Epigenetic Mechanisms in Drug Relapse

A growing body of evidence from the past 15 years implicates epigenetic mechanisms in the behavioral effects of addictive drugs. The main focus of these studies has been epigenetic mechanisms of psychomotor sensitization and drug reinforcement, as assessed by the conditioned place preference and drug self-administration procedures. Some of these studies have documented long-lasting changes in the expression of epigenetic enzymes and molecules that persist for weeks after the last drug exposure. These observations have inspired more recent investigations on the epigenetic mechanisms of relapse to drug seeking after prolonged abstinence. Here, we review studies that have examined epigenetic mechanisms (e.g., histone modifications, chromatin remodeler–associated modifications, and DNA methylation) that contribute to relapse to cocaine, amphetamine, methamphetamine, morphine, heroin, nicotine, or alcohol seeking, as assessed in rodent models. We first provide a brief overview of studies that have examined persistent epigenetic changes in the brain after prolonged abstinence from noncontingent drug exposure or drug self-administration. Next, we review studies on the effect of either systemic or brain site–specific epigenetic manipulations on the reinstatement of drug-conditioned place preference after extinction of the learned preference, the reinstatement of drug seeking after operant drug self-administration and extinction of the drug-reinforced responding, and the incubation of drug craving (the time-dependent increase in drug seeking after cessation of drug self-administration). We conclude by discussing the implications of these studies for understanding mechanisms contributing to persistent relapse vulnerability after prolonged abstinence. We also discuss the implications of these results for translational research on the potential use of systemically administered epigenetic enzyme inhibitors for relapse prevention in human drug users.