Essential Role of SIRT1 Signaling in the Nucleus Accumbens in Cocaine and Morphine Action
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 regula...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Society for Neuroscience
2014
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| Online Access: | http://hdl.handle.net/1721.1/89141 https://orcid.org/0000-0002-3854-5968 |
| _version_ | 1826211754651156480 |
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| author | Ferguson, Deveroux Koo, Ja Wook Feng, Jian Heller, Elizabeth Rabkin, Jacqui Heshmati, Mitra Renthal, William Neve, Rachael L. Liu, Xiaochuan Shao, Ningyi Sartorelli, Vittorio Shen, Li Nestler, Eric J. |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Ferguson, Deveroux Koo, Ja Wook Feng, Jian Heller, Elizabeth Rabkin, Jacqui Heshmati, Mitra Renthal, William Neve, Rachael L. Liu, Xiaochuan Shao, Ningyi Sartorelli, Vittorio Shen, Li Nestler, Eric J. |
| author_sort | Ferguson, Deveroux |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:10:36Z |
| format | Article |
| id | mit-1721.1/89141 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:10:36Z |
| publishDate | 2014 |
| publisher | Society for Neuroscience |
| record_format | dspace |
| spelling | mit-1721.1/891412022-10-02T01:09:07Z 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 L. Liu, Xiaochuan Shao, Ningyi Sartorelli, Vittorio Shen, Li Nestler, Eric J. Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Neve, Rachael L. 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. National Institute on Drug Abuse Brain & Behavior Research Foundation UNCF-Merck Postdoctoral Fellowship 2014-09-02T19:03:32Z 2014-09-02T19:03:32Z 2013-10 2013-08 Article http://purl.org/eprint/type/JournalArticle 0270-6474 1529-2401 http://hdl.handle.net/1721.1/89141 Ferguson, D., J. W. Koo, J. Feng, E. Heller, J. Rabkin, M. Heshmati, W. Renthal, et al. “Essential Role of SIRT1 Signaling in the Nucleus Accumbens in Cocaine and Morphine Action.” Journal of Neuroscience 33, no. 41 (October 9, 2013): 16088–16098. https://orcid.org/0000-0002-3854-5968 en_US http://dx.doi.org/10.1523/jneurosci.1284-13.2013 Journal of Neuroscience Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Society for Neuroscience Society for Neuroscience |
| spellingShingle | Ferguson, Deveroux Koo, Ja Wook Feng, Jian Heller, Elizabeth Rabkin, Jacqui Heshmati, Mitra Renthal, William Neve, Rachael L. 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 |
| title | Essential Role of SIRT1 Signaling in the Nucleus Accumbens in Cocaine and Morphine Action |
| title_full | Essential Role of SIRT1 Signaling in the Nucleus Accumbens in Cocaine and Morphine Action |
| title_fullStr | Essential Role of SIRT1 Signaling in the Nucleus Accumbens in Cocaine and Morphine Action |
| title_full_unstemmed | Essential Role of SIRT1 Signaling in the Nucleus Accumbens in Cocaine and Morphine Action |
| title_short | Essential Role of SIRT1 Signaling in the Nucleus Accumbens in Cocaine and Morphine Action |
| title_sort | essential role of sirt1 signaling in the nucleus accumbens in cocaine and morphine action |
| url | http://hdl.handle.net/1721.1/89141 https://orcid.org/0000-0002-3854-5968 |
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