Matus OME, Calva NJC, Flores ZA, Leff GP, Antón PB

Language: Spanish
References: 23
Page: 137-145
PDF size: 438.98 Kb.

ABSTRACT

Drug addiction is a chronically relapsing disorder that has been characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and (3) emergence of a negative emotional state (e.g, dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented (defined as Substance Dependence by the Diagnostic and Statistical Manual of Mental Disorders [DSM] of the American Psychiatric Association). Acute exposure to drugs of abuse initiates molecular and cellular alterations in the Central Nervous System that lead to an increased overall vulnerability to addiction with subsequent drug exposures. These druginduced alterations employ changes in gene transcription that result in the synthesis of new proteins. Therefore, one of the important goals of addiction research is to identify the drug-induced gene expression changes in the specific brain structures related to the addictive properties of various drugs.
The molecular and genomic mechanisms by which drugs of abuse induce neuroplastic changes related to addiction remain largely unknown. Several studies have evaluated changes in gene and protein expression profiles in the brain after administration of drugs of abuse. Exposure to psychostimulants induces the activity-dependent gene expression of several transcription activators and repressors.
Genomic research strategies have recently transitioned from the search for unknown genes to the identification and evaluation of coordinated gene networks and transcriptional signatures. New opportunities arising from the analysis of these networks include identifying novel relationships between genes and signaling pathways, connecting biological processes with the regulation of gene transcription, and associating genes and gene expression with diseases. The identification of gene networks requires large gene expression data sets with multiple data points.
Functional genomics methods, studying the steady-state levels of these mRNA species, such as quantitative RT-PCR (qRT-PCR), whole-genome microarray analysis, and next generation sequencing methods, provide sensitive and high-throughput approaches to quantitatively examining mRNA (and miRNA) species present within the cells of the Nervous System.
Functional genomics studies can help to illuminate genes involved in the development of behaviors related to drug abuse and relapse liability, but cannot provide insight into post-translational modifications (e.g., phosphorylation and glycosylation of proteins after translation has occurred) or subcellular localization of the protein product. Therefore, using proteomic techniques presents the opportunity to assess the totality of gene expression, translation, modification, and localization. Unfortunately, the sensitivity of proteomic tools lags behind those of functional genomics. Moreover, examining the mRNA provides a restricted view of primarily the cell body. Indeed, from a systems biology standpoint, analysis of both mRNA and protein levels (as well as miRNA and epigenetic changes) will ultimately provide a more integrated view of the molecular underpinnings of addiction.
When applying proteomic technologies to addiction research, an understanding of the power of proteomic analysis is essential. After genetic information is transcribed into mRNA, a template is provided to the cell from which proteins will be synthesized.
Neuroproteomic studies offer great promise for increasing understanding of the biochemical basis of addiction. While proteomics is still an evolving field, proteomic approaches have proven useful for elucidating the molecular effects of several drugs of abuse. With a number of ongoing research programs in addiction proteomics and a growing number of investigators taking advantage of these tools, the addiction research field will benefit from a consideration of the capabilities and limitations of proteomic studies.
As with other biomedical research fields, drug abuse research is making use of new proteomic capabilities to examine changes in protein expression and modification on a large scale. To obtain the maximum benefit and scientific advancement from these new technologies, a clear understanding of the power and limitations of neuroproteomics is necessary. With the main limitation of neuroproteomic studies being the complexity of the proteome, approaches that focus these studies need to be employed. The salient message is that there is not a single best technical approach for all studies and that the main driver for the choice of proteomic technology and experimental design should be the advancement of the understanding and treatment of drug abuse.
An important area that has heretofore received limited attention is the experimental design and interpretation specific to neuroproteomic studies of drug abuse. These challenges include choice of animal model, ensuring sample quality, the complexity of brain tissue, confirming discovery findings, data analysis strategies, and integration of large data sets with the existing literature.
Epigenetics is the study of heritable changes other than those in the DNA sequence and encompasses two major modifications of DNA or chromatin: DNA methylation and post-translational modification of histones. In this context, now it is known that regulation of gene expression contribute to the long-term adaptations underlying the effects of drugs of abuse. The precise molecular events that are required for modification of chromatin and that underlie gene repression or activation have not been elucidated.
Recent reports have addressed this question and demonstrated that drugs of abuse modify specific methyl-CpG-binding proteins that control histone acetylation and gene expression. Further elucidation of the wide-range of histone modifications and the ensuing consequences on gene expression will be necessarily before the potential for drug development can be realized. It is important to characterize the molecular alterations underlying chromatin remodeling and the regulation of the epigenetics events by drugs of abuse. It is clear that modification in gene expression by drugs of abuse promote cellular changes.
This review is intended to provide guidance on recent advances in the field of drug addiction. This review also presents a number of experimental design and sample approaches that have been applied to genomic, proteomic and epigenetic studies of addiction. Coupled with new technologies for data collection, analysis, and reporting, these approaches represent the future of the addiction field and hold the key to unlocking the complex of profile of drug abuse disorders.

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