Nr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes

Nat Commun. 2020 Jan 24;11(1):504. doi: 10.1038/s41467-020-14331-y.


Endogenous homeostatic mechanisms can restore normal neuronal function following cocaine-induced neuroadaptations. Such mechanisms may be exploited to develop novel therapies for cocaine addiction, but a molecular target has not yet been identified. Here we profiled mouse gene expression during early and late cocaine abstinence to identify putative regulators of neural homeostasis. Cocaine activated the transcription factor, Nr4a1, and its target gene, Cartpt, a key molecule involved in dopamine metabolism. Sustained activation of Cartpt at late abstinence was coupled with depletion of the repressive histone modification, H3K27me3, and enrichment of activating marks, H3K27ac and H3K4me3. Using both CRISPR-mediated and small molecule Nr4a1 activation, we demonstrated the direct causal role of Nr4a1 in sustained activation of Cartpt and in attenuation of cocaine-evoked behavior. Our findings provide evidence that targeting abstinence-induced homeostatic gene expression is a potential therapeutic target in cocaine addiction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • CRISPR-Cas Systems / genetics
  • Cocaine / administration & dosage
  • Cocaine / pharmacology*
  • Epigenesis, Genetic* / drug effects
  • Female
  • Histones / metabolism
  • Homeostasis / drug effects*
  • Homeostasis / genetics
  • Male
  • Mice, Inbred C57BL
  • Neurons / drug effects
  • Neurons / metabolism
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Phenylacetates / pharmacology
  • Promoter Regions, Genetic / genetics
  • Protein Processing, Post-Translational
  • Synapsins / metabolism


  • Histones
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Phenylacetates
  • Synapsins
  • cytosporone B
  • Cocaine