Regulation of chromatin states by drugs of abuse

Abstract

Drug addiction involves long-term behavioral abnormalities and gene expression changes throughout the mesolimbic dopamine system. Epigenetic mechanisms establish/maintain alterations in gene expression in the brain, providing the impetus for investigations characterizing how epigenetic processes mediate the effects of drugs of abuse. This review focuses on evidence that epigenetic events, specifically histone modifications, regulate gene expression changes throughout the reward circuitry. Drugs of abuse induce changes in histone modifications throughout the reward circuitry by altering histone-modifying enzymes, manipulation of which reveals a role for histone modification in addiction-related behaviors. There is a complex interplay between these enzymes, resulting in a histone signature of the addicted phenotype. Insights gained from these studies are key to identifying novel targets for diagnosis and therapy.

Figure 1

Exposure to drugs of abuse results in epigenetic alterations throughout the brain reward circuitry. The major brain regions involved in mesolimbic reward pathway are depicted in the rodent 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 VTA to other regions of the reward circuitry. Many studies investigating epigenetic mechanisms of addiction have focused on the NAc as it is a major region of integration for rewarding stimuli. Modified from [2]with permission.

Figure 2/Table 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 (bottom) 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. Abbreviations: 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 from [40] with permission