Costa E, Chen Y, Dong E, Grayson DR, Kundakovic M, Maloku E et al. GABAergic promoter hypermethylation as a model to study the neurochemistry of schizophrenia vulnerability. Expert Rev Neurother 9: 87-98

Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 Taylor, Chicago, IL 60612, USA.
Expert Review of Neurotherapeutics (Impact Factor: 2.78). 02/2009; 9(1):87-98. DOI: 10.1586/14737175.9.1.87
Source: PubMed


The neuronal GABAergic mechanisms that mediate the symptomatic beneficial effects elicited by a combination of antipsychotics with valproate (a histone deacetylase inhibitor) in the treatment of psychosis (expressed by schizophrenia or bipolar disorder patients) are unknown. This prompted us to investigate whether the beneficial action of this combination results from a modification of histone tail covalent esterification or is secondary to specific chromatin remodeling. The results suggest that clozapine, or sulpiride associated with valproate, by increasing DNA demethylation with an unknown mechanism, causes a chromatin remodeling that brings about a beneficial change in the epigenetic GABAergic dysfunction typical of schizophrenia and bipolar disorder patients.

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Available from: Dennis Robert Grayson
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    • "This notion initially came from findings that there are low levels of reelin and glutamic acid decarboxylase 67 (GAD67) are in the brains of people with schizophrenia and bipolar disorder.18,19,20) These data suggested that the down regulation of these transcripts were due to hyper-methylation of their gene promoters.21,22,23) Subsequently, it has been shown that clozapine and sulpiride, but not haloperidol or olanzapine, induced de-methylation of the hyper-methylated of the reelin and GAD67 promoters in mice pre-treated with L-methionine to hyper-methylate the promoters of these genes in the cortex and striatum of mice brain.24) "
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    ABSTRACT: Psychiatric disorders are among the most debilitating of all medical illnesses. Whilst there are drugs that can be used to treat these disorders, they give sub-optimal recovery in many people and a significant number of individuals do not respond to any treatments and remain treatment resistant. Surprisingly, the mechanism by which psychotropic drugs cause their therapeutic benefits remain unknown but likely involves the underlying molecular pathways affected by the drugs. Hence, in this review, we have focused on recent findings on the molecular mechanism affected by antipsychotic, mood stabilizing and antidepressant drugs at the levels of epigenetics, intracellular signalling cascades and microRNAs. We posit that understanding these important interactions will result in a better understanding of how these drugs act which in turn may aid in considering how to develop drugs with better efficacy or increased therapeutic reach.
    Full-text · Article · Aug 2014 · Clinical Psychopharmacology and Neuroscience
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    • "For example, schizophrenia often is characterized by dysfunction of the GABA-using (i.e., GABAergic) signaling systems (Costa et al. 2003; Wassef et al. 2003). GABAergic neurons express high levels of DNMT 1, and excessive methylation (i.e., hypermethylation) of the promoter regions of genes involved in the GABA system may be a possible target for treating schizophrenia (Costa et al. 2007, 2009). "
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    ABSTRACT: Genetic and environmental factors play a role in the development of alcoholism. Whole-genome expression profiling has highlighted the importance of several genes that may contribute to alcohol abuse disorders. In addition, more recent findings have added yet another layer of complexity to the overall molecular mechanisms involved in a predisposition to alcoholism and addiction by demonstrating that processes related to genetic factors that do not manifest as DNA sequence changes (i.e., epigenetic processes) play a role. Both acute and chronic ethanol exposure can alter gene expression levels in specific neuronal circuits that govern the behavioral consequences related to tolerance and dependence. The unremitting cycle of alcohol consumption often includes satiation and self-medication with alcohol, followed by excruciating withdrawal symptoms and the resultant relapse, which reflects both the positive and negative affective states of alcohol addiction. Recent studies have indicated that behavioral changes induced by acute and chronic ethanol exposure may involve chromatin remodeling resulting from covalent histone modifications and DNA methylation in the neuronal circuits involving a brain region called the amygdala. These findings have helped identify enzymes involved in epigenetic mechanisms, such as the histone deacetylase, histone acetyltransferase, and DNA methyltransferase enzymes, as novel therapeutic targets for the development of future pharmacotherapies for the treatment of alcoholism.
    Full-text · Article · Mar 2012 · Alcohol research : current reviews
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    • "He was the first to show that the expression of serotonin in the brain was regionally selective (Costa et al., 1960), thatdbased on the effects of LSDdthere were likely multiple 5-HT receptors (Costa, 1956), the first to apply steady state kinetics to measure the turnover rates of 5-HT, NE and DA with isotopic and non-isotopic methods (Neff et al., 1969, 1971), the first to measure acetylcholine dynamics with mass fragmentography (Costa et al., 1983; Eva et al., 1987), and to assay the indoleamine content of single rat pineal glands (Cattabeni et al., 1972), the first to establish that an allosteric amplification of GABA-mediated receptors underlies the action of benzodiazepines (Costa and Guidotti, 1991; Guidotti et al., 1979), and all of the themes previously mentioned from DBI (the diazepam binding inhibitory peptide) to allopregnenolone and depression to reelin and schizophrenia. He was lastly one of the first to pursue epigenetic regulation as a source for mental illness (Guidotti et al., 1976) and his colleagues in Chicago have taken up that line of investigation (Costa et al., 2002, 2007, 2009). "
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    ABSTRACT: Throughout his long productive scientific career, Erminio Costa demonstrated several scholarly traits that illustrate a pattern for paths of successful achievement that should guide young scientists. Not only did he seek excellent training, he got and gave good mentoring. That guidance allowed him to ask important questions and to develop the methods necessary to obtain definitive answers by pursuing those questions in depth. Without question, he blazed trails in neuropharmacology that have been an inspiration to many others and me. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
    Preview · Article · Jun 2011 · Neuropharmacology
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