Abstract Acentralprobleminthetreatmentofethanol(EtOH)addictionistheprevalenceofrelapsetoEtOHuseeven after protracted intervals of forced or self-imposed abstinence. Advances have been made in elucidating the neurocircuitrythatmediatescravingandEtOHseeking,whichprovidesinsightsintotheneurobiologicalbasis of relapse. Functional brain imaging in humans and studies that use c-fos expression as a marker of neural activation in rodents implicate interconnected cortical and limbic brain regions in response to drug cue-, drug priming-, and stress-induced reinstatement. Major components of this circuitry include the medial prefrontal cortex(mPFC),basolateralamygdala(BLA),centralnucleusoftheamygdala(CeA),bednucleusofthestria terminalis(BNST),ventraltegmentalarea(VTA),nucleusaccumbens(NAC),hippocampus,thalamus(THAL), anddorsalstriatum.Thehypocretin(Hcrt)systemregulatesawiderangeofphysiologicalprocesses,including feeding,energymetabolism,arousal,andstress,andisrecruitedbydrugsofabuse.Ofinterestforthepresent proposal, recent studies have demonstrated a critical contribution of Hcrt in the modulation of stress and a possibleanxiolyticeffectofHcrtreceptor(Hcrt-r)antagonists.Furthermore,wehavecollectedconvincingdata that EtOH exposure recruits the Hcrt system. Specifically, we found that downregulation of Hcrt mRNA was observed in the lateral hypothalamus (the major source of Hcrt production) of animals that had a history of EtOHdependenceandthatblockadeofHcrt-rselectivelyreversedEtOHseekingvs.naturalrewardseeking. Chronic drug use is well known to dysregulate stress responses that are mediated by corticotropin-releasing factor (CRF) in both the hypothalamic-pituitary-adrenal (HPA) axis and extrahypothalamic brain stress areas outside the HPA axis (e.g., CeA and BNST). With repeated cycles of drug use, the HPA axis becomes hyporesponsive, accompanied by an increase in the extrahypothalamic CRF stress system response (i.e., CRF-CRF1 receptors). Importantly, a Hcrt/CRF interaction exists, and it has been proposed that Hcrt modulation of CRF neurons participates in the chronic relapsing, negative affective states that characterize drugaddiction.ConverginglinesofevidencefromhumanandanimalstudiessuggestthatimpairmentofmPFC functionduetodrugsofabuseexposureisakeyfactorinthetransitionfromgoal-directedtocompulsivedrug seeking.ThemPFCcontainsCRFinterneurons,andHcrtneuronsprojecttothemPFC.Thisproposalwilltest thehypothesisthatahistoryofEtOHdependencedysregulatesHcrtanditsinteractionwithCRFinthemPFC, particularly the infralimbic area (IL), and if this dysfunction will predict compulsive EtOH seeking (relapse) precipitatedbystressduringacute/early,late,andprotractedabstinencethatcouldexplaincompulsiveEtOH seeking.Fromtheperspectiveoffuturemedicationdevelopment,thisprojectislikelytohighlightapreviously unrecognizedmechanismintheetiologyofcompulsiveEtOHseekingduringabstinence;?ultimatelyleadingto theidentificationofnoveltherapeutictargetsforthepreventionofEtOHrelapse.