title: GPR88 in A2AR Neurons Enhances Anxiety-Like Behaviors.
abstract: GPR88 is an orphan G-protein-coupled receptor highly expressed in striatal dopamine D1 (receptor) R- and D2R-expressing medium spiny neurons. This receptor is involved in activity and motor responses, and we previously showed that this receptor also regulates anxiety-like behaviors. To determine whether GPR88 in D2R-expressing neurons contributes to this emotional phenotype, we generated conditional Gpr88 knock-out mice using adenosine A2AR (A2AR)-Cre-driven recombination, and compared anxiety-related responses in both total and A2AR-Gpr88 KO mice. A2AR-Gpr88 KO mice showed a selective reduction of Gpr88 mRNA in D2R-expressing, but not D1R-expressing, neurons. These mutant mice showed increased locomotor activity and decreased anxiety-like behaviors in light/dark and elevated plus maze tests. These phenotypes were superimposable on those observed in total Gpr88 KO mice, demonstrating that the previously reported anxiogenic activity of GPR88 operates at the level of A2AR-expressing neurons. Further, A2AR-Gpr88 KO mice showed no change in novelty preference and novelty-suppressed feeding, while these responses were increased and decreased, respectively, in the total Gpr88 KO mice. Also, A2AR-Gpr88 KO mice showed intact fear conditioning, while the fear responses were decreased in total Gpr88 KO. We therefore also show for the first time that GPR88 activity regulates approach behaviors and conditional fear; however, these behaviors do not seem mediated by receptors in A2AR neurons. We conclude that Gpr88 expressed in A2AR neurons enhances ethological anxiety-like behaviors without affecting conflict anxiety and fear responses.
authors: 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, CNRS UMR-7104, Université de Strasbourg , 67400 Illkirch-Graffenstaden, France.
authors: Aura Carole
authors: AC
authors: Meirsman
authors: 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, CNRS UMR-7104, Université de Strasbourg , 67400 Illkirch-Graffenstaden, France.
authors: Anne
authors: A
authors: Robé
authors: Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles , 1070 Brussels, Belgium.
authors: Alban
authors: 0000-0002-0682-5877
authors: A
authors: de Kerchove d'Exaerde
authors: 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, CNRS UMR-7104, Université de Strasbourg, 67400 Illkirch-Graffenstaden, France; Department of Psychiatry, Faculty of Medicine, Douglas Research Center, McGill University, Montréal, Québec H4H 1R3, Canada.
authors: Brigitte Lina
authors: BL
authors: Kieffer
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D001362:Avoidance Learning; D001921:Brain / Q000378:metabolism; D002755:Choice Behavior / Q000502:physiology; D003213:Conditioning, Psychological / Q000502:physiology; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology; D005247:Feeding Behavior / Q000502:physiology; D005260:Female; D008297:Male; D008822:Mice, Transgenic; D009043:Motor Activity; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
chemical_list: C000600618:DRD2 protein, mouse; C583261:Drd1 protein, mouse; C485998:Gpr88 protein, mouse; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled
keywords: D2R-medium spiny neurons; G-protein-coupled receptors; amygdale; anxiety-like behavior; striatum