Essential role of SIRT1 signaling in the nucleus accumbens in cocaine and morphine action

Deveroux Ferguson, Ja Wook Koo, Jian Feng, Elizabeth Heller, Jacqui Rabkin, Mitra Heshmati, William Renthal, Rachael Neve, Xiaochuan Liu, Ningyi Shao, Vittorio Sartorelli, Li Shen, Eric J. Nestler

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

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 SIRT1 and SIRT2 in regulating behavioral responses to cocaine and morphine through actions in the nucleus accumbens (NAc), a key brain reward region. We show that chronic cocaine 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 cocaine and morphine. In contrast, the local knockdown of SIRT1 from theNAcof 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 toward novel signaling pathways involved in drug action.

Original languageEnglish (US)
Pages (from-to)16088-16098
Number of pages11
JournalJournal of Neuroscience
Volume33
Issue number41
DOIs
StatePublished - 2013
Externally publishedYes

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Nucleus Accumbens
Cocaine
Morphine
Sirtuins
Reward
Pharmaceutical Preparations
Histone Code
Dendritic Spines
Histone Deacetylases
Brain
Street Drugs
Transcription Factors
Neurons
Genes
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Ferguson, D., Koo, J. W., Feng, J., Heller, E., Rabkin, J., Heshmati, M., ... Nestler, E. J. (2013). Essential role of SIRT1 signaling in the nucleus accumbens in cocaine and morphine action. Journal of Neuroscience, 33(41), 16088-16098. https://doi.org/10.1523/JNEUROSCI.1284-13.2013

Essential role of SIRT1 signaling in the nucleus accumbens in cocaine and morphine action. / Ferguson, Deveroux; Koo, Ja Wook; Feng, Jian; Heller, Elizabeth; Rabkin, Jacqui; Heshmati, Mitra; Renthal, William; Neve, Rachael; Liu, Xiaochuan; Shao, Ningyi; Sartorelli, Vittorio; Shen, Li; Nestler, Eric J.

In: Journal of Neuroscience, Vol. 33, No. 41, 2013, p. 16088-16098.

Research output: Contribution to journalArticle

Ferguson, D, Koo, JW, Feng, J, Heller, E, Rabkin, J, Heshmati, M, Renthal, W, Neve, R, Liu, X, Shao, N, Sartorelli, V, Shen, L & Nestler, EJ 2013, 'Essential role of SIRT1 signaling in the nucleus accumbens in cocaine and morphine action', Journal of Neuroscience, vol. 33, no. 41, pp. 16088-16098. https://doi.org/10.1523/JNEUROSCI.1284-13.2013
Ferguson, Deveroux ; Koo, Ja Wook ; Feng, Jian ; Heller, Elizabeth ; Rabkin, Jacqui ; Heshmati, Mitra ; Renthal, William ; Neve, Rachael ; Liu, Xiaochuan ; Shao, Ningyi ; Sartorelli, Vittorio ; Shen, Li ; Nestler, Eric J. / Essential role of SIRT1 signaling in the nucleus accumbens in cocaine and morphine action. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 41. pp. 16088-16098.
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