title: Mice Lacking GPR88 Show Motor Deficit, Improved Spatial Learning, and Low Anxiety Reversed by Delta Opioid Antagonist.
abstract: GPR88 is an orphan G protein coupled receptor highly enriched in the striatum, and previous studies have focused on GPR88 function in striatal physiology. The receptor is also expressed in other brain areas, and here we examined whether GPR88 function extends beyond striatal-mediated responses.
  
  
  
  We created Gpr88 knockout mice and examined both striatal and extrastriatal regions at molecular and cellular levels. We also tested striatum-, hippocampus-, and amygdala-dependent behaviors in Gpr88(-/-) mice using extensive behavioral testing.
  
  
  
  We found increased G protein coupling for delta opioid receptor (DOR) and mu opioid, but not other Gi/o coupled receptors, in the striatum of Gpr88 knockout mice. We also found modifications in gene transcription, dopamine and serotonin contents, and dendritic morphology inside and outside the striatum. Behavioral testing confirmed striatal deficits (hyperactivity, stereotypies, motor impairment in rotarod). In addition, mutant mice performed better in spatial tasks dependent on hippocampus (Y-maze, novel object recognition, dual solution cross-maze) and also showed markedly reduced levels of anxiety (elevated plus maze, marble burying, novelty suppressed feeding). Strikingly, chronic blockade of DOR using naltrindole partially improved motor coordination and normalized spatial navigation and anxiety of Gpr88(-/-) mice.
  
  
  
  We demonstrate that GPR88 is implicated in a large repertoire of behavioral responses that engage motor activity, spatial learning, and emotional processing. Our data also reveal functional antagonism between GPR88 and DOR activities in vivo. The therapeutic potential of GPR88 therefore extends to cognitive and anxiety disorders, possibly in interaction with other receptor systems.
authors.affiliation: 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, National de la Recherche Scientifique UMR-7104, Université de Strasbourg, Illkirch, France.
authors.forename: Aura C
authors.initials: AC
authors.lastname: Meirsman
authors.affiliation: 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, National de la Recherche Scientifique UMR-7104, Université de Strasbourg, Illkirch, France.; Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique UMR-0085, National de la Recherche Scientifique UMR-7247, Université François Rabelais de Tours, Nouzilly, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Le Merrer
authors.affiliation: Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique UMR-0085, National de la Recherche Scientifique UMR-7247, Université François Rabelais de Tours, Nouzilly, France.
authors.forename: Lucie P
authors.initials: LP
authors.lastname: Pellissier
authors.affiliation: Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale UMR-894 - Université Paris Descartes, Paris, France.
authors.forename: Jorge
authors.initials: J
authors.lastname: Diaz
authors.affiliation: Département de Neurobiologie des rythmes, Institut des Neurosciences Cellulaires et Intégratives, National de la Recherche Scientifique UPR-3212, Université de Strasbourg, Strasbourg, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Clesse
authors.affiliation: 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, National de la Recherche Scientifique UMR-7104, Université de Strasbourg, Illkirch, France.. Electronic address: Brigitte.Kieffer@douglas.mcgill.ca.
authors.forename: Brigitte L
authors.initials: BL
authors.lastname: Kieffer
authors.affiliation: 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, National de la Recherche Scientifique UMR-7104, Université de Strasbourg, Illkirch, France.; Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique UMR-0085, National de la Recherche Scientifique UMR-7247, Université François Rabelais de Tours, Nouzilly, France.
authors.forename: Jérôme A J
authors.initials: JA
authors.lastname: Becker
mesh_terms: D000679:Amygdala / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009069:Movement Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D065853:Spatial Learning / Q000187:drug effects / Q000502:physiology*
chemical_list: C485998:Gpr88 protein, mouse; D009292:Narcotic Antagonists; D043562:Receptors, G-Protein-Coupled; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D012701:Serotonin; D009271:Naltrexone; C055382:naltrindole; D004298:Dopamine
keywords: Ethological scoring of anxiety; GPR88 agonist-induced GTPγS binding; Gene clustering; Medium spiny neurons; Psychiatric disorders; Spatial learning