The Search for Candidate Genes of Alcoholism: Evidence from Expression Profiling Studies

Sommer, Wolfgang; Arlinde, C.; Heilig, Markus

doi:10.1080/13556210412331327821

Cited by 29 publications

(16 citation statements)

References 54 publications

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“…MAPK14 was also identified as a differentially expressed gene in carefully carried out microarray studies and analyses in alcohol-preferring AA (alko, alcohol) rats vs alcoholavoiding ANA (alko, non-alcohol) rats. 108,109 Our data show that alcohol-preferring iP rats have a lower baseline level of MAPK14 than alcohol-non-preferring iNP rats in the CP. Additionally, our data show that those levels are increased by chronic alcohol (Table 2).…”

Section: Fibronectinmentioning

confidence: 89%

Candidate genes, pathways and mechanisms for alcoholism: an expanded convergent functional genomics approach

Bertsch

Strother

et al. 2006

Pharmacogenomics J

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We describe a comprehensive translational approach for identifying candidate genes for alcoholism. The approach relies on the cross-matching of animal model brain gene expression data with human genetic linkage data, as well as human tissue data and biological roles data, an approach termed convergent functional genomics. An analysis of three animal model paradigms, based on inbred alcohol-preferring (iP) and alcohol-non-preferring (iNP) rats, and their response to treatments with alcohol, was used. A comprehensive analysis of microarray gene expression data from five key brain regions (frontal cortex, amygdala, caudate-putamen, nucleus accumbens and hippocampus) was carried out. The Bayesian-like integration of multiple independent lines of evidence, each by itself lacking sufficient discriminatory power, led to the identification of high probability candidate genes, pathways and mechanisms for alcoholism. These data reveal that alcohol has pleiotropic effects on multiple systems, which may explain the diverse neuropsychiatric and medical pathology in alcoholism. Some of the pathways identified suggest avenues for pharmacotherapy of alcoholism with existing agents, such as angiotensin-converting enzyme (ACE) inhibitors. Experiments we carried out in alcohol-preferring rats with an ACE inhibitor show a marked modulation of alcohol intake. Other pathways are new potential targets for drug development. The emergent overall picture is that physical and physiological robustness may permit alcohol-preferring individuals to withstand the aversive effects of alcohol. In conjunction with a higher reactivity to its rewarding effects, they may able to ingest enough of this nonspecific drug for a strong hedonic and addictive effect to occur.

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Section: Fibronectinmentioning

confidence: 89%

Candidate genes, pathways and mechanisms for alcoholism: an expanded convergent functional genomics approach

Bertsch

Strother

et al. 2006

Pharmacogenomics J

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show abstract

“…This is usually seen in the analysis of brain tissue when mild stimuli are applied or different rat strains are evaluated [Rimondini et al, 2002;Sommer et al, 2005]. In addition, we deal with a highly heterogeneous tissue and all the nonaffected cells will mask any effect on a distinct cell population.…”

Section: Discussionmentioning

confidence: 99%

Exposure of rat brain to 915 MHz GSM microwaves induces changes in gene expression but not double stranded DNA breaks or effects on chromatin conformation

Belyaev

Koch

Terenius

et al. 2006

Bioelectromagnetics

110

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We investigated whether exposure of rat brain to microwaves (MWs) of global system for mobile communication (GSM) induces DNA breaks, changes in chromatin conformation and in gene expression. An exposure installation was used based on a test mobile phone employing a GSM signal at 915 MHz, all standard modulations included, output power level in pulses 2 W, specific absorption rate (SAR) 0.4 mW/g. Rats were exposed or sham exposed to MWs during 2 h. After exposure, cell suspensions were prepared from brain samples, as well as from spleen and thymus. For analysis of gene expression patterns, total RNA was extracted from cerebellum. Changes in chromatin conformation, which are indicative of stress response and genotoxic effects, were measured by the method of anomalous viscosity time dependencies (AVTD). DNA double strand breaks (DSBs) were analyzed by pulsed-field gel electrophoresis (PFGE). Effects of MW exposure were observed on neither conformation of chromatin nor DNA DSBs. Gene expression profiles were obtained by Affymetrix U34 GeneChips representing 8800 rat genes and analyzed with the Affymetrix Microarray Suite (MAS) 5.0 software. In cerebellum from all exposed animals, 11 genes were upregulated in a range of 1.34-2.74 fold and one gene was downregulated 0.48-fold (P < .0025). The induced genes encode proteins with diverse functions including neurotransmitter regulation, blood-brain barrier (BBB), and melatonin production. The data shows that GSM MWs at 915 MHz did not induce PFGE-detectable DNA double stranded breaks or changes in chromatin conformation, but affected expression of genes in rat brain cells.

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“…Although we found a number of changes in gene expression reminiscent of those seen in mammalian models suggesting conservation of adaptive pathways, a number of novel genes were also identified. The majority of published microarray analyses compare frontal cortex or nucleus accumbens in control and drug-treated animals (Li et al, 2004;Rimondini et al, 2002) (for reviews, see Pollock, 2002;Rhodes and Crabbe, 2005;Sommer et al, 2005;Yuferov et al, 2005). The rationale for this approach is twofold: (1) these are the primary brain regions shown to be involved in mammalian reward responses and (2) the complexity of the mammalian brain may lead to subtle differences being obscured if whole brain tissue were used.…”

Section: Discussionmentioning

confidence: 99%

Gene expression changes in a zebrafish model of drug dependency suggest conservation of neuro-adaptation pathways

Kily

Cowe

Hussain

et al. 2008

Journal of Experimental Biology

152

123

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SUMMARYAddiction is a complex psychiatric disorder considered to be a disease of the brain's natural reward reinforcement system. Repeated stimulation of the 'reward' pathway leads to adaptive changes in gene expression and synaptic organization that reinforce drug taking and underlie long-term changes in behaviour. The primitive nature of reward reinforcement pathways and the near universal ability of abused drugs to target the same system allow drug-associated reward and reinforcement to be studied in non-mammalian species. Zebrafish have proved to be a valuable model system for the study of vertebrate development and disease. Here we demonstrate that adult zebrafish show a dose-dependent acute conditioned place preference (CPP) reinforcement response to ethanol or nicotine. Repeated exposure of adult zebrafish to either nicotine or ethanol leads to a robust CPP response that persists following 3·weeks of abstinence and in the face of adverse stimuli, a behavioural indicator of the establishment of dependence. Microarray analysis using whole brain samples from drug-treated and control zebrafish identified 1362 genes that show a significant change in expression between control and treated individuals. Of these genes, 153 are common to both ethanol-and nicotine-treated animals. These genes include members of pathways and processes implicated in drug dependence in mammalian models, revealing conservation of neuro-adaptation pathways between zebrafish and mammals.Supplementary material available online at

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The Search for Candidate Genes of Alcoholism: Evidence from Expression Profiling Studies

Cited by 29 publications

References 54 publications

Candidate genes, pathways and mechanisms for alcoholism: an expanded convergent functional genomics approach

Candidate genes, pathways and mechanisms for alcoholism: an expanded convergent functional genomics approach

Exposure of rat brain to 915 MHz GSM microwaves induces changes in gene expression but not double stranded DNA breaks or effects on chromatin conformation

Gene expression changes in a zebrafish model of drug dependency suggest conservation of neuro-adaptation pathways

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