Essential Role of SIRT1 Signaling in the Nucleus Accumbens in Cocain and Morphine Action

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Departmental Papers (Department of Systems Pharmacology and Translational Therapeutics)
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Biochemistry, Biophysics, and Structural Biology
Chemicals and Drugs
Genetics and Genomics
Neuroscience and Neurobiology
Pharmacology, Toxicology and Environmental Health
Pharmacy and Pharmaceutical Sciences
Substance Abuse and Addiction
Translational Medical Research
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Ferguson, Deveroux
Koo, Ja Wook
Feng, Jian
Rabkin, Jacqui
Heshmati, Mitra
Renthal, William
Liu, Xiaochuan
Shao, Ningyi
Sartorelli, Vittorio

Sirtuins (SIRTs), class III histone deacetylases, are well characterized for their control of cellular physiology in peripheral tissues, but their influence in brain under normal and pathological conditions remains poorly understood. Here, we establish an essential role for brain reward region. We show that chronic cocain administration increases SIRT1 and SIRT2 expression in the mouse NAc, while chronic morphine administration induces SIRT1 expression alone, with no regulation of all other sirtuin family members observed. Drug induction of SIRT1 and SIRT2 is mediated in part at the transcriptional level via the drug-induced transcription factor ΔFosB and is associated with robust histone modifications at the Sirt1 and Sirt2 genes. Viral-mediated overexpression of SIRT1 or SIRT2 in the NAc enhances the rewarding effects of both cocain and morphine. In contrast, the local knockdown of SIRT1 from the NAc of floxed Sirt1 mice decreases drug reward. Such behavioral effects of SIRT1 occur in concert with its regulation of numerous synaptic proteins in NAc as well as with SIRT1-mediated induction of dendritic spines on NAc medium spiny neurons. These studies establish sirtuins as key mediators of the molecular and cellular plasticity induced by drugs of abuse in NAc, and of the associated behavioral adaptations, and point towards novel signaling pathways involved in drug action.

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At the time of this publication, Dr. Heller was affiliated with the Icahn School of Medicine at Mount Sinai, but she is now a faculty member at the University of Pennsylvania.
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