Sami Ben Hamida1, Sueli Mendonça-Netto2, Tanzil Mahmud Arefin3, Md Taufiq Nasseef4, Laura-Joy Boulos1, Michael McNicholas4, Aliza Toby Ehrlich1, Eleanor Clarke4, Luc Moquin4, Alain Gratton4, Emmanuel Darcq4, Laura Adela Harsan5, Rafael Maldonado2, Brigitte Lina Kieffer6. 1. Département de Médecine Translationnelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U-964, Centre National de la Recherche Scientifique UMR-7104, University of Strasbourg, Illkirch-Graffenstaden, Strasbourg, France; Douglas Mental Health Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada. 2. Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. 3. Department of Radiology, Medical Physics, Medical Center University of Freiburg, Faculty of Medicine, Freiburg, Germany; Bernstein Center Freiburg, University of Freiburg, Freiburg, Germany; Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, New York. 4. Douglas Mental Health Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada. 5. Engineering Science, Computer Science and Imaging Laboratory, Integrative Multimodal Imaging in Healthcare, University of Strasbourg - Centre National de la Recherche Scientifique, Strasbourg, France; Department of Biophysics and Nuclear Medicine, Faculty of Medicine, University Hospital Strasbourg, Strasbourg, France; Department of Radiology, Medical Physics, Medical Center University of Freiburg, Faculty of Medicine, Freiburg, Germany. 6. Département de Médecine Translationnelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U-964, Centre National de la Recherche Scientifique UMR-7104, University of Strasbourg, Illkirch-Graffenstaden, Strasbourg, France; Douglas Mental Health Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada. Electronic address: brigitte.kieffer@douglas.mcgill.ca.
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.
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.
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