title: Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward.
abstract: μ-opioid receptors (MORs) are necessary for the analgesic and addictive effects of opioids such as morphine, but the MOR-expressing neuronal populations that mediate the distinct opiate effects remain elusive. Here we devised a new conditional bacterial artificial chromosome rescue strategy to show, in mice, that targeted MOR expression in a subpopulation of striatal direct-pathway neurons enriched in the striosome and nucleus accumbens, in an otherwise MOR-null background, restores opiate reward and opiate-induced striatal dopamine release and partially restores motivation to self administer an opiate. However, these mice lack opiate analgesia or withdrawal. We used Cre-mediated deletion of the rescued MOR transgene to establish that expression of the MOR transgene in the striatum, rather than in extrastriatal sites, is needed for the restoration of opiate reward. Our study demonstrates that a subpopulation of striatal direct-pathway neurons is sufficient to support opiate reward-driven behaviors and provides a new intersectional genetic approach to dissecting neurocircuit-specific gene function in vivo.
authors.affiliation: 1] Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA. [2] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [3] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [4] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Cui
authors.affiliation: 1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [2] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [3] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [4] Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Sean B
authors.initials: SB
authors.lastname: Ostlund
authors.affiliation: Department of Psychology, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Alex S
authors.initials: AS
authors.lastname: James
authors.affiliation: 1] Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA. [2] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [3] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [4] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Chang Sin
authors.initials: CS
authors.lastname: Park
authors.affiliation: 1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [2] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [3] Intellectual Development and Disabilities Research Center, Semel Institute for Neuroscience, University of California, Los Angeles, Los Angeles, California, USA. [4] Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Weihong
authors.initials: W
authors.lastname: Ge
authors.affiliation: 1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [2] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [3] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [4] Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Kristofer W
authors.initials: KW
authors.lastname: Roberts
authors.affiliation: 1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [2] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [3] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [4] Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Nitish
authors.initials: N
authors.lastname: Mittal
authors.affiliation: 1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [2] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [3] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [4] Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Niall P
authors.initials: NP
authors.lastname: Murphy
authors.affiliation: 1] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [2] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [3] Intellectual Development and Disabilities Research Center, Semel Institute for Neuroscience, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cepeda
authors.affiliation: Institut de Génétique et Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (CNRS)/Institut National de la Santé et de la Recherche Médicale (INSERM)/Université de Strasbourg (UdS), Illkirch, France.
authors.forename: Brigitte L
authors.initials: BL
authors.lastname: Kieffer
authors.affiliation: 1] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [2] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [3] Intellectual Development and Disabilities Research Center, Semel Institute for Neuroscience, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Levine
authors.affiliation: 1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [2] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [3] Department of Psychology, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: James David
authors.initials: JD
authors.lastname: Jentsch
authors.affiliation: 1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [2] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [3] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [4] Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Walwyn
authors.affiliation: 1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [2] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [3] Intellectual Development and Disabilities Research Center, Semel Institute for Neuroscience, University of California, Los Angeles, Los Angeles, California, USA. [4] Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA. [5] Translational Stem Cell Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yi E
authors.initials: YE
authors.lastname: Sun
authors.affiliation: 1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [2] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [3] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [4] Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Evans
authors.affiliation: 1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [2] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [3] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [4] Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Nigel T
authors.initials: NT
authors.lastname: Maidment
authors.affiliation: 1] Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA. [2] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [3] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [4] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004745:Enkephalins / Q000235:genetics; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D009434:Neural Pathways / Q000502:physiology*; D009474:Neurons / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000188:drug therapy / Q000235:genetics; D010147:Pain Measurement / Q000187:drug effects; D011498:Protein Precursors / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000378:metabolism*; D012201:Reward; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy
chemical_list: D004745:Enkephalins; D009292:Narcotic Antagonists; D009294:Narcotics; D011498:Protein Precursors; D017450:Receptors, Opioid, mu; D049452:Green Fluorescent Proteins; D009270:Naloxone; D009020:Morphine; C033660:preproenkephalin; D004298:Dopamine