title: Caenorhabditis elegans as a Model to Study the Molecular and Genetic Mechanisms of Drug Addiction.
abstract: Drug addiction takes a massive toll on society. Novel animal models are needed to test new treatments and understand the basic mechanisms underlying addiction. Rodent models have identified the neurocircuitry involved in addictive behavior and indicate that rodents possess some of the same neurobiologic mechanisms that mediate addiction in humans. Recent studies indicate that addiction is mechanistically and phylogenetically ancient and many mechanisms that underlie human addiction are also present in invertebrates. The nematode Caenorhabditis elegans has conserved neurobiologic systems with powerful molecular and genetic tools and a rapid rate of development that enables cost-effective translational discovery. Emerging evidence suggests that C. elegans is an excellent model to identify molecular mechanisms that mediate drug-induced behavior and potential targets for medications development for various addictive compounds. C. elegans emit many behaviors that can be easily quantitated including some that involve interactions with the environment. Ethanol (EtOH) is the best-studied drug-of-abuse in C. elegans and at least 50 different genes/targets have been identified as mediating EtOH's effects and polymorphisms in some orthologs in humans are associated with alcohol use disorders. C. elegans has also been shown to display dopamine and cholinergic system-dependent attraction to nicotine and demonstrate preference for cues previously associated with nicotine. Cocaine and methamphetamine have been found to produce dopamine-dependent reward-like behaviors in C. elegans. These behavioral tests in combination with genetic/molecular manipulations have led to the identification of dozens of target genes/systems in C. elegans that mediate drug effects. The one target/gene identified as essential for drug-induced behavioral responses across all drugs of abuse was the cat-2 gene coding for tyrosine hydroxylase, which is consistent with the role of dopamine neurotransmission in human addiction. Overall, C. elegans can be used to model aspects of drug addiction and identify systems and molecular mechanisms that mediate drug effects. The findings are surprisingly consistent with analogous findings in higher-level organisms. Further, model refinement is warranted to improve model validity and increase utility for medications development.
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA. Electronic address: eenglema@iupui.edu.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Engleman
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Katner
authors.affiliation: Department of Psychology, Purdue School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA.
authors.forename: Bethany S
authors.initials: BS
authors.lastname: Neal-Beliveau
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D004195:Disease Models, Animal; D019966:Substance-Related Disorders / Q000235:genetics*
keywords: Caenorhabditis elegans; addiction; behavior; cocaine; ethanol; genes; methamphetamine; model; nicotine
references.citation: Methods Mol Biol. 2012;829:31-48
references.pmid: 22231805
references.citation: PLoS Genet. 2010 Aug;6(8). pii: e1001057. doi: 10.1371/journal.pgen.1001057
references.pmid: 20714347
references.citation: Genes Brain Behav. 2013 Mar;12(2):250-62
references.pmid: 22853648
references.citation: Annu Rev Neurosci. 2005;28:451-501
references.pmid: 16022603
references.citation: Nature. 1995 Apr 13;374(6523):640-3
references.pmid: 7715703
references.citation: Chem Biodivers. 2008 Nov;5(11):2431-41
references.pmid: 19035572
references.citation: Cell. 2003 Dec 12;115(6):655-66
references.pmid: 14675531
references.citation: Neurosci Biobehav Rev. 2003 Aug;27(5):457-91
references.pmid: 14505687
references.citation: Cell Mol Neurobiol. 2006 Jul-Aug;26(4-6):593-618
references.pmid: 16724276
references.citation: Handb Exp Pharmacol. 2005;(168):283-97
references.pmid: 16596778
references.citation: Angew Chem Int Ed Engl. 2011 May 16;50(21):4774-807
references.pmid: 21500322
references.citation: Genes Brain Behav. 2012 Jun;11(4):387-97
references.pmid: 22239914
references.citation: Eur J Neurosci. 2013 Mar;37(5):743-56
references.pmid: 23351035
references.citation: Cell. 2001 Apr 20;105(2):221-32
references.pmid: 11336672
references.citation: Alcohol Clin Exp Res. 2012 Nov;36(11):1840-50
references.pmid: 22486589
references.citation: Trends Pharmacol Sci. 1992 May;13(5):177-84
references.pmid: 1604710
references.citation: Methods Mol Biol. 2012;829:243-56
references.pmid: 22231818
references.citation: Science. 1998 Dec 11;282(5396):2028-33
references.pmid: 9851919
references.citation: Addiction. 2007 Dec;102(12):1863-70
references.pmid: 18031422
references.citation: Neuropsychopharmacology. 2012 May;37(6):1409-21
references.pmid: 22218088
references.citation: Neurosci Biobehav Rev. 2011 Oct;35(9):1847-53
references.pmid: 21182861
references.citation: Science. 1998 Dec 11;282(5396):2012-8
references.pmid: 9851916
references.citation: Alcohol Clin Exp Res. 2015 Aug;39(8):1292-311
references.pmid: 26173477
references.citation: Pharmacogenetics. 2004 Feb;14(2):73-81
references.pmid: 15077008
references.citation: Genes Brain Behav. 2009 Aug;8(6):578-85
references.pmid: 19614755
references.citation: Alcohol Clin Exp Res. 2011 Feb;35(2):194-202
references.pmid: 21058960
references.citation: Cell. 1998 Sep 4;94(5):679-89
references.pmid: 9741632
references.citation: EMBO Rep. 2002 Jan;3(1):56-62
references.pmid: 11751572
references.citation: Pharmacol Biochem Behav. 2012 Nov;103(1):119-55
references.pmid: 22841890
references.citation: PLoS One. 2009;4(6):e5946
references.pmid: 19536276
references.citation: Recent Dev Alcohol. 2003;16:263-81
references.pmid: 12638642
references.citation: Neuron. 2004 Jun 10;42(5):731-43
references.pmid: 15182714
references.citation: Alcohol Clin Exp Res. 1995 Dec;19(6):1423-9
references.pmid: 8749805
references.citation: Genes Brain Behav. 2015 Jan;14(1):98-135
references.pmid: 25565358
references.citation: Alcohol Clin Exp Res. 2004 Aug;28(8):1137-44
references.pmid: 15318111
references.citation: Alcohol Clin Exp Res. 2008 May;32(5):853-67
references.pmid: 18336629
references.citation: Curr Drug Abuse Rev. 2012 Sep;5(3):227-42
references.pmid: 22998621
references.citation: Behav Neurosci. 2012 Jun;126(3):445-56
references.pmid: 22642886
references.citation: Bioessays. 2004 Jan;26(1):39-49
references.pmid: 14696039
references.citation: J Neurosci. 2002 May 1;22(9):3332-7
references.pmid: 11978808
references.citation: WormBook. 2007;:1-21
references.pmid: 18050502
references.citation: Neurosci Lett. 2011 Jul 1;498(1):99-103
references.pmid: 21565252
references.citation: Front Physiol. 2014 Sep 09;5:346
references.pmid: 25249984
references.citation: Neuropharmacology. 2014 Jan;76 Pt B:269-75
references.pmid: 23810828
references.citation: Learn Mem. 2010 Apr;17(4):191-201
references.pmid: 20335372
references.citation: Neuropsychopharmacology. 2010 Jan;35(1):217-38
references.pmid: 19710631
references.citation: WormBook. 2010;:1-6
references.pmid: 20432508
references.citation: Alcohol. 2014 May;48(3):209-15
references.pmid: 24268381
references.citation: Mol Biol Cell. 2009 Jan;20(1):43-55
references.pmid: 18923141
references.citation: PLoS One. 2014;9(8):e105999
references.pmid: 25162400
references.citation: Curr Opin Neurobiol. 2015 Feb;30:112-21
references.pmid: 25486626
references.citation: PLoS One. 2012;7(5):e35192
references.pmid: 22574115
references.citation: Nat Neurosci. 2009 Oct;12(10):1293-9
references.pmid: 19749751
references.citation: Elife. 2014;3. doi: 10.7554/eLife.02938
references.pmid: 24915976
references.citation: J Neurosci. 2000 Dec 1;20(23):8802-11
references.pmid: 11102488
references.citation: Am J Physiol Cell Physiol. 2001 Jun;280(6):C1616-22
references.pmid: 11350757
references.citation: Front Aging Neurosci. 2014 May 19;6:89
references.pmid: 24904406
references.citation: Genetics. 2015 Jan;199(1):135-49
references.pmid: 25342716
references.citation: Science. 2002 Jul 26;297(5581):623-6
references.pmid: 12142542
references.citation: Neuron. 2001 Dec 6;32(5):867-81
references.pmid: 11738032
references.citation: Ann N Y Acad Sci. 2010 Feb;1187:101-21
references.pmid: 20201848
references.citation: Alcohol Clin Exp Res. 2014 Jan;38(1):267-74
references.pmid: 23909817
references.citation: Neurotox Res. 2008 Oct;14(2-3):185-9
references.pmid: 19073425
references.citation: Invert Neurosci. 2011 Dec;11(2):73-83
references.pmid: 22068627
references.citation: Genes Brain Behav. 2008 Aug;7(6):669-76
references.pmid: 18397381
references.citation: Neurosci Bull. 2014 Aug;30(4):595-600
references.pmid: 25008572
references.citation: Science. 2001 Nov 2;294(5544):1030-8
references.pmid: 11691980
references.citation: Pharmacol Biochem Behav. 2009 Feb;91(4):481-8
references.pmid: 19121334
references.citation: Ann N Y Acad Sci. 2008 Oct;1141:76-95
references.pmid: 18991952
references.citation: Mol Neurobiol. 2013 Dec;48(3):465-89
references.pmid: 23494747
references.citation: J Neurochem. 2005 Aug;94(3):774-85
references.pmid: 15992384
references.citation: Nat Rev Genet. 2007 Jul;8(7):518-32
references.pmid: 17549065
references.citation: Genes Brain Behav. 2004 Oct;3(5):266-72
references.pmid: 15344920
references.citation: Elife. 2015;4. doi: 10.7554/eLife.06683
references.pmid: 25898004
references.citation: Physiol Behav. 2003 Jun;79(1):95-101
references.pmid: 12818714
references.citation: PLoS One. 2014;9(3):e92965
references.pmid: 24681782
references.citation: Pharmacol Biochem Behav. 2005 Jun;81(2):285-99
references.pmid: 15932767
references.citation: Neurosci Biobehav Rev. 2011 Jan;35(3):912-38
references.pmid: 21036191
references.citation: Curr Pharm Des. 2011;17(14):1323-32
references.pmid: 21524263
references.citation: PLoS One. 2010;5(5):e10422
references.pmid: 20454655
references.citation: J Neurosci. 2014 Jul 16;34(29):9562-73
references.pmid: 25031399
references.citation: Addict Biol. 2007 Sep;12(3-4):227-462
references.pmid: 17678505
references.citation: Neuropharmacology. 2015 Sep;96(Pt B):263-73
references.pmid: 25661700
references.citation: J Addict Res Ther. 2013 Aug 20;Suppl 4:null
references.pmid: 25419478
references.citation: WormBook. 2006;:1-29
references.pmid: 18050433
references.citation: Cell. 2006 Nov 3;127(3):621-33
references.pmid: 17081982
references.citation: Biosci Biotechnol Biochem. 2015;79(3):462-9
references.pmid: 25428810
references.citation: Mol Pharmacol. 1998 Oct;54(4):601-9
references.pmid: 9765501
references.citation: Neuroscience. 1980;5(6):967-89
references.pmid: 7402460
references.citation: Nat Neurosci. 2011 May;14(5):612-9
references.pmid: 21499254
references.citation: Proc Natl Acad Sci U S A. 2015 Mar 10;112(10):3032-7
references.pmid: 25713357