Overall The Alcohol Research Center of The Scripps Research Institute (TSRI-ARC) proposes to continue its interdisciplinary program focused on the theme of the central nervous system effects of alcohol. For this renewal application, the TSRI-ARC (P60) will consist of 9 components, including 3 Cores (Administrative, Animal Models and Information Dissemination) and 5 Research Projects (Molecular, Neurophysiology, Neurocircuitry,Neurochemistry,andClinical).TheoverallhypothesisoftheTSRI-ARCasanintegratedwhole isthatthecentralstresssystemsbecomeactivatedduringthewithdrawal/negativeaffectstageandpersistinto protracted abstinence (in the preoccupation/anticipation stage), and such neuroadaptive changes associated with chronic drinking also produce an evolving set of neurobehavioral symptoms that include hypohedonia, anxiety,irritability,negativeaffect,hyperarousal,andsleepdisturbances,allofwhichcontributetorelapseand impede recovery. The specific subhypotheses are: 1) The transition from acute withdrawal to protracted abstinence includes compulsive-like responding for ethanol and negative emotional behavior that involves changesininterconnectedbrainareas:theextendedamygdala,themedialprefrontalcortex,andtheanterior insula. 2) The altered activity in these circuits reflects actions of stress-related system including glucocorticoids, serotonin, hypocretin, and corticotropin-releasing factor. 3) Cellular neuroadaptations are associated with altered dynamics of the microtubule cytoskeleton, which may in turn mediate the structural remodelingofneuronaldendrites.4)NovelneurobiologicaltargetsidentifiedbytheTSRI-ARCwillsignificantly attenuate the reinstatement of compulsive-like alcohol seeking, excessive drinking, and anxiety-like behavior;? and5)drugcandidatesforthesetargetswillbeactiveinahumanlabmodelofprotractedabstinencewhere they will reduce drinking, craving, negative affect, and executive function deficits. We believe the proposed innovative approaches for testing these hypotheses will provide valuable insight into novel approaches for treatingalcoholismandrelapseinthehumans. TheTSRI-ARCalsosupportstheCenteratLarge,whichincludes:31R01s,10R21s,3U01s,1U24,2R37s, 2 R13s, and one T32 NIAAA training grant associated with this grant. Members of the Center at Large have access to the Cores of the TSRI-ARC, the NIAAA Integrative Neuroscience Initiative on Alcoholism (INIA) Consortia.TrainingandinformationdisseminationtotheSanDiegocommunitywillbeeffectedbythetraining opportunitiesoftheCenterincludingaT32NIAAAtraininggrantandtheInformationDisseminationCore.
This Center proposes to continue its interdisciplinary program focused on the theme of the central nervous system?s effects of alcohol. Dysregulation in the brain stress system mediates the transition from acute withdrawaltoprotractedabstinencetopromotevulnerabilitytorelapse,andourARCisdesignedtotranslate our discoveries of preclinical TSRI-ARC studies for potential therapeutic use using proof-of-concept human laboratorytesting.Webelievethisprojectwillprovidevaluableinsightintonovelapproachesforunderstanding andtreatingalcoholisminthehumanpopulation.
|Matzeu, Alessandra; Terenius, Lars; Martin-Fardon, Remi (2018) Exploring Sex Differences in the Attenuation of Ethanol Drinking by Naltrexone in Dependent Rats During Early and Protracted Abstinence. Alcohol Clin Exp Res 42:2466-2478|
|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|
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