Activity-dependent epigenetic remodeling in cocaine use disorder

Substance use disorder (SUD) is a behavioral disorder characterized by cycles of abstinence, drug seeking, and relapse. SUD is characterized by aberrant learning processes which develop after repeated exposure to drugs of abuse. At the core of this phenotype is the persistence of symptoms, such as craving and relapse to drug seeking, long after the cessation of drug use. The neural basis of these behavioral changes has been linked to dysfunction in neural circuits across the brain; however, the molecular drivers that allow for these changes to persist beyond the lifespan of any individual protein remain opaque. Epigenetic adaptations – where DNA is modified to increase or decrease the probability of gene expression at key genes – have been identified as a mechanism underlying the long-lasting nature of drug-seeking behavior. Thus, to understand SUD, it is critical to define the interplay between neuronal activation and longer-term changes in transcription and epigenetic remodeling and define their role in addictive behaviors. In this review, we discuss the current understanding of drug-induced changes to circuit function, recent discoveries in epigenetic mechanisms that mediate these changes, and, ultimately, how these adaptations drive the persistent nature of relapse, with emphasis on adaptations in models of cocaine use disorder. Understanding the complex interplay between epigenetic gene regulation and circuit activity will be critical in elucidating the neural mechanisms underlying SUD. This, with the advent of novel genetic-based techniques, will allow for the generation of novel therapeutic avenues to improve treatment outcomes in SUD.