Role of DNA methylation in the nucleus accumbens in incubation of cocaine craving

Renaud Massart, Royi Barnea, Yahav Dikshtein, Matthew Suderman, Oren Meir, Michael Hallett, Pamela Kennedy, Eric J. Nestler, Moshe Szyf, Gal Yadid

Research output: Contribution to journalArticlepeer-review

112 Scopus citations


One of the major challenges of cocaine addiction is the high rate of relapse to drug use after periods of withdrawal. During the first few weeks of withdrawal, cue-induced cocaine craving intensifies, or “incubates,” and persists over extended periods of time. Although several brain regions and molecular mechanisms were found to be involved in this process, the underlying epigenetic mechanisms are still unknown. Herein, we used a rat model of incubation of cocaine craving, in which rats were trained to self-administer cocaine (0.75 mg/kg, 6 h/d, 10 d), and cue-induced cocaine-seeking was examined in an extinction test after 1 or 30 d of withdrawal. We show that the withdrawal periods, as well as cue-induced cocaine seeking, are associated with broad, time-dependent enhancement of DNA methylation alterations in the nucleus accumbens (NAc). These gene methylation alterations were partly negatively correlated with gene expression changes. Furthermore, intra-NAc injections of a DNA methyltransferase inhibitor (RG108, 100 µM) abolished cue-induced cocaine seeking on day 30, an effect that persisted 1 month, whereas the methyl donor S-adenosylmethionine (500 µM) had an opposite effect on cocaine seeking. We then targeted two proteins whose genes were demethylated by RG108-estrogen receptor 1 (ESR1) and cyclin-dependent kinase 5 (CDK5). Treatment with an intra-NAc injection of the ESR1 agonist propyl pyrazole triol (10 nM) or the CDK5 inhibitor roscovitine (28 µM) on day 30 of withdrawal significantly decreased cue-induced cocaine seeking. These results demonstrate a role for NAc DNA methylation, and downstream targets of DNA demethylation, in incubation of cocaine craving.

Original languageEnglish
Pages (from-to)8042-8058
Number of pages17
JournalJournal of Neuroscience
Issue number21
StatePublished - 27 May 2015

Bibliographical note

Publisher Copyright:
© 2015 the authors.


  • Cocaine addiction
  • DNA methylation
  • Incubation of cocaine craving
  • Nucleus accumbens


Dive into the research topics of 'Role of DNA methylation in the nucleus accumbens in incubation of cocaine craving'. Together they form a unique fingerprint.

Cite this