It is a complex issue: emerging connections between epigenetic regulators in drug addiction

Abstract

Drug use leads to addiction in some individuals, but the underlying brain mechanisms that control the transition from casual drug use to an intractable substance use disorder (SUD) are not well understood. Gene x environment interactions such as the frequency of drug use and the type of substance used likely to promote maladaptive plastic changes in brain regions that are critical for controlling addiction‐related behavior. Epigenetics encompasses a broad spectrum of mechanisms important for regulating gene transcription that are not dependent on changes in DNA base pair sequences. This review focuses on the proteins and complexes contributing to epigenetic modifications in the nucleus accumbens (NAc) following drug experience. We discuss in detail the three major mechanisms: histone acetylation and deacetylation, histone methylation, and DNA methylation. We discuss how drug use alters the regulation of the associated proteins regulating these processes and highlight how experimental manipulations of these proteins in the NAc can alter drug‐related behaviors. Finally, we discuss the ways that histone modifications and DNA methylation coordinate actions by recruiting large epigenetic enzyme complexes to aid in transcriptional repression. Targeting these multiprotein epigenetic enzyme complexes – and the individual proteins that comprise them – might lead to effective therapeutics to reverse or treat SUDs in patients.

Histone deacetylase inhibition reduces ventral tegmental area dopamine neuronal hyperexcitability involving AKAP150 signaling following maternal deprivation in juvenile male rats

“…Histone hyperacetylation of chromatin by HDAC inhibition using HDAC inhibitors (HDACi) has been shown to improve learning and memory by impacting synaptic plasticity (Graff et al, 2014; Graff & Tsai, 2013). Additionally, the novel use of HDACi has been proposed in a wide variety of neurological conditions such as post‐traumatic stress disorder (Whittle & Singewald, 2014), depression (Misztak, Panczyszyn‐Trzewik, & Sowa‐Kucma, 2018), spinal cord injury (Zhang, Fujita, Matsuzaki, & Yamashita, 2018), and addiction (Anderson et al, 2019; Kennedy et al, 2013; Kennedy & Harvey, 2015) due to the ability of HDACi to penetrate the central nervous system and attenuate the negative symptoms associated with these conditions through epigenetic and non‐epigenetic mechanisms.…”

Knockdown of the histone di-methyltransferase G9a in nucleus accumbens shell decreases cocaine self-administration, stress-induced reinstatement, and anxiety

“…Drug addiction in particular may involve regulation of the histone di-methyltransferase G9a (also called EHMT2 and KMT1C) [9]. G9a and/or H3K9me2 levels are reduced in the nucleus accumbens (NAc) following exposure to numerous drugs of abuse, including cocaine [10,11] and morphine [12].…”

Addiction in focus: molecular mechanisms, model systems, circuit maps, risk prediction and the quest for effective interventions

“…These authors invoke epigenetic changes that may be passed on through the germline, whereby this mechanism of epigenetic transgenerational inheritance may provide a link between paternal drug exposure and addiction susceptibility in the offspring. Review of the proteins and complexes contributing to epigenetic modifications (histone acetylation and deacetylation, histone methylation and DNA methylation) following drug experience, specifically in the nucleus accumbens, and the experimental manipulations of these proteins, provides an in depth glimpse into the potential for developing effective therapeutics to reverse or treat substance use disorders in patients (Anderson et al ., ). Beyond cellular and molecular targets, potential interventions could also target change in core behaviours in drug addiction.…”