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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Comprehensive Center (P60)
Project #
5P60AA006420-37
Application #
9836781
Study Section
Special Emphasis Panel (ZAA1)
Project Start
Project End
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
37
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Kononoff, Jenni; Melas, Philippe A; Kallupi, Marsida et al. (2018) Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood. Sci Rep 8:13893
Verheij, Michel M M; Contet, Candice; Karel, Peter et al. (2018) Median and Dorsal Raphe Serotonergic Neurons Control Moderate Versus Compulsive Cocaine Intake. Biol Psychiatry 83:1024-1035
Schmeichel, Brooke E; Matzeu, Alessandra; Koebel, Pascale et al. (2018) Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats. Neuropsychopharmacology 43:2373-2382
Kononoff, Jenni; Kallupi, Marsida; Kimbrough, Adam et al. (2018) Systemic and Intra-Habenular Activation of the Orphan G Protein-Coupled Receptor GPR139 Decreases Compulsive-Like Alcohol Drinking and Hyperalgesia in Alcohol-Dependent Rats. eNeuro 5:
Kreisler, A D; Mattock, M; Zorrilla, E P (2018) The duration of intermittent access to preferred sucrose-rich food affects binge-like intake, fat accumulation, and fasting glucose in male rats. Appetite 130:59-69
Varodayan, F P; Khom, S; Patel, R R et al. (2018) Role of TLR4 in the Modulation of Central Amygdala GABA Transmission by CRF Following Restraint Stress. Alcohol Alcohol 53:642-649
McClatchy, Daniel B; Yu, Nam-Kyung; Martínez-Bartolomé, Salvador et al. (2018) Structural Analysis of Hippocampal Kinase Signal Transduction. ACS Chem Neurosci :
Berger, Anthony L; Henricks, Angela M; Lugo, Janelle M et al. (2018) The Lateral Habenula Directs Coping Styles Under Conditions of Stress via Recruitment of the Endocannabinoid System. Biol Psychiatry 84:611-623
Mason, Barbara J; Quello, Susan; Shadan, Farhad (2018) Gabapentin for the treatment of alcohol use disorder. Expert Opin Investig Drugs 27:113-124
Varodayan, Florence P; Sidhu, Harpreet; Kreifeldt, Max et al. (2018) Morphological and functional evidence of increased excitatory signaling in the prelimbic cortex during ethanol withdrawal. Neuropharmacology 133:470-480

Showing the most recent 10 out of 211 publications