versão impressa ISSN 0185-3325
MATUS ORTEGA, Maura Epifanía et al. Addictions, genomic findings. Salud Ment [online]. 2012, vol.35, n.2, pp.129-135. ISSN 0185-3325.
The phrase "X is a gene for Y" and the preformationist concept of gene action that underlies it are inappropriate for psychiatric disorders such as depression, aggression, sexual orientation, obesity, infidelity, alcoholism, or schizophrenia. Drug addictions are complex, chronic, and mental diseases. Genetic studies of twins and families have suggested that genetic factors might account for 40 to 60% of the overall factors in the risk to the development of drug addictions. In addition, numerous studies aiming to discover genetic variants or candidate genes, including genome-wide linkage scans, candidate gene association studies, gene expression, and genome-wide association studies, have also suggested that multiple genes and genomic regions or markers might play important roles in the development of addictions. A primary behavioral pathology in drug addiction is the overpowering motivational strength and decreased ability to control the desire to obtain drugs. Among the most insidious characteristics of drug addiction is the recurring desire to take drugs even after many years of abstinence. Equally sinister is the compromised ability of addicts to suppress drug seeking in response to that desire even when confronted with seriously adverse consequences. The enduring vulnerability to relapse is a primary feature of the addiction disorder and has been identified as a point were pharmacotherapeutic intervention may be most effectively employed. In order to fashion rationale pharmacotherapy it is necessary to understand the neurobiological underpinnings of craving, relapse, choice, and control, and the last decade has seen significant advances, toward achieving this goal. The fact that the vulnerability to relapse in addicts can persist after years of abstinence implies that addiction is caused by long-lasting changes in brain function as a result of repeated drug use, genetic disposition, and environmental associations made with drugs use. Therefore, understanding neurobiological aspects of drug addiction requires the comprehension of the physiological mechanisms that convey to the enduring neuroplasticity. The goal of this review is to explore how the advances in ge-nomics and proteomics may unleash the understanding of the cellular underpinnings of drug addiction and how the recent advances in functional genomics and proteomics may be expected to improve dramatically the treatment of addictive disorders. Applying genomics and proteomics to drug addiction studies will lead to the identification of genes and their protein products that control the brain reward pathways of the brain and their adaptations to drugs of abuse, as well as variations in these genes and proteins that confer genetic risk for addiction and related disorders. Additionally, this review describes recent findings of addictive drugs-inducing altered changes in gene regulation which produce significant cellular modifications on neuronal function in both human and animal brains as detected in animal models of drug abuse. A major goal of drug abuse research is to identify and understand drug-induced changes in brain function that are common to most if not all drugs of abuse, as well as these may underlie drug dependence and addiction. This work describes recent studies whose purpose is to examine the drugs of abuse effect changes in gene and protein expression that converge in common molecular pathways. One of this recent reports using microarrays analysis to assay brain gene expression in the anterior prefrontal cortex (aPFC) of post mortem brains of 42 cocaine, cannabis and/or phencyclidine human cases compared to 30 individual cases, which were characterized by toxicology and drug abuse history. Another study depicted herewith is focused on how the use of drugs frequently begins and escalates during adolescence, with long-term adverse consequences. The study designed a rodent model of adolescence to mirror cocaine use patterns in teenagers. Microarrays analysis was employed to assay brain gene expression in post mortem PFC of rodents treated with cocaine during adolescence. Results from the study revealed that treatment caused acute alterations in the expression of genes encoding cell adhesion molecules and transcription factors within the PFC. Cocaine alters gene expression patterns and histone modification in the PFC. Furthermore observed decreases in histone metylation, which may indicate a role of chromatin remodeling in the observed changes in gene expression patterns. Chromatin remodeling is an important regulatory mechanism for cocaine-induced neural and behavioral plasticity in the striatum. Most of the gene expression changes induced by cocaine were transient. However, if early cocaine exposure triggered changes in cell structure/adhesion, the impact of those alterations could be long-lasting. It is important to consider that the PFC in humans is involved in a large range of different functions, including working memory, action planning, response inhibition, decision-making, reward processes, and social behavior. Any lasting impact cocaine has on these functions could be detrimental, particularly in adolescents. Findings suggest that exposure to cocaine during adolescence has far-reaching molecular and behavioral consequences in the rat PFC that develop over time and endure long after drug administration has ceased. These neuroadaptations could have serious implications, particularly in the developing brain. However, only a causal relationship between these cocaine-induced molecular and behavioral adaptations can be inferred at this time. Therefore, humans who abused cocaine, cannabis and/or phen-cyclidine share a decrease in transcription of calmoduline-related genes and increased transcription related to lipid/colesterol and Gol-gi/ER function. 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 drug-induced alterations enhance molecular 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 specific brain structures shown to be vulnerable to the addictive properties of drugs of abuse. These changes represent common molecular features of drug abuse, which may underlie changes in synaptic function and plasticity that could have important ramification for decision-making capabilities in drug addiction. Eventually, all of these discoveries can be exploited for clinical applications as diverse as improved treatments diagnostic tests, and ultimately disease prevention and cure.
Palavras-chave : Addiction; gene expression; drugs of abuse.