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brain sciences Article StressandWithdrawalfromChronicEthanolInduce SelectiveChanges inNeuroimmunemRNAsin DifferingBrainSites DarinJ.Knapp1,2,†,*,KathrynM.Harper1,†,BuddyA.Whitman1,3,†,ZacharyZimomra1 and GeorgeR.Breese1,2,3,4,5 1 BowlesCenter forAlcoholStudies,TheUniversityofNorthCarolinaatChapelHill,CB7178,ChapelHill, NC27599-7178,USA;Kathryn_harper@med.unc.edu(K.M.H.);bawhitman@gmail.com(B.A.W.); zzimomra@kent.edu(Z.Z.);george_breese@med.unc.edu(G.R.B.) 2 DepartmentofPsychiatry,TheUniversityofNorthCarolinaatChapelHill,CB7178,ChapelHill, NC27599-7178,USA 3 CurriculuminNeurobiology,TheUniversityofNorthCarolinaatChapelHill,CB7178,ChapelHill, NC27599-7178,USA 4 DepartmentofPharmacology,TheUniversityofNorthCarolinaatChapelHill,CB7178,ChapelHill, NC27599-7178,USA 5 UNCNeuroscienceCenter,TheUniversityofNorthCarolinaatChapelHill,CB7178,ChapelHill, NC27599-7178,USA * Correspondence:Darin_knapp@med.unc.edu;Tel.:+1-919-966-0505;Fax:+1-919-966-5679 † Theseauthorscontributedequally to thiswork. AcademicEditor:DonnaGruol Received: 16April2016;Accepted: 20 July2016;Published: 27 July2016 Abstract:Stress isastrongrisk factor inalcoholic relapseandmayexerteffects thatmimicaspectsof chronicalcoholexposureonneurobiological systems.With theneuroimmunesystembecominga prominent focus in thestudyof theneurobiological consequencesof stress, aswellaschronicalcohol exposureprovingtobeavaluablefocusinthisregard, thepresentstudysoughttocomparetheeffects of stress andchronic ethanol exposureon inductionof components of theneuroimmune system. Ratswereexposed toeither1hexposure toamild stressor (restraint) or exposure towithdrawal from15daysofchronicalcoholexposure (i.e.,withdrawal fromchronicethanol,WCE)andassessed forneuroimmunemRNAsinbrain.Restraint stressaloneelevatedchemokine(C–Cmotif) ligand2 (CCL2), interleukin-1-beta (IL-1β), tumornecrosis factoralpha (TNFα) andtoll-like receptor4 (TLR4) mRNAsinthecerebral cortexwithin4hwithareturntoacontrol levelby24h. These increaseswere notaccompaniedbyan increase incorrespondingproteins. Withdrawal fromWCEalsoelevated cytokines,butdidsotovaryingdegreesacrossdifferentcytokinesandbrainregions. In thecortex, stressandWCEinducedCCL2,TNFα, IL-1β, andTLR4mRNAs. In thehypothalamus,onlyWCE inducedcytokines (CCL2andIL-1β)while in thehippocampus,WCEstrongly inducedCCL2while stressandWCEinducedIL-1β. In theamygdala,onlyWCEinducedCCL2. Finally—basedonthe previouslydemonstratedroleofcorticotropin-releasingfactor1(CRF1)receptor inhibitioninblocking WCE-inducedcytokinemRNAs—theCRF1receptorantagonistCP154,526wasadministered toa subgroupofstressedratsandfoundtobeinactiveagainst inductionofCCL2,TNFα,or IL-1βmRNAs. Thesedifferential results suggest that stressandWCEmanifestbroadneuroimmuneeffects inbrain dependingonthecytokineandbrainregion,andthatCRFinhibitionmaynotbearelevantmechanism innon-alcoholexposedanimals.Overall, theseeffectsarecomplex in termsof theirneuroimmune targets and neuroanatomical specificity. Further investigation of the differential distribution of cytokine inductionacrossneuroanatomical regions, individualcell types (e.g.,neuronalphenotypes andglia), severityof chronic alcohol exposure, aswell as acrossdiffering stress typesmayprove useful inunderstandingdifferentialmechanismsof inductionandfor targetingselect systemsfor pharmacotherapeutic intervention inalcoholism. BrainSci. 2016,6, 25 83 www.mdpi.com/journal/brainsci