RT Journal Article
SR Electronic
T1 Essential Role of SIRT1 Signaling in the Nucleus Accumbens in Cocaine and Morphine Action
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 16088
OP 16098
DO 10.1523/JNEUROSCI.1284-13.2013
VO 33
IS 41
A1 Deveroux Ferguson
A1 Ja Wook Koo
A1 Jian Feng
A1 Elizabeth Heller
A1 Jacqui Rabkin
A1 Mitra Heshmati
A1 William Renthal
A1 Rachael Neve
A1 Xiaochuan Liu
A1 Ningyi Shao
A1 Vittorio Sartorelli
A1 Li Shen
A1 Eric J. Nestler
YR 2013
UL http://www.jneurosci.org/content/33/41/16088.abstract
AB 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 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 toward novel signaling pathways involved in drug action.