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  • Review Article
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Transcriptional and epigenetic mechanisms of addiction

Key Points

  • We propose that changes in the transcriptional potential of genes, through the actions of drug-regulated transcription factors, chromatin modifications and non-coding RNAs, contribute substantially to the neuroadaptations that underlie addiction. This Review highlights key examples of such transcriptional and epigenetic mechanisms of addiction, and identifies some of the novel potential targets for therapeutic intervention during the addiction process.

  • The nucleus accumbens, a region that is central to the processing of reward and the addicting actions of virtually all drugs of abuse, contains a complex milieu of cell types. It receives input from, and sends signals to various brain regions. Chronic exposure to drugs of abuse alters gene expression patterns, as well as the morphology (and ultimately the functional activity) of nucleus accumbens neurons — neuroadaptations that contribute importantly to the addiction process.

  • Chronic exposure to drugs of abuse alters the expression or activity of numerous transcription factors, including ΔFOSB, cyclic AMP-responsive element binding (CREB), nuclear factor-κB (NF-κB) and myocyte-specific enhancer factor 2 (MEF2). Manipulation of these factors, specifically in the nucleus accumbens or other parts of the brain's reward circuitry, alters specific molecular, cellular and behavioural responses in rodent models of addiction, which points to the functional role of these factors and their target genes in addiction.

  • Epigenetic regulation underlies many adaptations of an adult organism to environmental stimuli, such as those seen in drug addiction. Post-translational modification of histone tails and direct modification of DNA, as well as altered levels or activity of a host of other chromatin remodelling proteins, mediate the ability of drugs of abuse, after chronic exposure, to alter the expression of specific genes in the brain's reward circuitry.

  • Ongoing studies of chromatin regulation in addiction models support the view that epigenetic changes at individual genes alter not only the steady-state levels of their expression but also their inducibility in response to a subsequent stimulus. We propose that these latent epigenetic changes, termed gene 'priming' and 'desensitization', alter an individual's adaptability and contribute substantially to the addicted state.

  • Several recent studies have implicated microRNAs in addiction-related behaviours in animal models, and several specific microRNAs, whose expression is altered by drugs of abuse in brain reward regions, have been shown to regulate the expression of several proteins strongly linked to addiction.

  • Among the key questions for future research are: what controls the recruitment or expulsion of individual transcriptional and chromatin-regulatory proteins to a particular target gene? What controls the formation and maintenance of distinct epigenetic states at particular genes? How are the actions of drugs of abuse, all of which initially target the synapse, transduced to the neuronal nucleus to regulate the epigenetic state and transcriptional potential of individual genes?

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.

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Figure 1: Brain reward circuitry.
Figure 2: Mechanisms of transcriptional and epigenetic regulation by drugs of abuse.
Figure 3: Gene priming and desensitization.
Figure 4: Epigenetic basis of drug regulation of gene expression.

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Acknowledgements

Preparation of this Review was supported by grants from the US National Institute on Drug Abuse (NIDA).

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Glossary

Limbic system

A collection of cortical and subcortical structures that are important for processing memory and emotional information. Prominent structures include the hippocampus and amygdala.

Sensitization

Enhanced drug responsiveness — on the behavioural, cellular and/or molecular levels — with repeated exposure to a constant dose.

Self-administration

A form of operant conditioning using a drug as a reward, generally by administration through an intravenous line that is controlled directly by the animal's actions.

Medium spiny neurons

(MSNs). The main cell population of the ventral and dorsal striatum; these GABAergic projection neurons form the two main outputs of these structures, called the direct pathway (D1-type MSNs) and indirect pathway (D2-type MSNs).

Degron domains

A specific amino acid sequence that targets a protein for degradation through proteasomal or other proteolytic processes.

Conditioned place-preference

A behavioural test in which animals learn to prefer an environment that is associated with rewarding drug administration. It provides an indirect measure of drug reward.

Tolerance

Reduced drug responsiveness with repeated exposure to a constant dose.

Dominant-negative mutant

A mutant molecule that forms heteromeric complexes with the wild-type protein's targets to yield a non-functional complex. This antagonizes the activity of the endogenous wild-type protein.

Dendritic spine

A small protrusion from a dendrite that is typically associated with synaptic input from a glutamatergic axon at its tip but may receive other inputs along its sides or neck.

Dependence

A physiological state that develops to compensate for persistent drug exposure and that gives rise to a withdrawal syndrome after cessation of drug exposure.

Histone deacetylases

Enzymes that catalyse the deacetylation of histone amino-terminal tails.

Nucleosome

The basic building block of chromatin in which 147 base pairs of DNA are wrapped (1.7 turns) around a core histone octamer.

Histone acetyltransferases

Enzymes that catalyse the acetylation of histone amino-terminal tails.

Histone methyltransferases

Enzymes that catalyse the methylation of histone amino-terminal tails.

Histone demethylases

Enzymes that catalyse the demethylation of histone amino-terminal tails.

Sirtuins

Proteins that have been categorized as Class III histone deacetylases, but that also serve as protein deacetylases for many non-histone proteins and as part of transcription-repressive complexes, seemingly independently of catalytic activity.

DNA methyltransferases

Enzymes that methylate cytosine nucleotides, in CpG sequences, in DNA.

Hypomorphic

A mutation that causes a wild-type gene product to be produced at a reduced level.

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Robison, A., Nestler, E. Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci 12, 623–637 (2011). https://doi.org/10.1038/nrn3111

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