The Role of microRNAs in Drug Addiction

Alcoholism is a multifactorial disease of unclear molecular underpinnings. Currently, we are witnessing a major shift in our understanding of the functional elements of the genome, which could help us to discover novel insights into the nature of alcoholism. In humans, the vast majority of the genome encodes non-protein-coding DNA with unclear function. Recent research has started to unveil this mystery by describing the functional relevance of microRNAs, and examining which genes are regulated by non-protein-coding DNA. Here, I describe alcohol regulation of microRNAs and provide examples of microRNAs that control the expression of alcohol-relevant genes. Emphasis is put on the potential of microRNAs in explaining the polygenic nature of alcoholism and prospects of microRNA research and future directions of this burgeoning field.

Introduction

Alcoholism is a complex, human disease, with strong genetic and environmental components (Pinto and Ansseau, 2009). Mounting evidence, accumulated over several decades, leaves practically no doubt that genetic factors contribute significantly to the development and maintenance of alcohol addiction. However, all these data suggest that there is no single gene responsible for alcoholism, but rather that alcoholism is a polygenic disease by nature (Tabakoff et al., 2009). Several loci bear the risk associated with alcoholism, and certain loci are linked to specific phenotypes, such as tolerance, withdrawal, etc. (Tabakoff et al., 2009). It is thought that genes located within these loci express products with altered abundance or products with altered function that puts an organism at higher risk of developing alcoholism upon exposure to alcohol. Human linkage and association studies have identified several candidate genes for susceptibility toward alcoholism (e.g., alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ADLH), gamma-aminobutyric acid (GABA) A receptor subunits, muscarinic receptors, opioid receptors, etc.), which have been replicated in multiple studies. Animal models, including invertebrate models, have identified candidate genes for specific alcohol phenotypes (Davies et al., 2003, Tabakoff et al., 2009). However, much of the genetic variation contributing to alcoholism has yet to be identified. In addition to genetic factors, there is an important contribution of environmental factors to alcoholism. Multiple environmental factors (e.g., stress) substantially contribute to the risk of becoming an alcoholic (Breese et al., 2005, Fox et al., 2007, Madrid et al., 2001, Sinha, 2007). Importantly, alcohol addiction cannot develop without exposure to alcohol and thus susceptible individuals must be in an environment where alcohol is available. Based on epidemiological data, the International Center for Alcohol Policies (ICAP) has created worldwide guidelines for alcohol consumption. In the United States, women should consume no more than one standard drink (14 g EtOH = 12 fl. oz of beer, 5 fl. oz of wine, 1 fl. oz of distilled spirits) per day, while men should consume no more than two standard drinks per day (Ferreira and Willoughby, 2008) to avoid the detrimental effects of alcohol. However, there is surprisingly little data describing molecular underpinnings of alcohol exposure and an associated probability of development of alcoholism. Therefore, it is important to understand how different alcohol exposure patterns can lead to different qualitative and/or quantitative changes in molecular pathways relevant for development of addiction.

In this chapter, we will describe some recent advances in our understanding of alcohol regulation of molecular processes, which should help in answering these questions. We will focus specifically on the role of microRNAs, newly discovered regulators of gene expression, and their potential to explain the effects of alcohol on multiple molecular pathways and the polygenic nature of alcoholism.