Essential Role of SIRT1 Signaling in the Nucleus Accumbens in Cocaine and Morphine Action
| Autor: | Vittorio Sartorelli, Mitra Heshmati, Elizabeth A. Heller, Ja Wook Koo, Eric J. Nestler, Jian Feng, Rachael L. Neve, Jacqui Rabkin, Deveroux Ferguson, Xiaochuan Liu, Ning-Yi Shao, Li Shen, William Renthal |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Narcotics Chromatin Immunoprecipitation Dendritic spine Immunoblotting Drug action Nucleus accumbens Medium spiny neuron SIRT2 Nucleus Accumbens Cocaine-Related Disorders Mice Sirtuin 2 Cocaine Dopamine Uptake Inhibitors Reward Sirtuin 1 Animals Oligonucleotide Array Sequence Analysis Morphine biology Reverse Transcriptase Polymerase Chain Reaction General Neuroscience Articles Mice Inbred C57BL enzymes and coenzymes (carbohydrates) Sirtuin biology.protein Brain stimulation reward Morphine Dependence Neuroscience hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | The Journal of Neuroscience. 33:16088-16098 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.1284-13.2013 |
| Popis: | 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 theSirt1andSirt2genes. 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 floxedSirt1mice 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. |
| Databáze: | OpenAIRE |
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