Metabolomics in Drug Response and Addiction

What Is Metabolomics?

Metabolomics is the newest addition to the “omics” science. An “omics” has been defined as a neologism referring to a holistic view on biologic macromolecules, such as in genomics or proteomics. Genomics aims to understand the structure and function of the genome by studying all nucleotide sequences, including the structural genes, regulatory sequences, and noncoding DNA sequences in the chromosomes of any organism. It also examines the molecular mechanisms that maintain genomic integrity and allow its transmission and the expression including any interplay of genetic and environmental factors in disease. Proteomics involves the identification and study of the complete set of proteins in a species and the determination of their role in physiologic and pathophysiologic functions. Together with these and other “omics” technologies, metabolomics contribute to the detailed understanding of the in vivo function of gene products, biochemical analysis, and regulatory networks. The metabolomics represents the collection of all low-molecular-weight molecules found in a given cell and can provide a snapshot of the physiology of a cell at a given time during development and differentiation including responses to food, drugs, and other challenges.

Biochemists view metabolomics as metabolites profiling or the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification. Biologists, particularly geneticists, on the other hand, view it as the science of a highly complex and organized biochemical network in which small molecules, such as metabolic substrates and products, lipids, small peptides, vitamins, amino acids, signaling molecules, and other protein cofactors, are interacting between them and with other biological macromolecules in the metabolome. These small molecules are acting usually at very low concentrations in tissue-signaling functions. Along with the understanding of the in vivo interaction of gene products, metabolomics also contributes a great deal to the mathematical description and simulation of the whole cell in the systems biology approach. Systems biology tries to integrate genomic, proteomic, transcriptomic, and metabolomic information to give a more complete picture of living organisms ( Fig. 14.1 ). Here, the biological events in organisms are systematically interpreted through the combination of complex measurements from various methods resulting in high-throughput data. In this chapter, we discuss addiction as a problem of systems biology with emphasis on metabolomics.

Substance Abuse and Its Effect on Health and Economy

Substance use, abuse, and addiction that include but are not limited to alcohol, nicotine, opioids, cocaine, cannabinoids, methamphetamine, and amphetamine, continue to be a significant public health concern and pose tremendous cost to our society. In the United States alone, in 1998, the economic cost associated with illicit drug use was estimated to be US$280 billion, for nicotine US$158 billion, and for alcohol abuse US$185 billion, with an average annual increase of 3.8% per year. This brings the combined total estimated economic impact of substance abuse in the United States to over half a trillion dollars. Recent data indicate that approximately 1.6 million people in the United States abuse or are dependent on prescription opioids. In the United Kingdom, the cost associated with alcohol abuse is approximately $39 billion each year. Drug and alcohol abuse is a major cause of morbidity and mortality both in the United States and worldwide. Alcohol use disorders including liver and heart diseases account for 4% of the global burden of disease and cause 1.8 million deaths. The excessive burden of drug abuse on our health and economy makes it necessary for us to better understand how these drugs affect the metabolomics of our cellular systems, mechanisms of action in different parts of the body, and factors that determine the variability of addictive responses. A better insight into these mechanisms will offer a better understanding of the problem as well as identify effective treatment and preventative approaches to addiction, which remains insidious in most societies.

Substance Abuse Leads to Addiction

At the center of the problem of substance abuse is addiction to these substances. It has been long hypothesized that the combination of genetic and environmental factors following drug use and abuse alters cellular physiology. This alteration is expected to be cell and organ specific. In due course, it may follow physiological adaptation, leading to an urge for the drug response and the development of addiction. Evidence for the involvement of genes in the drug addiction process comes from classical epidemiological and genetic studies. Data from both animal and humans support the relevance of genetic influences in substance abuse and dependence. Twin studies, for example, have shown robust genetic components for alcohol, opiate, cocaine, and tobacco addictions.

The major target of virtually all drugs in the human or animal body, either directly or indirectly, is the nervous system—specifically one or more pathways deep within the brain. Drug-related, especially alcohol-related, brain damage and associated neuropsychological changes have been well documented (see Oscar-Berman et al. ). There is increasing evidence that long-lasting changes in the brain result from the progression of casual user to addict. Acute drug intoxication is accompanied by highly localized and dynamic patterns of brain activation and deactivation, as well as complex cascades of transcriptional reprogramming.

All compounds with abuse potential have the ability to disrupt information processing in the brain by subverting or affecting the expression of gene(s) involved in one or more of the common neurotransmitter systems (i.e., gamma-aminobutyric acid, glutamate, acetylcholine, dopamine, serotonin, and opioid peptides). However, an early increase in dopamine signaling has been one of the most consistent observations across studies of the reinforcing effects of drugs of abuse. Although studies with various knockout mice have emphasized the role of specific gene products working in the brain (see Mayfield et al., such as Homer 2, opioid receptors, and alpha 4 nicotinic receptors in conferring either protection from or increased risks of addiction). In addition it is apparent that the contribution of any single gene in the development of addition for any drug is only a small part of the picture. Like most familial behavioral phenotypes, drug and alcohol use disorders result from the complex interaction of multiple genes. This complexity may account for ongoing challenges associated with the development of addiction and solutions to deal with them. Needless to say, multiple genes exert their effects in the context of genetic networks, which are typically under the influence of environmental factors. These early effects initiated by the gene product induced by drugs or alcohol most likely cascade through the signaling pathways and generate a domino effect. To understand the complete molecular or gene expression changes that may occur in the brain due to drug and alcohol use it is important to capture those changes as a whole and perform a systematic analysis. One novel and effective approach that has been used in recent years to decipher and unravel this complex mystery is metabolomics.

Metabolomics: The Beginning

The completion of the human genome project has made it possible to investigate the whole genome using high-throughput technologies and analyze data via a systems approach (see Fig. 14.1 ). Derivation of molecular-based strategies, development of new computer application and technologies, and the application of bioinformatics are accelerating the elucidation of molecular underpinnings of human diseases as well as helping to effectively prevent, diagnose, and treat these diseases. These strategies can also be successfully applied in addiction-related disorders.

Since molecular biology’s early years, biological questions have been successfully approached mainly by studying individual gene function(s) and gene products, one or a few at a time. Despite understanding the cause of many biological problems, however, many fundamental biological questions remain to be answered. This is mainly because the majority of gene products function together, interacting with other gene products and influencing multiple pathways. Therefore, biological processes should be considered as complex networks of interconnected components. In addition to studying the components individually, it is important to study the combined nature of these gene products in the metabolomic networks and pathways.

Metabolomics in Addiction Research: Current Approach