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Review
, 148, 747-765

Neuroepigenetics and Addiction

Affiliations
Review

Neuroepigenetics and Addiction

Deena M Walker et al. Handb Clin Neurol.

Abstract

Drug addiction involves long-term behavioral abnormalities that arise in response to repeated exposure to drugs of abuse in vulnerable individuals. It is a multifactorial syndrome involving a complex interplay between genes and the environment. Evidence suggests that the underlying mechanisms regulating these persistent behavioral abnormalities involve changes in gene expression throughout the brain's reward circuitry, in particular, in the mesolimbic dopamine system. In the past decade, investigations have begun to reveal potential genes involved in the risk for addiction through genomewide association studies. Additionally, a crucial role for epigenetic mechanisms, which mediate the enduring effects of drugs of abuse on the brain in animal models of addiction, has been established. This chapter focuses on recent evidence that genetic and epigenetic regulatory events underlie the changes throughout the reward circuitry in humans, as well as animal models of addiction. While further investigations are necessary, a picture of genetic and epigenetic mechanisms involved in addiction is beginning to emerge and the insight gained from these studies will be key to the identification of novel targets for improved diagnosis and treatment of addiction syndromes in humans.

Keywords: DNA methylation; addiction; chromatin; epigenetics; genomewide association studies; histone modifications; small noncoding RNAs; substance abuse disorder.

Figures

Fig. 48.1
Fig. 48.1
The reward circuitry of the brain is similar across species and is activated by drugs of abuse. The major brain regions involved in the mesolimbic reward pathway are depicted in the human (A) and rodent (B) brain: dopaminergic neurons (green) in the ventral tegmental area (VTA) project to the nucleus accumbens (NAC), prefrontal cortex (PFC), amygdala (AMY), and hippocampus (HPC). The NAC also receives glutamatergic (red) innervation from the PFC, AMY, and HPC. While the mechanisms of action are specific for each drug, most drugs of abuse increase dopaminergic signaling from the VTA to other regions of the reward circuitry. Studies investigating the contribution of genetic factors to the addicted phenotype have focused on identifying markers in vulnerable human subjects that presumably result in altered sensitivity and function of the mesolimbic dopamine system. On the other hand, studies investigating epigenetic mechanisms of drug abuse have focused on the NAC in animal models of addiction, as it is a major region of integration for rewarding stimuli. (Modified with permission from Pena CJ, Bagot RC, Labonte B, et al. (2014) Epigenetic signaling in psychiatric disorders. J Mol Biol 426: 3389–3412.)
Fig. 48.2
Fig. 48.2
Addiction is a complex phenotype that is regulated by both genetic and environmental factors. Information from the environment is recognized by the brain or body and in turn elicits a response, which often involves changes in gene expression, as indicated by the blue arrows. These gene–environment interactions are relayed by epigenetic mechanisms, including chromatin modifications, DNA methylation, and the expression of noncoding RNAs. Vulnerability to substance abuse has both genetic and environmental risk factors that act in concert to produce the phenotype but exposure to drugs of abuse (indicated with the red arrow) is necessary for the behavioral phenotype to emerge. The details of gene–environment interactions through the full life cycle of addiction are highly iterative and remain incompletely understood. AMY, amygdala; HPC, hippocampus; PFC, prefrontal cortex; SNPs, single-nucleotide polymorphisms; VTA, ventral tegmental area.
Fig. 48.3 and Table 48.1
Fig. 48.3 and Table 48.1
Chromatin modifications regulated by drugs of abuse. The illustration (top) indicates histone octamers in a repressive (left) or permissive (right) state. Enzymes involved in maintaining these states and associated transcription factors are indicated and histone tails with specific residues are highlighted as targets of modification: H3 residues subject to methylation or acetylation are indicated in green on the left and H4 residues subject to acetylation are indicated in purple on the right. Table 48.1 lists histone tail modifications of specific residues that are altered in response to drugs of abuse. Arrows indicate an increase (yellow), decrease (blue), or no effect (gray) in specific modifications; Ø indicates that no information is available. 2Me, dimethylation; 3Me, trimethylation; Ac, acetylation; Amphet, amphetamine; AMY, amygdala; Bdnf, brain-derived neurotrophic factor; CaMKII, calcium/calmodulin-dependent kinase II alpha; Cbp, CREB-binding protein; cFos, FBJ murine osteosarcoma viral oncogene homolog; CPP, conditioned place preference; DG, dentate gyrus; Egr1, early growth response protein 1; Ehmt2, euchromatic histone-lysine N-methyltransferase 2; Gria1, glutamate receptor, ionotropic, AMPA 1; Gria2, glutamate receptor, ionotropic, AMPA 2; Grin1, glutamate receptor, ionotropic, N-methyl-D-aspartate 1; Grin2b, glutamate receptor, ionotropic, N-methyl-D-aspartate 2B; LC, locus coeruleus; Meth, methamphetamine; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; Nr4a2, nuclear receptor subfamily 4, group A, member 2; Otxr, oxytocin receptor; Pdyn, prodynorphin; Pnoc, pronociceptin; Dlg4, discs, large homolog 4; postsynaptic density protein 95, PSD-95; Suv39h1, suppressor of variegation 3–9 homolog 1; VTA, ventral tegmental area; WD, withdrawal. (Modified with permission from Vialou et al. (2013).)

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