**Epigenetics and Drug Abuse**

Ryan M. Bastle and Janet L. Neisewander

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/101986

#### **Abstract**

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20 Recent Advances in Drug Addiction Research and Clinical Applications

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Gene expression and inheritance are not only a function of the DNA code, but also epigenetic mechanisms that regulate DNA accessibility, transcription, and translation of the genetic code into a functional protein. Epigenetic mechanisms are invoked by life experiences, including stress and exposure to drugs of abuse, and the resulting changes in gene expression can be inherited by future generations. This chapter highlights recent research demonstrating epigenetic changes in response to drug exposure with a focus on three different mechanisms: DNA methylation, histone modification, and noncod‐ ing RNAs. We briefly describe each of these mechanisms and then provide key examples of drug-induced changes involving these mechanisms, as well as epigenetic manipula‐ tions that alter effects of drugs. We then review cutting-edge technologies, including viral-mediated gene transfer and gene editing, that are being used to manipulate epigenetic processes with temporal and cell-type specificity. We also describe and provide examples of intergenerational epigenetic modifications, a topic that has interesting implications for how addiction-related traits may be passed down across generations. Finally, we discuss how this research provides a greater understanding of drug addiction and may lead to novel molecular targets for preventions and interven‐ tions for drug abuse.

**Keywords:** DNA methylation, histone modification, noncoding RNA, cocaine, alcohol

### **1. Introduction**

One of the most compelling questions in the field of drug abuse is why some individuals who experiment with drugs go on to develop substance use disorders (SUDs) while others do not. Both a family history of SUDs and stressful life events increase one's vulnerability to develop SUDs [1, 2]. Historically, these risk factors were viewed as "nature and nurture" making separate contributions to an addiction phenotype. However, recent advances in the field of epigenetics

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

demonstrate that "nurture" changes "nature" by modifying whether or not a given gene will be expressed. Understanding how one's environment (e.g., drug-taking behavior, stress, and learning) can alter gene expression in the brain may give insight into how drug addiction develops, how it may be passeddown into future generations, andperhaps, how it can be better treated.

While the DNA sequence of a gene can be modified directly (e.g., mutations, deletions, insertions, translocations, etc.) resulting in altered gene expression, epigenetics regulates gene expression by mechanisms other than changes to the DNA sequence. It has long been known that epigenetic mechanisms largely control cell differentiation by allowing some genes to be expressed and others to be silenced at various points in time during development. Indeed, even though all human cells possess the same DNA (with the exception of egg and sperm cells), what differentiates a given cell type from others (e.g., a neuron versus a liver cell) is the epigenetic mechanisms that permit or deny its genes to be transcribed and translated into cell type-specific functional proteins [3]. Beyond the hard-wire epigenetic programming of gene expression during development, epigenetic mechanisms also provide dynamic and heritable means of altering gene expression in response to environmental change. For example, either stressful life experiences or a history of chronic drug intake can invoke chemical modifications to either the DNA or the histone proteins that are involved in storing the DNA. Such epigenetic changes have an impact on how accessible the DNA is for gene transcription. Epigenetic changes can also be long lasting and passed down to future generations. In this way, not only does experience with stress and/or drugs place one's self at risk for SUDs, but also one's offspring due to heritable epigenetic modifications. Even in the more proximal time frame of an individual's lifespan, epigenetic mechanisms provide a "working memory" for gene expression changes that are involved in brain plasticity [4]. Brain plasticity changes resulting from drug exposure are thought to be the crux of the dysfunction underlying addiction [5]. An exciting implication of understanding the role of epigenetic changes in drug-induced brain plasticity is that new strategies for therapeutic interventions may be discovered.

In this chapter, we review three epigenetic mechanisms that have been found to impact drug abuse-related behaviors in animal models: (1) chemical modifications to DNA, (2) chemical modifications to histones, and (3) the induction of noncoding RNAs that regulate gene expression. We will begin with a brief explanation of how drugs modify intracellular signaling pathways that propagate to the cell nucleus, leading to epigenetic changes. We will then provide a brief description of the epigenetic mechanisms listed above, followed by examples of how drugs of abuse invoke these mechanisms and how pharmacologically targeting the epigenome can alter drug-abuse-related behavior. Next, we will cover the latest developments in genetic tools that provide precise manipulation of epigenetic enzymes, further elucidating the roles of these specific molecules. We will also review literature supporting transgenera‐ tional inheritance of epigenetic changes associated with a history of drug intake. We conclude by discussing important future directions for research investigating epigenetic mechanisms associated with drug addiction.
