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The concentration-dependent effects of ethanol on Caenorhabditis elegans behaviour

Abstract

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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Abbreviations

EPG:

electropharyngeogram

References

  1. Davies AG, Bettinger JC, Thiele TR, Judy ME, McIntire SL . Natural variation in the npr-1 gene modifies ethanol responses of wild strains of C. elegans. Neuron 2004; 42: 731–743.

    Article  CAS  PubMed  Google Scholar 

  2. Kauhanen J, Karvonen MK, Pesonen U, Koulu M, Tuomainen TP, Uusitupa MI et al. Neuropeptide Y polymorphism and alcohol consumption in middle-aged men. Am J Med Genet 2000; 93: 117–121.

    Article  CAS  PubMed  Google Scholar 

  3. Thiele TE, Sparta DR, Hayes DM, Fee JR . A role for neuropeptide Y in neurobiological responses to ethanol and drugs of abuse. Neuropeptides 2004; 38: 235–243.

    Article  CAS  PubMed  Google Scholar 

  4. Wen T, Parrish CA, Xu D, Wu Q, Shen P . Drosophila neuropeptide F and its receptor, NPFR1, define a signaling pathway that acutely modulates alcohol sensitivity. Proc Natl Acad Sci USA 2005; 102: 2141–2146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Carta M, Mameli M, Valenzuela CF . Alcohol potently modulates climbing fiber-->Purkinje neuron synapses: role of metabotropic glutamate receptors. J Neurosci 2006; 26: 1906–1912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kwon JY, Hong M, Choi MS, Kang S, Duke K, Kim S et al. Ethanol-response genes and their regulation analyzed by a microarray and comparative genomic approach in the nematode Caenorhabditis elegans. Genomics 2004; 83: 600–614.

    Article  CAS  PubMed  Google Scholar 

  7. Buck KJ, Metten P, Belknap JK, Crabbe JC . Quantitative trait loci involved in genetic predisposition to acute alcohol withdrawal in mice. J Neurosci 1997; 17: 3946–3955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Edenberg HJ, Dick DM, Xuei X, Tian H, Almasy L, Bauer LO et al. Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations. Am J Hum Genet 2004; 74: 705–714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Moore MS, DeZazzo J, Luk AY, Tully T, Singh CM, Heberlein U . Ethanol intoxication in Drosophila: genetic and pharmacological evidence for regulation by the cAMP signaling pathway. Cell 1998; 93: 997–1007.

    Article  CAS  PubMed  Google Scholar 

  10. Pandey SC, Zhang H, Roy A, Xu T . Deficits in amygdaloid cAMP-responsive element-binding protein signaling play a role in genetic predisposition to anxiety and alcoholism. J Clin Invest 2005; 115: 2762–2773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cowmeadow RB, Krishnan HR, Atkinson NS . The slowpoke gene is necessary for rapid ethanol tolerance in Drosophila. Alcohol Clin Exp Res 2005; 29: 1777–1786.

    Article  CAS  PubMed  Google Scholar 

  12. Dopico AM, Anantharam V, Treistman SN . Ethanol increases the activity of Ca(++)-dependent K+ (mslo) channels: functional interaction with cytosolic Ca++. J Pharmacol Exp Ther 1998; 284: 258–268.

    CAS  PubMed  Google Scholar 

  13. Davies AG, Pierce-Shimomura JT, Kim H, VanHoven MK, Thiele TR, Bonci A et al. A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans. Cell 2003; 115: 655–666.

    Article  CAS  PubMed  Google Scholar 

  14. Barry JA, Gawrisch K . Direct NMR evidence for ethanol binding to the lipid-water interface of phospholipid bilayers. Biochemistry 1994; 33: 8082–8088.

    Article  CAS  PubMed  Google Scholar 

  15. Mayfield RD, Lewohl JM, Dodd PR, Herlihy A, Liu J, Harris RA . Patterns of gene expression are altered in the frontal and motor cortices of human alcoholics. J Neurochem 2002; 81: 802–813.

    Article  CAS  PubMed  Google Scholar 

  16. Eckenhoff RG, Yang BJ . Absence of pressure antagonism of ethanol narcosis in C. elegans. Neuroreport 1994; 6: 77–80.

    Article  CAS  PubMed  Google Scholar 

  17. Morgan PG, Sedensky MM . Mutations affecting sensitivity to ethanol in the nematode, Caenorhabditis elegans. Alcohol Clin Exp Res 1995; 19: 1423–1429.

    Article  CAS  PubMed  Google Scholar 

  18. Dhawan R, Dusenbery DB, Williams PL . Comparison of lethality, reproduction, and behavior as toxicological endpoints in the nematode Caenorhabditis elegans. J Toxicol Environ Health A 1999; 58: 451–462.

    Article  CAS  PubMed  Google Scholar 

  19. Rand JB, Johnson CD . Genetic pharmacology: interactions between drugs and gene products in Caenorhabditis elegans. Methods Cell Biol 1995; 48: 187–204.

    Article  CAS  PubMed  Google Scholar 

  20. Davies AG, McIntire SL . Using C. elegans to screen for targets of ethanol and behavior-altering drugs. Biol Proc Online 2004; 6: 113–119.

    Article  CAS  Google Scholar 

  21. Williamson VM, Long M, Theodoris G . Isolation of Caenorhabditis elegans mutants lacking alchohol dehydrogenase activity. Biochem Genet 1991; 29: 313–324.

    Article  CAS  PubMed  Google Scholar 

  22. Avery L, Horvitz HR . Effects of starvation and neuroactive drugs on feeding in Caenorhabditis elegans. J Exp Zool 1990; 253: 263–270.

    Article  CAS  PubMed  Google Scholar 

  23. Crowder MC . Ethanol targets: a BK channel cocktail in C. elegans. Trends in Neurosci 2004; 27: 579–582.

    Article  CAS  Google Scholar 

  24. Hawasli AH, Saifee O, Liu C, Nonet ML, Crowder CM . Resistance to volatile anesthetics by mutations enhancing excitatory neurotransmitter release. Genetics 2004; 168: 831–843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Brenner S . The genetics of Caenorhabditis elegans. Genetics 1974; 77: 71–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Papaioannou S, Marsden D, Franks CJ, Walker RJ, Holden-Dye L . Role of a FMRFamide-like family of neuropeptides in the pharyngeal nervous system of Caenorhabditis elegans. J Neurobiol 2005; 65: 304–319.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Funded by a studentship in Integrative Brain Science from the Biotechnology and Biological Sciences Research Council (UK). Neil Hopper was supported by a Wellcome Trust Career Development Fellowship.

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Correspondence to L Holden-Dye.

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The authors declare no competing financial interest.

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Mitchell, P., Bull, K., Glautier, S. et al. The concentration-dependent effects of ethanol on Caenorhabditis elegans behaviour. Pharmacogenomics J 7, 411–417 (2007). https://doi.org/10.1038/sj.tpj.6500440

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