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. 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.
