title: A novel anxiogenic role for the delta opioid receptor expressed in GABAergic forebrain neurons.
abstract: BACKGROUND
  The delta opioid receptor (DOR) is broadly expressed throughout the nervous system; it regulates chronic pain, emotional responses, motivation, and memory. Neural circuits underlying DOR activities have been poorly explored by genetic approaches. We used conditional mouse mutagenesis to elucidate receptor function in GABAergic neurons of the forebrain.
  
  
  METHODS
  We characterized DOR distribution in the brain of Dlx5/6-CreXOprd1(fl/fl) (Dlx-DOR) mice and tested main central DOR functions through behavioral testing.
  
  
  RESULTS
  The DOR proteins were strongly deleted in olfactory bulb and striatum and remained intact in cortex and basolateral amygdala. Olfactory perception, circadian activity, and despair-like behaviors were unchanged. In contrast, locomotor stimulant effects of SNC80 (DOR agonist) and SKF81297 (D1 agonist) were abolished and increased, respectively. The Dlx-DOR mice showed lower levels of anxiety in the elevated plus maze, opposing the known high anxiety in constitutive DOR knockout animals. Also, Dlx-DOR mice reached the food more rapidly in a novelty suppressed feeding task, despite their lower motivation for food reward observed in an operant paradigm. Finally, c-fos protein staining after novelty suppressed feeding was strongly reduced in amygdala, concordant with the low anxiety phenotype of Dlx-DOR mice.
  
  
  CONCLUSIONS
  We demonstrate that DORs expressed in the forebrain mediate the described locomotor effect of SNC80 and inhibit D1-stimulated hyperactivity. Our data also reveal an unanticipated anxiogenic role for this particular DOR subpopulation, with a potential novel adaptive role. In emotional responses, DORs exert dual anxiolytic and anxiogenic roles, both of which may have implications in the area of anxiety disorders.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Chu Sin Chung
authors.affiliation: Department of Biochemistry and Physiology, Faculty of Health and Medical Sciences, Institute of Biosciences and Medicine, University of Surrey, Guildford, Surrey, United Kingdom.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Keyworth
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Martin-Garcia
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Charbogne
authors.affiliation: Douglas Hospital Research Center, Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Darcq
authors.affiliation: Department of Biochemistry and Physiology, Faculty of Health and Medical Sciences, Institute of Biosciences and Medicine, University of Surrey, Guildford, Surrey, United Kingdom.
authors.forename: Alexis
authors.initials: A
authors.lastname: Bailey
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Filliol
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Matifas
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Department of Molecular and Cellular Physiology, Department of Neurosurgery, Stanford Neurosciences Institute, Stanford University, Palo Alto, California.
authors.forename: Grégory
authors.initials: G
authors.lastname: Scherrer
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch, France.
authors.forename: Abdel-Mouttalib
authors.initials: AM
authors.lastname: Ouagazzal
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Gaveriaux-Ruff
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch, France.
authors.forename: Katia
authors.initials: K
authors.lastname: Befort
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.affiliation: Department of Biochemistry and Physiology, Faculty of Health and Medical Sciences, Institute of Biosciences and Medicine, University of Surrey, Guildford, Surrey, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Kitchen
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch, France.; Douglas Hospital Research Center, Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.. Electronic address: brigitte.kieffer@douglas.mcgill.ca.
authors.forename: Brigitte L
authors.initials: BL
authors.lastname: Kieffer
mesh_terms: D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D001522:Behavior, Animal / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009042:Motivation / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects; D009830:Olfactory Bulb / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D016548:Prosencephalon / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000819:agonists; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; D001552:Benzazepines; D018491:Dopamine Agonists; D010879:Piperazines; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017465:Receptors, Opioid, delta; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; C067113:SK&F 81297
keywords: Conditional gene knockout; Delta opioid receptor; Emotion; GABAergic forebrain neurons; Locomotion; Motivation