Journal Article

Transcriptional and epigenetic mechanisms of addiction

Robison, Alfred J., Nestler, Eric J.

2011

Overview

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? Chronic drug exposure induces long-term changes in the brain, which are partly due to alterations in gene expression. Robison and Nestler review the mechanisms by which drugs of abuse alter the transcriptional potential of genes through the regulation of transcription factors and epigenetic mechanisms, including the regulation of gene expression by non-coding RNAs. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/2584 / 692/700/565/1436/434 / Animal Genetics and Genomics / Animals / Behavior, Addictive - genetics / Behavioral Sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Brain research / Care and treatment / Child development / Desensitization (Psychology) / DNA methylation / Drug abuse / Drug addiction / Epigenesis, Genetic / Epigenetics / Gene expression / Gene Expression Regulation / Genes / Genetic aspects / Genotype & phenotype / Humans / Hypotheses / Methylation / Neurobiology / Neurosciences / Prescription drugs / review-article / Risk factors / Substance-Related Disorders - genetics / Transcription factors / Transcription, Genetic