title: A differential role for neuropeptides in acute and chronic adaptive responses to alcohol: behavioural and genetic analysis in Caenorhabditis elegans.
abstract: Prolonged alcohol consumption in humans followed by abstinence precipitates a withdrawal syndrome consisting of anxiety, agitation and in severe cases, seizures. Withdrawal is relieved by a low dose of alcohol, a negative reinforcement that contributes to alcohol dependency. This phenomenon of 'withdrawal relief' provides evidence of an ethanol-induced adaptation which resets the balance of signalling in neural circuits. We have used this as a criterion to distinguish between direct and indirect ethanol-induced adaptive behavioural responses in C. elegans with the goal of investigating the genetic basis of ethanol-induced neural plasticity. The paradigm employs a 'food race assay' which tests sensorimotor performance of animals acutely and chronically treated with ethanol. We describe a multifaceted C. elegans 'withdrawal syndrome'. One feature, decrease reversal frequency is not relieved by a low dose of ethanol and most likely results from an indirect adaptation to ethanol caused by inhibition of feeding and a food-deprived behavioural state. However another aspect, an aberrant behaviour consisting of spontaneous deep body bends, did show withdrawal relief and therefore we suggest this is the expression of ethanol-induced plasticity. The potassium channel, slo-1, which is a candidate ethanol effector in C. elegans, is not required for the responses described here. However a mutant deficient in neuropeptides, egl-3, is resistant to withdrawal (although it still exhibits acute responses to ethanol). This dependence on neuropeptides does not involve the NPY-like receptor npr-1, previously implicated in C. elegans ethanol withdrawal. Therefore other neuropeptide pathways mediate this effect. These data resonate with mammalian studies which report involvement of a number of neuropeptides in chronic responses to alcohol including corticotrophin-releasing-factor (CRF), opioids, tachykinins as well as NPY. This suggests an evolutionarily conserved role for neuropeptides in ethanol-induced plasticity and opens the way for a genetic analysis of the effects of alcohol on a simple model system.
authors.affiliation: School of Biological Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Philippa
authors.initials: P
authors.lastname: Mitchell
authors.forename: Richard
authors.initials: R
authors.lastname: Mould
authors.forename: James
authors.initials: J
authors.lastname: Dillon
authors.forename: Steven
authors.initials: S
authors.lastname: Glautier
authors.forename: Ioannis
authors.initials: I
authors.lastname: Andrianakis
authors.forename: Christopher
authors.initials: C
authors.lastname: James
authors.forename: Amanda
authors.initials: A
authors.lastname: Pugh
authors.forename: Lindy
authors.initials: L
authors.lastname: Holden-Dye
authors.forename: Vincent
authors.initials: V
authors.lastname: O'Connor
mesh_terms: D000223:Adaptation, Psychological / Q000187:drug effects*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D005247:Feeding Behavior / Q000187:drug effects; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009479:Neuropeptides / Q000494:pharmacology*; D010641:Phenotype; D011187:Posture; D017476:Receptors, Neuropeptide Y / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D051036:Large-Conductance Calcium-Activated Potassium Channels; C468272:NPR-1 protein, C elegans; D009479:Neuropeptides; D017476:Receptors, Neuropeptide Y; C494845:slo-1 protein, C elegans; D000431:Ethanol
references.citation: Philos Trans R Soc Lond B Biol Sci. 2008 Oct 12;363(1507):3125-35
references.pmid: 18640910
references.citation: Curr Biol. 2003 Sep 30;13(19):1715-20
references.pmid: 14521838
references.citation: J Neurobiol. 2003 Jan;54(1):161-78
references.pmid: 12486703
references.citation: Cell. 1998 Jun 12;93(6):997-1007
references.pmid: 9635429
references.citation: Psychopharmacology (Berl). 2010 Mar;209(1):103-11
references.pmid: 20112009
references.citation: Nat Neurosci. 2005 Jan;8(1):18-9
references.pmid: 15592467
references.citation: Neuron. 2000 Oct;28(1):261-71
references.pmid: 11086999
references.citation: Nature. 2005 Aug 11;436(7052):845-7
references.pmid: 16094367
references.citation: Trends Neurosci. 2007 Aug;30(8):399-406
references.pmid: 17629579
references.citation: Genomics. 2004 Apr;83(4):600-14
references.pmid: 15028283
references.citation: Cell. 2009 May 29;137(5):949-60
references.pmid: 19464045
references.citation: Pharmacopsychiatry. 2003 Nov;36 Suppl 3:S255-8
references.pmid: 14677088
references.citation: Nat Neurosci. 2005 Nov;8(11):1442-4
references.pmid: 16251985
references.citation: Int J Parasitol. 2007 Dec;37(14):1577-88
references.pmid: 17583712
references.citation: J Neurobiol. 2003 Aug;56(2):178-97
references.pmid: 12838583
references.citation: J Neurosci. 1999 Nov 1;19(21):9557-69
references.pmid: 10531458
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9070-5
references.pmid: 18591672
references.citation: Cell. 2006 Oct 6;127(1):199-211
references.pmid: 17018286
references.citation: Cell. 2003 Dec 12;115(6):655-66
references.pmid: 14675531
references.citation: J Comp Neurol. 2004 Aug 2;475(4):540-50
references.pmid: 15236235
references.citation: J Neurosci. 2007 Mar 7;27(10):2718-26
references.pmid: 17344409
references.citation: Alcohol Clin Exp Res. 1998 Feb;22(1):3-9
references.pmid: 9514280
references.citation: Mol Biol Cell. 2009 Jan;20(1):43-55
references.pmid: 18923141
references.citation: Neuron. 2004 Jun 10;42(5):731-43
references.pmid: 15182714
references.citation: Science. 2008 Mar 14;319(5869):1536-9
references.pmid: 18276852
references.citation: Alcohol Clin Exp Res. 2006 May;30(5):745-53
references.pmid: 16634842
references.citation: Alcohol Clin Exp Res. 2004 Oct;28(10):1469-80
references.pmid: 15597078
references.citation: Curr Opin Investig Drugs. 2010 Jan;11(1):63-71
references.pmid: 20047160
references.citation: Psychopharmacology (Berl). 1997 Jan;129(2):99-111
references.pmid: 9040115
references.citation: Alcohol Clin Exp Res. 2008 May;32(5):853-67
references.pmid: 18336629
references.citation: Nat Neurosci. 2005 Nov;8(11):1471-80
references.pmid: 16251990
references.citation: Cell. 1998 Sep 4;94(5):679-89
references.pmid: 9741632
references.citation: Br J Pharmacol. 2008 May;154(2):299-315
references.pmid: 18311194
references.citation: Neuropsychopharmacology. 2008 Feb;33(3):643-52
references.pmid: 17473837
references.citation: Alcohol Clin Exp Res. 2004 Oct;28(10):1449-58
references.pmid: 15597076
references.citation: Genetics. 1974 May;77(1):71-94
references.pmid: 4366476
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):8809-10
references.pmid: 18583480
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3184-91
references.pmid: 15689400
references.citation: J Neurochem. 2006 Sep;98(6):1999-2012
references.pmid: 16945111
references.citation: J Neurosci. 2001 Dec 1;21(23):9265-72
references.pmid: 11717360
references.citation: Alcohol Clin Exp Res. 2004 Feb;28(2):268-78
references.pmid: 15112934
references.citation: Pharmacogenomics J. 2007 Dec;7(6):411-7
references.pmid: 17325734
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):14000-5
references.pmid: 11717458
references.citation: Neuropharmacology. 2009;56 Suppl 1:18-31
references.pmid: 18725236
references.citation: Philos Trans R Soc Lond B Biol Sci. 2008 Oct 12;363(1507):3147-58
references.pmid: 18640921
references.citation: Neuron. 2001 Dec 6;32(5):867-81
references.pmid: 11738032
references.citation: Peptides. 2007 Feb;28(2):480-3
references.pmid: 17239487
references.citation: Pharmacol Biochem Behav. 2004 Nov;79(3):439-50
references.pmid: 15582015
references.citation: Alcohol Clin Exp Res. 2005 Oct;29(10):1777-86
references.pmid: 16269907
references.citation: Genetics. 1983 Aug;104(4):619-47
references.pmid: 11813735
references.citation: Lancet Neurol. 2003 Aug;2(8):463-72
references.pmid: 12878434
references.citation: Am J Addict. 2000 Spring;9(2):103-12
references.pmid: 10934572
references.citation: Ann N Y Acad Sci. 2008 Dec;1148:136-40
references.pmid: 19120101
references.citation: Prog Neurobiol. 2007 May;82(1):33-55
references.pmid: 17383075
references.citation: J Neurogenet. 2009;23(1-2):111-9
references.pmid: 19101835
references.citation: Br Med J. 1976 May 1;1(6017):1058-61
references.pmid: 773501
references.citation: Genes Brain Behav. 2008 Aug;7(6):669-76
references.pmid: 18397381
references.citation: Alcohol Clin Exp Res. 1995 Dec;19(6):1423-9
references.pmid: 8749805