title: Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food.
abstract: Mu opioid receptors (MORs) are central to pain control, drug reward, and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in gamma-aminobutyric acidergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward.
  
  
  
  We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in gamma-aminobutyric acidergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology, and microdialysis; probed neuronal activation by c-Fos immunohistochemistry and resting-state functional magnetic resonance imaging; and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food.
  
  
  
  Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area, local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, and neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures.
  
  
  
  Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus, beyond a well-established role in reward processing, operating at the level of local ventral tegmental area neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors.
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; Douglas Mental Health Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
authors.forename: Pauline
authors.initials: P
authors.lastname: Charbogne
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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Gardon
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-García
authors.affiliation: Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, United Kingdom.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Keyworth
authors.affiliation: Section on Neuronal Structure, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Aya
authors.initials: A
authors.lastname: Matsui
authors.affiliation: Department of Radiology, Medical Physics, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Mechling
authors.affiliation: Department of Radiology, Medical Physics, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bienert
authors.affiliation: Douglas Mental Health Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
authors.forename: Md Taufiq
authors.initials: MT
authors.lastname: Nasseef
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.
authors.forename: Anne
authors.initials: A
authors.lastname: Robé
authors.affiliation: Douglas Mental Health Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
authors.forename: Luc
authors.initials: L
authors.lastname: Moquin
authors.affiliation: Douglas Mental Health Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Darcq
authors.affiliation: Douglas Mental Health Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
authors.forename: Sami
authors.initials: S
authors.lastname: Ben Hamida
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Robledo
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.
authors.forename: Audrey
authors.initials: A
authors.lastname: Matifas
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; Laboratoire de Neurosciences Cognitives et Adaptatives, Université de Strasbourg Faculté de Psychologie, Strasbourg, France; Laboratoire de Neurosciences Cognitives et Adaptatives, UMR 7364, Centre National de la Recherche Scientifique, Strasbourg, France.
authors.forename: Katia
authors.initials: K
authors.lastname: Befort
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.
authors.forename: Claire
authors.initials: C
authors.lastname: Gavériaux-Ruff
authors.affiliation: Laboratory of Engineering, Informatics and Imaging, Integrative Multimodal Imaging in Healthcare, UMR 7357, University of Strasbourg, Strasbourg, France; University Hospital Strasbourg, Department of Biophysics and Nuclear Medicine, Strasbourg, France; Department of Radiology, Medical Physics, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany.
authors.forename: Laura-Adela
authors.initials: LA
authors.lastname: Harsan
authors.affiliation: Department of Radiology, Medical Physics, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: von Elverfeldt
authors.affiliation: Department of Radiology, Medical Physics, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Hennig
authors.affiliation: Douglas Mental Health Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
authors.forename: Alain
authors.initials: A
authors.lastname: Gratton
authors.affiliation: Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Kitchen
authors.affiliation: Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, United Kingdom; Institute of Medical and Biomedical Education, St. George's University of London, London, United Kingdom.
authors.forename: Alexis
authors.initials: A
authors.lastname: Bailey
authors.affiliation: Section on Neuronal Structure, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Veronica A
authors.initials: VA
authors.lastname: Alvarez
authors.affiliation: Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
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; Douglas Mental Health Institute, Department of Psychiatry, 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; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005247:Feeding Behavior / Q000502:physiology*; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology*; D003932:Heroin / Q000008:administration & dosage*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000008:administration & dosage; D009042:Motivation / Q000187:drug effects / Q000502:physiology*; D009294:Narcotics / Q000008:administration & dosage*; D009434:Neural Pathways / Q000502:physiology; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology
chemical_list: D009294:Narcotics; D017450:Receptors, Opioid, mu; D003932:Heroin; D009020:Morphine
keywords: Conditional gene knockout; Dopamine; Motivation; Mu opioid receptor; Opiate; Reward