Genetical genomic determinants of alcohol consumption in rats and humans

Tabakoff, Boris; Saba, Laura; Printz, Morton P.; Flodman, Pam; Hodgkinson, Colin A.; Goldman, David; Koob, George F.; Richardson, H. G.; Kechris, Katerina; Bell, Richard L.; Hübner, Norbert; Heinig, Matthias; Pravenec, Michal; Mangion, Jonathan; Legault, Lucie; Dongier, M; Conigrave, Katherine M.; Whitfield, John B.; Saunders, John B.; Grant, Bridget F.; Hoffman, Paula L.

doi:10.1186/1741-7007-7-70

Cited by 140 publications

(187 citation statements)

References 119 publications

(125 reference statements)

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“…Ethanol and/or IVM were co-applied with ATP for 20 s. Submaximal ATP concentrations that ranged from EC 5 to EC 10 were used in these studies that are designated as EC 10 throughout the manuscript. We have previously shown that ethanol inhibition of ATP function on P2X4Rs is more robust and reliable when tested in the presence of low concentrations of ATP (typically EC [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] ) [11,13]. ATPactivated EC 10 responses were measured before and after each ethanol application to take into account possible shifts in the baseline current values.…”

Section: Methodsmentioning

confidence: 99%

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Tryptophan 46 is a site for ethanol and ivermectin action in P2X4 receptors

Popova

Trudell

et al. 2013

Purinergic Signalling

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ATP-gated purinergic P2X4 receptors (P2X4Rs) are the most alcohol-sensitive P2XR subtype. We recently reported that ivermectin (IVM), an antiparasitic used in animals and humans, antagonized ethanol inhibition of P2X4Rs. Furthermore, IVM reduced ethanol intake in mice. The first molecular model of the rat P2X4R, built onto the Xray crystal structure of zebrafish P2X4R, revealed an action pocket for both ethanol and IVM formed by Asp331, Met336 in TM2 and Trp46, and Trp50 in TM1 segments. The role of Asp331 and Met336 was experimentally confirmed. The present study tested the hypothesis that Trp46 plays a role in ethanol and IVM modulation of P2X4Rs. Trp46 was mutated to residues with different physicochemical properties and the resultant mutants tested for ethanol and IVM responses using Xenopus oocyte expression system and twoelectrode voltage clamp. Nonaromatic substitutions at position 46 reduced ethanol inhibition at higher concentrations and switched IVM potentiation to inhibition. Simultaneous substitution of alanine at positions Trp46 and Met336 also resulted in similar changes in ethanol and IVM responses. Furthermore, a new molecular model based on the open pore conformation of zebrafish P2X4R suggested a role for Tyr42 that was further supported experimentally. Our previous and current findings, combined with our preliminary evidence of increased ethanol consumption in P2X4R knockout mice, suggest that the ethanol and IVM action pocket in P2X4Rs formed by positions 42, 46, 331, and 336 presents a potential target for medication development for alcohol use disorders.

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Section: Methodsmentioning

confidence: 99%

“…In vitro, they are inhibited by a broad range of ethanol concentrations beginning well below the concentrations considered legally intoxicating in the United States (0.08 % or 17 mM) [11][12][13][14][15][16][17]. Evidence from genetic and genomic studies [18,19] suggests that these receptors play a role in regulating ethanol intake.…”

Section: Introductionmentioning

confidence: 99%

Tryptophan 46 is a site for ethanol and ivermectin action in P2X4 receptors

Popova

Trudell

et al. 2013

Purinergic Signalling

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“…The application of comprehensive, integrative approaches will define the future of alcohol research (Rodd et al, 2007;Tabakoff et al, 2009;Tapocik et al, 2013) and promises to be fruitful in elucidating the mechanisms underlying alcohol addiction. Genetic and biological studies in animal models or post-mortem human brain, with epidemiological and clinical surveys on human subjects, should be integrated with genomic data.…”

Section: Systems Biology and Integration Of Proteomics With Complemenmentioning

confidence: 99%

“…Of all the other substances of abuse, alcohol is by far the most harmful despite it being a legal drug (Nutt et al, 2010). Genetic, neurobiological, environmental, and psychosocial risk factors influence some individuals to develop compulsive and uncontrolled consumption of alcoholic beverages despite serious negative consequences (Koob and Le Moal, 2001;Koob, 2006;Mayfield et al, 2008;Phillips and Belknap, 2002;Potenza et al, 2011;Tabakoff et al, 2009). The molecular mechanisms underlying alcohol dependence involve different neurochemical systems and brain regions.…”

Section: Introductionmentioning

confidence: 99%

Proteomic Approaches and Identification of Novel Therapeutic Targets for Alcoholism

Gorini

Harris

Mayfield

2013

Neuropsychopharmacol

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Recent studies have shown that gene regulation is far more complex than previously believed and does not completely explain changes at the protein level. Therefore, the direct study of the proteome, considerably different in both complexity and dynamicity to the genome/transcriptome, has provided unique insights to an increasing number of researchers. During the past decade, extraordinary advances in proteomic techniques have changed the way we can analyze the composition, regulation, and function of protein complexes and pathways underlying altered neurobiological conditions. When combined with complementary approaches, these advances provide the contextual information for decoding large data sets into meaningful biologically adaptive processes. Neuroproteomics offers potential breakthroughs in the field of alcohol research by leading to a deeper understanding of how alcohol globally affects protein structure, function, interactions, and networks. The wealth of information gained from these advances can help pinpoint relevant biomarkers for early diagnosis and improved prognosis of alcoholism and identify future pharmacological targets for the treatment of this addiction.

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“…For instance, NIAAA intramural researcher Mark Egli argues that researchers' efforts might be better directed towards developing "rapid, inexpensive tests which yield the same information as the more elaborate models, although they may be less obvious models of alcoholism" (Egli 2005, 315). Others argue that experimental designs where the physiology and behavior of the animals strongly resembles human drinking can be used to identify novel genes or signaling pathways involved in drinking, which may point the way towards new drug targets or susceptibility genes in humans (Tabakoff et al 2009). …”

Section: Situating Animals In Valid Experimental Contextsmentioning

confidence: 99%

Making Organisms Model Human Behavior: Situated Models in North-American Alcohol Research, since 1950

Ankeny¹,

Leonelli²,

Nelson³

et al. 2014

Sci Context

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Argument:We examine the criteria used to validate the use of nonhuman organisms in North-American alcohol addiction research from the 1950s to the present day. We argue that this field, where the similarities between behaviors in humans and nonhumans are particularly difficult to assess, has addressed questions of model validity by transforming the situatedness of non-human organisms into an experimental tool. We demonstrate that model validity does not hinge on the standardization of one type of organism in isolation, as often the case with genetic model organisms. Rather, organisms are viewed as necessarily situated: they cannot be understood as a model for human behavior in isolation from their environmental conditions. Hence the environment itself is standardized as part of the modeling process; and model validity is assessed with reference to the environmental conditions under which organisms are studied.

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Genetical genomic determinants of alcohol consumption in rats and humans

Cited by 140 publications

References 119 publications

Tryptophan 46 is a site for ethanol and ivermectin action in P2X4 receptors

Tryptophan 46 is a site for ethanol and ivermectin action in P2X4 receptors

Proteomic Approaches and Identification of Novel Therapeutic Targets for Alcoholism

Making Organisms Model Human Behavior: Situated Models in North-American Alcohol Research, since 1950

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