Increased alcohol seeking in mice lacking Gpr88 involves dysfunctional mesocorticolimbic networks

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• dc.contributor.author Hamida, Sami Ben
• dc.contributor.author Mendonça Netto, Sueli
• dc.contributor.author Arefin, Tanzil Mahmud
• dc.contributor.author Nasseef, Md Taufiq
• dc.contributor.author Boulos, Laura-Joy
• dc.contributor.author McNicholas, Michael
• dc.contributor.author Ehrlich, Aliza Toby
• dc.contributor.author Clarke, Eleanor
• dc.contributor.author Moquin, Luc
• dc.contributor.author Gratton, Alain
• dc.contributor.author Darcq, Emmanuel
• dc.contributor.author Harsan, Laura Adela
• dc.contributor.author Maldonado, Rafael, 1961-
• dc.contributor.author Kieffer, Brigitte L.
• dc.date.accessioned 2023-04-21T06:15:13Z
• dc.date.available 2023-04-21T06:15:13Z
• dc.date.issued 2018
• dc.description.abstract Backgound: Alcohol use disorder (AUD) is devastating and poorly treated, and innovative targets are actively sought for prevention and treatment. The orphan G protein-coupled receptor GPR88 is enriched in mesocorticolimbic pathways, and Gpr88 knockout mice show hyperactivity and risk-taking behavior, but a potential role for this receptor in drug abuse has not been examined. Methods: We tested Gpr88 knockout mice for alcohol-drinking and -seeking behaviors. To gain system-level understanding of their alcohol endophenotype, we also analyzed whole-brain functional connectivity in naïve mice using resting-state functional magnetic resonance imaging. Results: Gpr88 knockout mice showed increased voluntary alcohol drinking at both moderate and excessive levels, with intact alcohol sedation and metabolism. Mutant mice also showed increased operant responding and motivation for alcohol, while food and chocolate operant self-administration were unchanged. Alcohol place conditioning and alcohol-induced dopamine release in the nucleus accumbens were decreased, suggesting reduced alcohol reward in mutant mice that may partly explain enhanced alcohol drinking. Seed-based voxelwise functional connectivity analysis revealed significant remodeling of mesocorticolimbic centers, whose hallmark was predominant weakening of prefrontal cortex, ventral tegmental area, and amygdala connectional patterns. Also, effective connectivity from the ventral tegmental area to the nucleus accumbens and amygdala was reduced. Conclusions: Gpr88 deletion disrupts executive, reward, and emotional networks in a configuration that reduces alcohol reward and promotes alcohol seeking and drinking. The functional connectivity signature is reminiscent of alterations observed in individuals at risk for AUD. The Gpr88 gene, therefore, may represent a vulnerability/resilience factor for AUD, and a potential drug target for AUD treatment.
• dc.description.sponsorship This work was supported by National Institutes of Health/National Institute of Drug Abuse Grant No. 05010 (to BLK); National Institute on Alcohol Abuse and Alcoholism Grant No. 16658 (to BLK); the Canada Fund for Innovation and the Canada Research Chairs (to BLK); Spanish Ministerio de Economía y Competitividad-MINECO Grant No. #SAF2014-59648-P/FEDER (to RM); Instituto de Salud Carlos III RETICS-RTA Grant No. RD12/0028/0023/FEDER (to RM); Ministerio de Sanidad, Servicios Sociales e Igualdad, Plan Nacional sobre Drogas Grant No. PNSD-2013-068 (to RM); Generalitat de Catalunya AGAUR Grant No. 2014-SGR-1547 (to RM); a 2015 Catalan Institution for Research and Advanced Studies Academia Award (to RM); the Brazilian government's CAAP scholarship (Programa Ciência Sem Froteiras) (to SM-N); and the NeuroTime Erasmus+: Erasmus Mundus program of the European Commission. This publication/communication reflects the views only of the authors, and the Commission cannot be held responsible for any use which may be made of the information contained therein.
• dc.format.mimetype application/pdf
• dc.identifier.citation Ben Hamida S, Mendonça-Netto S, Arefin TM, Nasseef MT, Boulos LJ, McNicholas M, Ehrlich AT, Clarke E, Moquin L, Gratton A, Darcq E, Harsan LA, Maldonado R, Kieffer BL. Increased alcohol seeking in mice lacking Gpr88 involves dysfunctional mesocorticolimbic networks. Biol Psychiatry. 2018 Aug 1;84(3):202-12. DOI: 10.1016/j.biopsych.2018.01.026
• dc.identifier.doi http://dx.doi.org/10.1016/j.biopsych.2018.01.026
• dc.identifier.issn 0006-3223
• dc.identifier.uri http://hdl.handle.net/10230/56530
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Biol Psychiatry. 2018 Aug 1;84(3):202-12
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2014-59648-P
• dc.rights © Elsevier http://dx.doi.org/10.1016/j.biopsych.2018.01.026
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Amygdala
• dc.subject.keyword Ethanol voluntary drinking
• dc.subject.keyword Gpr88 knockout mice
• dc.subject.keyword Operant self-administration
• dc.subject.keyword Orphan G protein–coupled receptor
• dc.subject.keyword Prefrontal cortex
• dc.subject.keyword Resting-state functional magnetic resonance imaging
• dc.subject.keyword Ventral tegmental area
• dc.title Increased alcohol seeking in mice lacking Gpr88 involves dysfunctional mesocorticolimbic networks
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion