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Review
, 12 (11), 623-37

Transcriptional and Epigenetic Mechanisms of Addiction

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Review

Transcriptional and Epigenetic Mechanisms of Addiction

Alfred J Robison et al. Nat Rev Neurosci.

Abstract

Investigations of long-term changes in brain structure and function that accompany chronic exposure to drugs of abuse suggest that alterations in gene regulation contribute substantially to the addictive phenotype. Here, we review multiple mechanisms by which drugs alter the transcriptional potential of genes. These mechanisms range from the mobilization or repression of the transcriptional machinery - including the transcription factors ΔFOSB, cyclic AMP-responsive element binding protein (CREB) and nuclear factor-κB (NF-κB) - to epigenetics - including alterations in the accessibility of genes within their native chromatin structure induced by histone tail modifications and DNA methylation, and the regulation of gene expression by non-coding RNAs. Increasing evidence implicates these various mechanisms of gene regulation in the lasting changes that drugs of abuse induce in the brain, and offers novel inroads for addiction therapy.

Figures

Figure 1
Figure 1. Brain reward circuitry
The brain on the left depicts dopaminergic afferents (light blue arrows) which originate in the ventral tegmental area (blue) and release dopamine in the nucleus accumbens (red) and many other limbic targets. Also shown are other monoaminergic nuclei — the noradrenergic locus coeruleus (green) and serotonergic dorsal raphe (yellow) — which modulate drug reward and other actions. The brain on the right highlights glutamatergic regions that are important for reward: medial prefrontal cortex (green), orbitofrontal cortex (yellow), anterior cingulate cortex (dark blue), thalamus (purple), hippocampus (orange), and amygdala (aqua), all of which send excitatory projections to the nucleus accumbens (red). Drugs of abuse alter this reward circuitry in complex ways, which lead to addiction.
Figure 2
Figure 2. Mechanisms of transcriptional and epigenetic regulation by drugs of abuse
In eukaryotic cells, DNA is organized by wrapping around histone octomers to form nucleosomes, which are then further organized and condensed to form chromosomes (right). Only by temporarily unraveling compacted chromatin can the DNA of a specific gene be made accessible to the transcriptional machinery. Drugs (left) act through synaptic targets to alter intracellular signaling cascades, which leads to the activation or inhibition of transcription factors and of many other nuclear targets including chromatin regulatory proteins; the detailed mechanisms involved in the latter remain poorly understood. This leads to the induction or repression of particular genes, including those for noncoding RNAs; altered expression of some of these genes can in turn further regulate gene transcription. It is hypothesized that some of these drug-induced changes at the chromatin level are extremely stable and thereby underlie the long-lasting behaviors that define addiction. CREB, cAMP response element binding protein; DNMTs, DNA methyltransferases; HATs, histone acetyltransferases; HDACs, histone deacetylases; HDMs, histone demethylases; HMTs, histone methyltransferases; MEF2, myocyte enhancing factor-2; NFκB, nuclear factor κB; pol II, polymerase II.
Figure 3
Figure 3. Gene priming and desensitization
In addition to regulating the steady-state expression levels of certain genes, cocaine induces latent effects at many other genes, which alter their inducibility in response to a subsequent stimulus. A. Analysis of mRNA expression after acute or chronic cocaine. Heat maps marked with an asterisk (*) show all genes that are upregulated in the NAc 1 hr after a cocaine challenge in naive animals (acute), in animals treated repeatedly with cocaine (repeated + acute), or in animals after 1 wk of withdrawal from repeated cocaine (repeated wd + acute). Associated heat maps show how the same genes were affected under the other two conditions. Desensitized transcriptional responses after repeated cocaine are indicated (***). B. Early evidence suggests that epigenetic mechanisms are important in mediating such gene priming and desensitization and that many such changes are latent, meaning that they are not reflected by stable changes in steady-state mRNA levels. Rather, such changes alter chromatin structure such that later drug challenge induces a given gene to a greater (primed) or lesser (desensitized) extent based on the epigenetic modifications induced by previous chronic drug exposure. A major goal of current research is to identify the chromatin signatures that underlie gene priming and desensitization.
Figure 4
Figure 4. Epigenetic basis of drug regulation of gene expression
The figure is based on the mechanisms by which chronic cocaine, through ΔFosB, activates the cdk5 gene (top) and represses the c-fos gene (bottom). Top: ΔFosB binds to the cdk5 gene and recruits several co-activators, including CBP (CREB binding protein) — a type of histone acetyltransferase (HAT) leading to increased histone acetylation, transcription factor BRG1 (also known as brahma-related gene 1) — a type of chromatin remodeling factor — and SUG1 (proteasome 26S ATPase subunit 5), another type of chromatin regulatory protein. ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. Bottom: In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). The gene also shows increased G9a binding and repressive histone methylation (despite global decreases in these marks). The net result is c-fos gene repression. As transcriptional regulatory complexes contain dozens or hundreds of proteins, much further work is needed to further define the activational and repressive complexes that cocaine recruits to particular genes to mediate their transcriptional regulation and to explore the range of distinct activational and repressive complexes involved in cocaine action.

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