Epigenetics of Drug Addiction

Abstract

Substance use disorders (SUDs) are chronic brain diseases characterized by transitions from recreational to compulsive drug use and aberrant drug craving that persists for months to years after abstinence is achieved. The transition to compulsive drug use implies that plasticity is occurring, altering the physiology of the brain to precipitate addicted states. Epigenetic phenomena represent a varied orchestra of transcriptional tuning mechanisms that, in response to environmental stimuli, create and maintain gene expression-mediated physiological outcomes. Therefore, epigenetic mechanisms represent a convergent regulatory framework through which the plasticity required to achieve an addicted state can arise and then persist long after drug use has ended. In the first section, we will introduce basic concepts in epigenetics, such as chromatin architecture, histones and their posttranslational modifications, DNA methylation, noncoding RNAs, and transcription factors, along with methods for their investigation. We will then examine the implications of these mechanisms in SUDs, with a particular focus on cocaine-mediated neuroepigenetic plasticity across multiple behavioral models of addiction.

Figure 1.

Epigenetic priming in substance use disorders. Represented here are four examples of observed patterns of neuroepigenetic regulation following acute versus chronic exposures to drugs of abuse. Gene A represents a repressed locus that can be activated by acute exposures, yet following periods of abstinence, becomes primed at the level of chromatin to be hyperactivated upon reintroduction to drug stimuli. Gene B, on the other hand, represents a permissive gene that becomes repressed by acute exposures and then remains inappropriately repressed during withdrawal and in response to subsequent drug priming and/or cue reexposures. Gene C represents a gene that might become activated by acute drug exposures, similar to gene A. However, following chronic drug use and withdrawal, gene C becomes inappropriately repressed, so that upon subsequent drug exposures, the locus remains in a chronically repressed state. Gene D, although not activated by acute exposures, becomes aberrantly activated by chronic drug experiences and then primed during abstinence, such that reexposure to drugs of abuse and/or their associated cues result in hyperpermissiveness of the gene product. (TF) transcription factor, (RNAPII) RNA polymerase II transcriptional complex.