Neuroscience Bulletin

, Volume 30, Issue 4, pp 595–600 | Cite as

Nematodes feel a craving - Using Caenorhabditis elegans as a model to study alcohol addiction



Alcohol is the most frequently-used addictive drug. However, the mechanism by which its consumption leads to addiction remains largely elusive. Given the conservation of behavioral reactions to alcohol, Caenorhabitis elegans (C. elegans) has been effectively used as a model system to investigate the relevant molecular targets and pathways mediating these responses. In this article, we review the roles of BK channels (also called SLO-1), the lipid microenvironment, receptors, the synaptic machinery, and neurotransmitters in both the acute and chronic effects of alcohol. We provide an overview of the genes and mechanisms involved in alcoholismrelated behaviors in C. elegans.


C. elegans substance abuse ethanol BK channel 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. [1]
    Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by doublestranded RNA in Caenorhabditis elegans. Nature 1998, 391: 806–811.PubMedCrossRefGoogle Scholar
  2. [2]
    Montgomery MK, Fire A. Double-stranded RNA as a mediator in sequence-specific genetic silencing and co-suppression. Trends Genet 1998, 14: 255–258.PubMedCrossRefGoogle Scholar
  3. [3]
    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.PubMedCrossRefGoogle Scholar
  4. [4]
    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.PubMedCrossRefGoogle Scholar
  5. [5]
    Ikemoto Y, Ono K, Yoshida A, Akaike N. Delayed activation of large-conductance Ca2+-activated K channels in hippocampal neurons of the rat. Biophys J 1989, 56: 207–212.PubMedCentralPubMedCrossRefGoogle Scholar
  6. [6]
    Wang Z-W, Saifee O, Nonet ML, Salkoff L. SLO-1 potassium channels control quantal content of neurotransmitter release at the C. elegans neuromuscular junction. Neuron 2001, 32: 867–881.PubMedCrossRefGoogle Scholar
  7. [7]
    Hu H, Shao L-R, Chavoshy S, Gu N, Trieb M, Behrens R, et al. Presynaptic Ca2+-activated K+ channels in glutamatergic hippocampal terminals and their role in spike repolarization and regulation of transmitter release. J Neurosci 2001, 21: 9585–9597.PubMedGoogle Scholar
  8. [8]
    Li W, Gao S, Lv C, Wu Y, Guo Z, Ding J, et al. Characterization of voltage-and Ca2+-activated K+ channels in rat dorsal root ganglion neurons. J Cell Physiol 2007, 212: 348–357.PubMedCrossRefGoogle Scholar
  9. [9]
    Lind PA, Macgregor S, Vink JM, Pergadia ML, Hansell NK, De Moor MHM, et al. A genomewide association study of nicotine and alcohol dependence in Australian and Dutch populations. Twin Res Hum Genet 2010, 13: 10.PubMedCentralPubMedCrossRefGoogle Scholar
  10. [10]
    Bettinger JC, Leung K, Bolling MH, Goldsmith AD, Davies AG. Lipid environment modulates the development of acute tolerance to ethanol in Caenorhabditis elegans. PLoS One 2012, 7.Google Scholar
  11. [11]
    Brodie MS, Scholz A, Weiger TM, Dopico AM. Ethanol interactions with calcium-dependent potassium channels. Alcohol Clin Exp Res 2007, 31: 1625–1632.PubMedCrossRefGoogle Scholar
  12. [12]
    Siggins GR, Roberto M, Nie Z. The tipsy terminal: presynaptic effects of ethanol. Pharmacol Ther 2005, 107: 80–98.PubMedCrossRefGoogle Scholar
  13. [13]
    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.PubMedCrossRefGoogle Scholar
  14. [14]
    Gruss M, Henrich M, Koenig P, Hempelmann G, Vogel W, Scholz A. Ethanol reduces excitability in a subgroup of primary sensory neurons by activation of BKCa channels. Eur J Neurosci 2001, 14: 1246–1256.PubMedCrossRefGoogle Scholar
  15. [15]
    Nonet ML, Staunton JE, Kilgard MP, Fergestad T, Hartwieg E, Horvitz HR, et al. Caenorhabditis elegans rab-3 mutant synapses exhibit impaired function and are partially depleted of vesicles. J Neurosci 1997, 17: 8061–8073.PubMedGoogle Scholar
  16. [16]
    Iwasaki K, Staunton J, Saifee O, Nonet M, Thomas JH. aex-3 encodes a novel regulator of presynaptic activity in C. elegans. Neuron 1997, 18: 613–622.PubMedCrossRefGoogle Scholar
  17. [17]
    Geppert M, Bolshakov VY, Siegelbaum SA, Takei K, De Camilli P, Hammer RE, et al. The role of Rab3A in neurotransmitter release. Nature 1994, 369 (6480): 493–497.CrossRefGoogle Scholar
  18. [18]
    Kapfhamer D, Bettinger JC, Davies AG, Eastman CL, Smail EA, Heberlein U, et al. Loss of RAB-3/A in Caenorhabditis elegans and the mouse affects behavioral response to ethanol. Genes Brain Behav 2008, 7: 669–676.PubMedCentralPubMedCrossRefGoogle Scholar
  19. [19]
    Fehr C, Shirley RL, Crabbe JC, Belknap JK, Buck KJ, Phillips TJ. The syntaxin binding protein 1 gene (Stxbp1) is a candidate for an ethanol preference drinking locus on mouse chromosome 2. Alcohol Clin Exp Res 2005, 29: 708–720.PubMedCrossRefGoogle Scholar
  20. [20]
    Graham ME, Edwards MR, Holden-Dye L, Morgan A, Burgoyne RD, Barclay JW. UNC-18 modulates ethanol sensitivity in Caenorhabditis elegans. Mol Biol Cell 2009, 20: 43–55.PubMedCentralPubMedCrossRefGoogle Scholar
  21. [21]
    Thorsell A. Neuropeptide Y (NPY) in alcohol intake and dependence. Peptides 2007, 28: 480–483.PubMedCrossRefGoogle Scholar
  22. [22]
    Thorsell A, Repunte-Canonigo V, O’Dell LE, Chen SA, King AR, Lekic D, et al. Viral vector-induced amygdala NPY overexpression reverses increased alcohol intake caused by repeated deprivations in Wistar rats. Brain 2007, 130: 1330–1337.PubMedCentralPubMedCrossRefGoogle Scholar
  23. [23]
    De Bono M, Bargmann CI. Natural variation in a neuropeptide Y receptor homolog modifies social behavior and food response in C. elegans. Cell 1998, 94: 679–689.PubMedCrossRefGoogle Scholar
  24. [24]
    Lee J, Jee C, McIntire SL. Ethanol preference in C. elegans. Genes Brain Behav 2009, 8: 578–585.PubMedCentralPubMedCrossRefGoogle Scholar
  25. [25]
    Jee C, Lee J, Lim JP, Parry D, Messing RO, McIntire SL. SEB-3, a CRF receptor-like GPCR, regulates locomotor activity states, stress responses and ethanol tolerance in Caenorhabditis elegans. Genes Brain Behav 2013, 12: 250–262.PubMedCrossRefGoogle Scholar
  26. [26]
    Johnson BE, Glauser DA, Dan-Glauser ES, Halling DB, Aldrich RW, Goodman MB. Alternatively spliced domains interact to regulate BK potassium channel gating. Proc Natl Acad Sci U S A 2011, 108: 20784–20789.PubMedCentralPubMedCrossRefGoogle Scholar
  27. [27]
    Feinberg-Zadek PL, Treistman SN. Beta-Subunits are important modulators of the acute response to alcohol in human BK channels. Alcohol Clin Exp Res 2007, 31: 737–744.PubMedCrossRefGoogle Scholar
  28. [28]
    Chen B, Ge Q, Xia X-M, Liu P, Wang SJ, Zhan H, et al. A novel auxiliary subunit critical to BK channel function in Caenorhabditis elegans. J Neurosci 2010, 30: 16651–16661.PubMedCentralPubMedCrossRefGoogle Scholar
  29. [29]
    Johnson JR, Kashyap S, Rankin K, Barclay JW. Rab-3 and unc-18 interactions in alcohol sensitivity are distinct from synaptic transmission. PLoS One 2013, 8: e81117.PubMedCentralPubMedCrossRefGoogle Scholar
  30. [30]
    Barclay J, Graham M, Edwards M, Johnson J, Morgan A, Burgoyne R. Presynaptic targets for acute ethanol sensitivity. Biochem Soc Trans 2010, 38: 172.PubMedCrossRefGoogle Scholar
  31. [31]
    Ward A, Walker VJ, Feng Z, Xu XZS. Cocaine modulates locomotion behavior in C. elegans. PLoS One 2009, 4: e5946.PubMedCentralPubMedCrossRefGoogle Scholar
  32. [32]
    Carvelli L, Matthies DS, Galli A. Molecular mechanisms of amphetamine actions in Caenorhabditis elegans. Mol pharmacol 2010, 78: 151–156.PubMedCentralPubMedCrossRefGoogle Scholar
  33. [33]
    Bargmann CI. Neurobiology of the Caenorhabditis elegans genome. Science 1998, 282: 2028–2033.PubMedCrossRefGoogle Scholar
  34. [34]
    Lewis JA, Wu CH, Berg H, Levine JH. The genetics of levamisole resistance in the nematode Caenorhabditis elegans. Genetics 1980, 95: 905–928.PubMedCentralPubMedGoogle Scholar
  35. [35]
    Garcia LR, Mehta P, Sternberg PW. Regulation of distinct muscle behaviors controls the C. elegans male’s copulatory spicules during mating. Cell 2001, 107: 777–788.PubMedCrossRefGoogle Scholar
  36. [36]
    Waggoner LE, Dickinson KA, Poole DS, Tabuse Y, Miwa J, Schafer WR. Long-term nicotine adaptation in Caenorhabditis elegans involves PKC-dependent changes in nicotinic receptor abundance. J Neurosci 2000, 20: 8802–8811.PubMedGoogle Scholar
  37. [37]
    Feng Z, Li W, Ward A, Piggott BJ, Larkspur ER, Sternberg PW, et al. A C. elegans model of nicotine-dependent behavior: regulation by TRP-family channels. Cell 2006, 127: 621–633.PubMedCentralPubMedCrossRefGoogle Scholar
  38. [38]
    Nieto-Fernandez F, Andrieux S, Idrees S, Bagnall C, Pryor SC, Sood R. The effect of opioids and their antagonists on the nocifensive response of Caenorhabditis elegans to noxious thermal stimuli. Invert Neurosci 2009, 9: 195–200.PubMedCentralPubMedCrossRefGoogle Scholar
  39. [39]
    McPartland JM, Glass M. Functional mapping of cannabinoid receptor homologs in mammals, other vertebrates, and invertebrates. Gene 2003, 312: 297–303.PubMedCrossRefGoogle Scholar
  40. [40]
    Lutz B. Molecular biology of cannabinoid receptors. Prostaglandins Leukot Essent Fatty Acids 2002, 66: 123–142.PubMedCrossRefGoogle Scholar
  41. [41]
    Lehtonen M, Reisner K, Auriola S, Wong G, Callaway JC. Mass-spectrometric Identification of Anandamide and 2-arachidonoylglycerol in Nematodes. Chem Biodivers 2008, 5: 2431–2441.PubMedCrossRefGoogle Scholar
  42. [42]
    Bargmann CI. High-throughput reverse genetics: RNAi screens in Caenorhabditis elegans. Genome Biol 2001, 2:1005. 1001–1003.CrossRefGoogle Scholar
  43. [43]
    Li W, Kang L, Piggott BJ, Feng Z, Xu XZ. The neural circuits and sensory channels mediating harsh touch sensation in Caenorhabditis elegans. Nat Commun 2011, 2: 315.PubMedCentralPubMedCrossRefGoogle Scholar
  44. [44]
    Piggott BJ, Liu J, Feng Z, Wescott SA, Xu XZ. The neural circuits and synaptic mechanisms underlying motor initiation in C. elegans. Cell 2011, 147: 922–933.PubMedCentralPubMedCrossRefGoogle Scholar
  45. [45]
    Stirman JN, Crane MM, Husson SJ, Wabnig S, Schultheis C, Gottschalk A, et al. Real-time multimodal optical control of neurons and muscles in freely behaving Caenorhabditis elegans. Nat Methods 2011, 8: 153–158.PubMedCentralPubMedCrossRefGoogle Scholar
  46. [46]
    Schroedel T, Prevedel R, Aumayr K, Zimmer M, Vaziri A. Brain-wide 3D imaging of neuronal activity in Caenorhabditis elegans with sculpted light. Nat Methods 2013, 10: 1013–1020.CrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.School of Life Sciences InstituteTongji UniversityShanghaiChina

Personalised recommendations