Invited reviewEpigenetic mechanisms of drug addiction
Introduction
Drug addiction can be viewed as maladaptive neural plasticity that occurs in vulnerable individuals in response to repeated exposure to a drug of abuse. That vulnerability is determined roughly half by genetic factors (although few specific causative genes have as yet been identified) and half by non-genetic factors which include environmental exposures as well as stochastic events during development. Once formed, in turn, addiction can drive life-long behavioral abnormalities.
These features of addiction suggest an important role for epigenetic mechanisms. The term epigenetics has several definitions; this review utilizes a broad one, which defines epigenetics as a series of biochemical processes through which changes in gene expression are achieved throughout the lifecycle of an organism without a change in DNA sequence (Jaenisch and Bird, 2003). Epigenetics can thus be viewed as the vehicle through which environment interacts with an individual's genome to determine all aspects of function, in health and disease. A subset of epigenetic changes are very stable, which makes them ideal mediators both of addiction vulnerability and of drug-induced brain maladaptations that underlie an addiction syndrome.
Within this context, there are three general roles that epigenetic mechanisms likely play in addiction (Tsankova et al., 2007; Robison and Nestler, 2011). First, repeated exposure to a drug of abuse in adolescence or adulthood causes addiction in vulnerable individuals by inducing stable changes in gene expression through epigenetic regulation of those specific genes. Such epigenetic regulation involves alterations in the steady state expression levels of a set of genes as well as changes in other genes' inducibility—both sensitization (priming) and desensitization—without a change in steady state expression. Regulation of gene inducibility can be seen as “latent” in that it would not be apparent by analysis of mRNA or protein levels. Epigenetic regulation of genes also alters the expression of splice isoforms of a gene, which is usually not apparent from traditional microarray analyses of expressed mRNAs. Second, epigenetic regulation mediates changes in steady state gene expression or inducibility of genes that occur throughout an individual's lifetime in response to a host of environmental exposures, which help determine that individual's vulnerability to drug exposure and addiction later in life (Hiroi and Agatsuma, 2005). Third, there is the possibility that drugs or other environmental exposures induce epigenetic changes in sperm or ova, which are then passed on to offspring and alter their vulnerability to addiction. Such trans-generational epigenetic inheritance of addiction vulnerability remains controversial.
Finally, because the large majority of investigations of epigenetic mechanisms have been carried out on cultured cells or peripheral tissues, studies of epigenetic regulation in addiction models will teach the field fundamental principles about epigenetics in the developing and adult nervous system. In this way, such work provides the first ever look at mechanisms of transcriptional regulation in brain, and will likely have enormous impact on the field.
Section snippets
Overview of mechanisms of epigenetic regulation
The 3 billion nucleotides of DNA in a mammalian genome would be ∼2 m long if stretched out linearly, yet fits within a microscopic cell nucleus due to its extraordinary degree of organization and compaction in chromatin—nuclear material composed of DNA, histones, and non-histone proteins (Jaenisch and Bird, 2003). The fundamental unit of chromatin is the nucleosome, which consists of ∼147 base pairs of DNA wrapped around a core histone octamer (∼1.65 turns). Each octamer contains two copies
Role of histone modifications in addiction
Increasing evidence is defining the mechanisms by which chronic exposure to a drug of abuse alters the steady state levels of mRNAs through chromatin regulatory mechanisms or primes or desensitizes additional genes for altered expression after some period of withdrawal (Fig. 3).
Role of DNA methylation in addiction
Given the hypothesized importance of DNA methylation in mediating sustained transcriptional change, it is unfortunate that there have not been more studies of this epigenetic mechanism in drug abuse models. Expression levels of DNMT3a in NAc are differentially altered by acute versus chronic cocaine exposure, and during extended withdrawal (Anier et al., 2010; LaPlant et al., 2010). Local knockout of DNMT3a from the NAc, or local infusion of the DNMT inhibitors RG108 or zebularine, increases
Role of noncoding RNAs in addiction
Multiple miRNAs are reported to be up- or downregulated by drugs of abuse. For instance, cocaine increases levels of miR-181a and decreases miR-124 and let-7d in rat striatum (Chandrasekar and Dreyer, 2009, 2011; Schaefer et al., 2010; Hwang et al., 2012; Sartor et al., 2012), and mimicking the direction of each of these changes enhances cocaine reward. Since miRNAs function via base-pairing with complementary sequences within mRNA molecules, it is possible to infer target mRNAs of drug-altered
Future directions
Although still in relatively early stages, work to date has demonstrated that many forms of epigenetic regulation are altered in brain reward regions by drugs of abuse and in turn serve to regulate drug action. Already these initial studies have raised several key questions that will need to be addressed moving forward.
One surprising finding is that drug exposure alters global levels of several histone modifications, such as increased histone acetylation or decreased H3K9me2 and H3K9me3 in NAc.
Conclusions
The ultimate goal of epigenetic studies of addiction is to understand how repeated exposure to a drug of abuse changes the brain in sustained ways to cause the lasting syndrome of addiction. Such studies are also important to understand how an individual's life experiences establish stable changes at genomic loci, which then help determine that individual's vulnerability to the addiction-causing effects of subsequent drug exposure. It is our expectation that these studies will reveal a host of
Acknowledgments
Preparation of this review was supported by grants from the National Institute on Drug Abuse.
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