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BrainSci. 2016,6, 25 complexandperhapsmorenuanced in their consequenceontheneuroimmunesystemthanmayhave previouslybeenappreciated. Suchfindingsprompt considerationsof theworkof otherswhere it wasshownthat theneuroimmunesystemmayresponddifferently tostressdependingonthedegree andnature of prior challenges [17,20]. In related research, Buck et al. [54] reported that a single doseofethanolbefore foot-shockstresshadnoeffecton immunefunctionanddidnotenhance the stress-induced increase in IL-1βmRNAin thePVN. Ingeneral, a secondchallengebeforeor after theWCEwould seemappropriate strategy togainnewevidence for thepossibility that an initial challengeto theneuroimmunesystemmaypermitoralter inductionofselectneuroimmunemediators byasecondchallenge. Thus, sufficientpreviousactivationof immune functionbychronicethanol exposuremight render stress capable of further increasing cytokinemRNAs, aspreviouslynoted behaviorally [2,4,10,55]. Thus, identificationof the conditionsunderwhichprior stress or chronic alcoholexposurealters futureresponses toeitherchallengewouldseemtobeaproductiveavenue forresearch. Whatever future combinatorial stress studiesmight reveal, thepresent resultsnonethelessdo providean interestingcontrastwithWhitmanetal. [38],whodemonstratedthataCRF1Rantagonist prevented thecytokinemRNAincreases inducedbytheWCEalone. Itwouldalsobeof interest to identifydifferentialphysiological effectsof thedrug incontextof the twochallenges. Forexample, inconsideringthe ideathatcytokinesmayhavespecificneurophysiologicalandbehavioralactions manifest inselectbrainregions (e.g., [9,56]), itwouldseemlikely thatbroadeningtheneuroanatomical focusof theseCRF/cytokine interactionswouldvery likelybeaproductiveendeavor (seealso [57]). Collectively, thesestudies implicateCRFinvolvement in the increasedexpressionofcytokinemRNAs during the24hwithdrawal fromtheWCEandsuggest that theremaybe functional consequences. In this regard, amygdala CRF-amplifiedCCL2 regulation of alcohol self-administration [58] and elevated CRF-dependent amygdala CCL2 in human alcoholics [48] are consistent with a role of cytokines and CRF interacting to regulate alcohol consumption. These findings considered in the context of chronic alcoholdependentCCL2 inductionwithin the central amygdala and robust elevationsof theTNFreceptor (Tnfrsf1a) inrats, support the idea thatneuroimmunemechanisms in theamygdalaarepotentially critical in thebehavioralpathology inalcoholism[59]. Thus, a future experiment should be undertaken to further examine the interactions of stress andWCE across additional relevantbrainregionsandtofurther isolaterelevantmechanisms. Likewise,basedupon thereportbyJohnsonetal. [22] thatnorepinephrine-receptorantagonistsblockedthestress increase in hypothalamic IL-1βprotein inducedbyinescapable tail shock(i.e., a severestress), andthefinding that thebeta-adrenergicagonist isoproterenolcanenhance IL-1production in theamygdala following chronicstress(Porterfieldetal., [39]), theeffectsofthisdrugclassonthecytokinemRNAchangesacross differentbrainregionsafterrestraintstress inthepresenceandabsenceofWCEshouldalsobeexplored. 5.Conclusions Thepresentfindingsprovideadditionalevidenceforneuroimmuneinvolvement inbrainfunction associatedwithstressorWCEandthedifferential inductionofneuroimmunemRNAsandaddsthe novelobservationthataCRF1Rantagonist is inactiveagainstamildstress. Theresultshereinshow thatsomeneuroimmunecomponentsarereadily inducible inabrain-region-dependentmannerwhile othersarenot. Suchevidenceadds toagrowingliterature that implicatesneuroimmunedysfunction inalcoholism,othersubstanceabusedisorders,andotherneurobehavioraldisordersassociatedwith stress [7,9,27,28,32,60,61].Ourfindingsandotherspromptquestionsabouthowsomechallengesexert specificneuroimmune effectswithinneuroanatomically limited areas and suggest further studies shouldbedonetoexaminecombinationsofchallenges/conditions thought to impactonalcoholism andassociatedneuropsychiatric conditions. Moreover, our findings, considered in the context of thedocumentedrolesof theneuroimmunesystemandstress inalcoholconsumptionandnegative emotionalsymptomsduetochronicethanolconsumption[9,58,62–65], support the idea thatspecific neuroimmuneprocesses are engaged inneurobehavioral processes fundamental to alcohol abuse. 96