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BrainSci. 2016,6, 25 Itmaybeproductive toaskwhetherriskof relapse inalcoholics relates todifferentialneuroimmune responses tostressasaconsequenceofpriorchronicethanolexposurehistoryandto furtherdevelop animalmodelsaroundthisconcept. Thesefindingsalsohavepotentiallybroader implications in that neuroimmunesystemdysfunctionhasbeen implicated inotherneurobehavioraldisordersaswell includinginsomnia[33],depression[31,34,66–68],andanxiety[6,35,60,69]. Inparticular,neuroimmune system regulation of anxiety associatedwith chronic alcohol andwithdrawal are notable [8,9,49]. Identifyingoverlappingandindependentneuroimmuneprocessesacross thesepathologieswouldbe worthyof furtherstudy. While thecurrentstudiesdocument thatneuralmechanismsassociatedwithstressmayat least partiallyoverlapwith themechanismsthatdrivecytokinemRNAexpressionafterWCE, theprofileof effects shownherein for the twochallengesdonotcompletelyoverlapacrossneuroimmunemarkeror brainregion. Further, theresponsesreportedhereinwereelicitedwithrelatively limitedchallenges (i.e., just1hofstressor15daysofexposure toethanol). Thus, itmaybevaluable toexaminesimilar endpoints following exposure to themore chronic and/or severe challenges/stressors that define manyneurobehavioraldisorders. Of these effects, one couldaskwhichare transient (yetperhaps behaviorallyrelevant),andwhichinducelongtermmaladaptationsthatinfluencebehavioralpathology. ByunderstandinghowstressandWCEengage theneuroimmunesystem,andworsenssymptoms, therapeuticoptionsbywhichtomitigatestress-associatedneuroimmunedysfunctionindrugaddiction andothercentralnervoussystemdisorderscouldemerge[29,32]. Acknowledgments:Theauthorswishto thankA.LeslieMorrowforgenerouscontributionof time, spaceand equipment to thisproject. Wealso acknowledgeBobAngel andToddO’Buckley for their excellent technical assistance. ThisworkwassupportedbytheNational InstitutesofHealth,National InstituteonAlcoholAbuseand Alcoholism(AA11605,AA14949,AA17462,AA021275,AA007573),andtheBowlesCenter forAlcoholStudies. AuthorContributions:D.J.K.participatedinallphasesof theresearch,was leadwriteronthemanuscriptand co-wrotethefundingbehindtheprojectwithG.R.B.;K.M.H.,B.A.W.,andZ.Z.assistedwithdietarymanipulations, assaysandstatistical summaries,whileB.A.W.preparedaninitial summarydraftof themanuscript.Allauthors reviewedandeditedmultipledraftsof themanuscript. Conflictsof Interest:Theauthorsdeclarenoconflictof interest. Abbreviations ANOVA analysisofvariance CCL2 chemokine (C-Cmotif) ligand2 CRF corticotropinreleasinghormone IL-1β interleukin-1beta mRNA messengerribonucleicacid S-D Sprague-Dawley TLR4 toll-likereceptor4 TNFα tumornecrosis factor-alpha WCE withdrawal fromchronicethanol qPCR quantitativepolymerasechainreaction References 1. Overstreet,D.H.;Knapp,D.J.;Breese,G.R.Accentuateddecrease insocial interaction inrats subjected to repeatedethanolwithdrawals.Alcohol. Clin. Exp.Res. 2002,26, 1259–1268. [CrossRef] [PubMed] 2. Rassnick, S.; Heinrichs, S.C.; Britton,K.T.; Koob,G.F.Microinjection ofCRFantagonist into the central nucleusof theamygdalareversesanxiogenic-likeeffectsofethanolwithdrawal.BrainRes. 1993,605, 25–32. [CrossRef] 3. Valdez,G.R.;Zorrilla,E.P.;Roberts,A.J.;Koob,G.F.Antagonismofcorticotropinreleasingfactorattenuates theenhancedresponsiveness tostressobservedduringprotractedethanolabstinence.Alcohol2003,29, 55–60. [CrossRef] 97