, via an ERK-dependent de novo protein synthesis. Although detected in dendrites, Arc accumulates in the nucleus in active zones of transcription where it colocalizes with phosphorylated histone-H3 (pH3), an important component of nucleosomal response. In vitro, Arc overexpression down-regulates pH3 without modifying ERK phosphorylation in the nucleus. In vivo, Arc-deficient mice display decreased heterochromatin domains, a high RNA-Pol II activity and enhanced c-Fos expression. These mice presented an exacerbated psychomotor sensitization and conditioned place preference induced by low doses of cocaine.ConclusionsCocaine 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