Departmental Papers (Department of Systems Pharmacology and Translational Therapeutics)

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Technical Report

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Journal of Neuroscience





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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.

Copyright/Permission Statement

Originally published in the Journal of Neuroscience © 2013 Society for Neuroscience. Now available Open Access under a Creative Commons Attribution International 4.0 License (CC BY 4.0).


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.



Date Posted: 24 January 2018

This document has been peer reviewed.