The slowpoke Gene Is Necessary for Rapid Ethanol Tolerance in Drosophila

Cowmeadow, Roshani B.; Krishnan, Harish R.; Atkinson, Nigel S.

doi:10.1097/01.alc.0000183232.56788.62

Cited by 118 publications

(180 citation statements)

References 47 publications

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“…Many biological phenomena contribute to ethanolinduced responses. These include the involvement of neuropeptide-Y related pathways, [1][2][3][4] glutamate receptors, 5,6 GABA receptors, 7,8 the cAMP signalling pathway, 9,10 the BK potassium channel, SLO-1 [11][12][13] , and membrane perturbation. 14 Many genes and proteins are conserved between Caenorhabditis elegans and humans, including many of those that have been identified as playing a possible role in the effects of ethanol.…”

Section: Introductionmentioning

confidence: 99%

The concentration-dependent effects of ethanol on Caenorhabditis elegans behaviour

et al. 2007

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The effects of ethanol on the brain are concentration dependent. Low concentrations (mM) intoxicate, while greater than 100 mM anaesthetize. Of most relevance to human alcohol addiction are mechanisms of intoxication. Previously, Caenorhabditis elegans has been employed in genetic screens to define effectors of intoxication. Here, we inform interpretation of these studies by providing evidence that ethanol rapidly equilibriates across C. elegans cuticle. Importantly, the effect of ethanol on muscle activity rapidly reaches steady-state, and the concentration-dependence of the effect is very similar in intact animals and exposed muscle. Thus the cuticle does not present an absorption barrier for ethanol, and furthermore the internal concentration is likely to approach that applied externally. Thus, modelling intoxication in C. elegans requires exposure to external ethanol less than 100 mM. Furthermore, the permeability of the cuticle to ethanol enables analysis of precisely controlled concentration-dependent effects of acute, chronic, and episodic ethanol exposure on behaviour.

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Section: Introductionmentioning

confidence: 99%

The concentration-dependent effects of ethanol on Caenorhabditis elegans behaviour

et al. 2007

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“…When exposed to alcohol, flies initially become hyperactive, but soon lose postural control and fall through the inebriometer at a rate that is correlated with their sensitivity. Following recovery, a second exposure reveals the development of tolerance reflected in a longer knockdown time (Moore et al 1998;Scholz et al 2000;Singh and Heberlein 2000;Cowmeadow et al 2005Cowmeadow et al , 2006Scholz et al 2005;Wen et al 2005;Morozova et al 2006Morozova et al , 2009Kong et al 2009). …”

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confidence: 99%

Transcriptional Networks for Alcohol Sensitivity in Drosophila melanogaster

2011

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Understanding the genetic architecture of polygenic traits requires investigating how complex networks of interacting molecules mediate the effect of genetic variation on organismal phenotypes. We used a combination of P-element mutagenesis and analysis of natural variation in gene expression to predict transcriptional networks that underlie alcohol sensitivity in Drosophila melanogaster. We identified 139 unique P-element mutations (124 in genes) that affect sensitivity or resistance to alcohol exposure. Further analyses of nine of the lines showed that the P-elements affected expression levels of the tagged genes, and P-element excision resulted in phenotypic reversion. The majority of the mutations were in computationally predicted genes or genes with unexpected effects on alcohol phenotypes. Therefore we sought to understand the biological relationships among 21 of these genes by leveraging genetic correlations among genetically variable transcripts in wild-derived inbred lines to predict coregulated transcriptional networks. A total of 32 ''hub'' genes were common to two or more networks associated with the focal genes. We used RNAi-mediated inhibition of expression of focal genes and of hub genes connected to them in the network to confirm their effects on alcohol-related phenotypes. We then expanded the computational networks using the hub genes as foci and again validated network predictions. Iteration of this approach allows a stepwise expansion of the network with simultaneous functional validation. Although coregulated transcriptional networks do not provide information about causal relationships among their constituent transcripts, they provide a framework for subsequent functional studies on the genetic basis of alcohol sensitivity.

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“…Extensive studies of the neuroadaptations accompanying tolerance development have shown genetic influences to be strong (Kalant et al 1971;Kalant 1998). Recent studies using the powerful genetic manipulations available in invertebrate species have extended the range of genetic influences thought to be responsible (Scholz et al 2000;Cowmeadow et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Neurogenetic studies of alcohol addiction

Crabbe

2008

Phil. Trans. R. Soc. B

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Neurogenetic studies of alcohol dependence have relied substantially on genetic animal models, particularly rodents. Studies of inbred strains, selectively bred lines and mutants bearing genes whose function has been targeted for over or under expression are reviewed. Studies focused on gene expression changes are the most recent contributors to this literature, and some genetic effects may work through epigenetic mechanisms. In a few instances, interesting parallels have been revealed between genetic risk in humans and studies in non-human animal models. Future approaches are likely to be increasingly complex.

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The slowpoke Gene Is Necessary for Rapid Ethanol Tolerance in Drosophila

Cited by 118 publications

References 47 publications

The concentration-dependent effects of ethanol on Caenorhabditis elegans behaviour

The concentration-dependent effects of ethanol on Caenorhabditis elegans behaviour

Transcriptional Networks for Alcohol Sensitivity in Drosophila melanogaster

Neurogenetic studies of alcohol addiction

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