The opioid epidemic has garnered much of the public’s attention in recent years, but addiction to psychostimulants continues to represent a substantial proportion of the overall addiction crisis the US. Most addictive drugs increase dopamine release in nucleus accumbens [1]. In addition, repeated drug exposure causes long-lasting neural changes that remain in place long after the drug is no longer onboard. This enduring neural plasticity is thought to be mediated in part by epigenetic mechanisms [2], processes that modulate gene expression without altering the DNA sequence. Methylation of DNA at cytosine-phospho-guanine (CpG) dinucleotides can alter the expression of genes and contributes to neuronal changes that play a role in memory and behavioral effects of addictive drugs [3, 4]. A challenging and active research area is to delineate how psychostimulant-induced increased dopamine neurotransmission translates to transcriptional and epigenetic changes that cause long-lasting changes in addiction-related behaviors [5].

In a recent Neuropsychopharmacology publication, Zipperly et al. [6] address this important question using a comprehensive combination of in vivo and in vitro cutting-edge approaches. Gadd45b, a member of the Growth arrest and DNA-damage-inducible gene family is important for synaptic plasticity and memory formation. Gadd45b is also associated with decreased methylation at CpG islands within regulatory DNA regions [3, 4]. Hence, Gadd45b lies at the intersection of experience-dependent neuronal activity and downstream regulation of DNA methylation states [7, 8], making it a promising candidate to link dopamine neurotransmission to cocaine-induced plasticity and epigenetic changes.

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