Editors' ChoiceNeurobiology

High on Sirtuins

Science Signaling  19 May 2009:
Vol. 2, Issue 71, pp. ec166
DOI: 10.1126/scisignal.271ec166

To better understand transcriptional changes associated with chronic use of cocaine, Renthal and colleagues did a genome-wide screen for mouse genes at which changes in histone modification by polyacetylation or dimethylation had occurred. These covalent changes in histones are associated with regulatory changes in gene transcription. The authors confirmed the regulation of numerous genes that had been detected as cocaine targets by direct measurements of mRNA abundance. However, they also identified new targets that appear to function in signaling in the nucleus accumbens, a brain region of reward circuitry where cocaine and other addictive drugs produce long-term changes. The authors saw alterations in histone modification at genes encoding the sirtuins Sirt1 and Sirt2. The sirtuins are themselves Class III NAD-dependent histone deacetylases that can deacetylate histones and other proteins. The sirtuins regulate a wide range of biological processes, including cell growth, apoptosis, organismal metabolism, and aging. The authors confirmed that chronic cocaine administration increased the abundance of mRNAs for Sirt1 and Sirt2 and increased deacetylase activity of the enzymes. Pharmacological manipulation of sirtuin activity in brain slices showed that sirtuin activation was associated with increased excitability of medium spiny neurons. In whole animals, administration of an inhibitor or activator showed that sirtuin activation enhanced a learned response to prefer a location that the animal associated with cocaine administration. Furthermore, inhibitor-infused rats decreased self-administration of cocaine in an animal model of addictive behavior. Analysis of the global changes in gene regulation with Ingenuity software for pathway analysis showed changes associated with numerous signaling pathways after chronic exposure of animals to cocaine. Some pathways, such as cyclic adenosine monophosphate (cAMP) signaling, mitogen-activated protein kinase (MAPK) signaling, and retinoic acid receptor signaling, have been previously implicated in cocaine action. New pathways, the biological relevance of which remains to be explored, included protein ubiquitination, Toll-like receptor signaling, and fibroblast growth factor receptor signaling.

W. Renthal, A. Kumar, G. Xiao, M. Wilkinson, H. E. Covington III, I. Maze, D. Sikder, A. J. Robison, Q. LaPlant, D. M. Dietz, S. J. Russo, V. Vialou, S. Chakravarty, T. J. Kodadek, A. Stack, M. Kabbaj, E. J. Nestler, Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins. Neuron 62, 335–348 (2009). [Online Journal]