Editors' ChoiceNeuroscience

Epigenetics of addiction

Sci. Signal.  03 Mar 2015:
Vol. 8, Issue 366, pp. ec50
DOI: 10.1126/scisignal.aab0040

Brain-derived neurotrophic factor (BDNF) mediates changes in neural plasticity induced by opiates, such as morphine, and stimulants, such as cocaine. One of the neural circuits affected by both opiates and stimulants is the brain's mesolimbic dopamine system, which consists of the ventral tegmental area (VTA) and its contacts with the nucleus accumbens (NAc). In the mouse, cocaine induces BDNF signaling and neural plasticity in the VTA-NAc circuit, whereas opiates, such as morphine, repress Bdnf expression in the VTA. Koo et al. found that, compared with controls, the abundance of Bdnf transcripts was reduced in VTA samples from human heroin addicts, from heroin self-administering rats, and from rats and mice treated chronically with morphine. The authors used quantitative chromatin immunoprecipitation (qChIP) analysis to compare histone modifications and transcription factor binding at the Bdnf locus in VTA cells from chronically morphine-treated and control rodents. Chronic morphine treatment caused RNA polymerase II to stall in the coding region of Bdnf and induced various changes in histone modifications at the Bdnf promoter, including an increase in the abundance of histone 3 trimethylated at Lys4 (H3K4me3). The abundance of H3K4me3 also increased in the promoter of Nuclear receptor–related 1 (Nurr1), which encodes a transcription factor that promotes Bdnf expression. Both Nurr1 and Bdnf are targets of the cAMP response element–binding protein (CREB), and the increased abundance of H3K4me3 correlated with reduced binding of activated CREB to these promoters in vivo. Furthermore, overexpression of the enzyme that catalyzes the H3K4me3 modification reduced activated CREB binding to the Bdnf promoter in the absence of morphine treatment. Overexpressing NURR1 in the VTA induced Bdnf expression, blocked morphine reward, and rescued a hyperlocomotive phenotype caused by morphine readministration after withdrawal. These findings highlight the complexity of epigenetic control of neural plasticity, though the mechanisms by which morphine induces histone modifications remain unidentified.

J. W. Koo, M. S. Mazei-Robison, Q. LaPlant, G. Egervari, K. M. Braunscheidel, D. N. Adank, D. Ferguson, J. Feng, H. Sun, K. N. Scobie, D. M. Damez-Werno, E. Ribeiro, C. J. Peña, D. Walker, R. C. Bagot, M. E. Cahill, S. A. R. Anderson, B. Labonté, G. E. Hodes, H. Browne, B. Chadwick, A. J. Robison, V. F. Vialou, C. Dias, Z. Lorsch, E. Mouzon, M. K. Lobo, D. M. Dietz, S. J. Russo, R. L. Neve, Y. L. Hurd, E. J. Nestler, Epigenetic basis of opiate suppression of Bdnf gene expression in the ventral tegmental area. Nat. Neurosci. 18, 415–422 (2015). [PubMed]