DOCSLIB.ORG

Development and Characterization of Novel Allosteric Modulators Acting on Metabotropic Glutamate Receptors 2 and 3

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Development and Characterization of Novel Allosteric Modulators Acting on Metabotropic Glutamate Receptors 2 and 3 DEVELOPMENT AND CHARACTERIZATION OF NOVEL ALLOSTERIC MODULATORS ACTING ON METABOTROPIC GLUTAMATE RECEPTORS 2 AND 3 By Cody James Wenthur Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in PHARMACOLOGY August, 2015 Nashville, Tennessee Approved: Professor Craig W. Lindsley Professor P. Jeffrey Conn Professor Randy D. Blakely Professor Aaron B. Bowman Professor Joey V. Barnett To my beloved wife, Brielle, the author of my happiness and To the untested truths, out beyond the ragged frontier ii ACKNOWLEDGEMENTS The following work was generously supported by financial assistance from the Howard Hughes Medical Institute / Vanderbilt University Medical Center Certificate Program in Molecular Medicine, the NIGMS Vanderbilt Pre-Doctoral Pharmacology Training Program, NCATS funds awarded through the Vanderbilt Institute for Clinical and Translational Research, the NIH Clinical Research Loan Repayment Program, and the NIH Molecular Libraries Program. These visionary awards enable scientific studies at the boundaries between disciplines, emphasize the importance of applied science, and champion the development of the next generation of translational researchers. It is no overstatement to say that without such incredible backing, this manuscript would never have come to fruition. Likewise, the continuous guidance and assistance of my committee members was essential. The insights and suggestions of Drs. Randy Blakely, Aaron Bowman, and Joey Barnett, along with their unwavering commitment to helping me pursue my career and research goals, were integral to the success of the project. The current and former chairs of my committee, Drs. Jeff Conn and Scott Daniels, respectively, have both gone far beyond the simple requirements of their positions, providing me with access to their labs, equipment, and expertise – I will always be grateful for the opportunity to have learned from them. I especially thank my mentor, Dr. Craig Lindsley, for always allowing me to branch out and explore new avenues for the project, for allowing me time to pursue iii additional techniques, for letting me pursue dissertation-enriching opportunities and grants, and for providing a professional, friendly atmosphere where a diverse group of students, post-docs, staff scientists, and faculty could work together to improve each other and pursue common goals. Those wonderful colleagues in the Lindsley lab, and throughout the Vanderbilt Center for Neuroscience Drug Discovery, are particularly worth thanking here. There are quite literally dozens of individuals in the VCNDD who have given me individual help over the years, including a number of undergraduate, rotation, and exchange students. No problem was ever too complex or too trivial for them to assist me with, and I am indebted to them all for their tireless support. While I do not have space to thank all of the VCNDD members individually, I must specifically thank Adam Walker, who was instrumental in the design and implementation of the electrophysiology experiments described within, along with Peter Martin, Lana Olson, Hyekyung Plumley, Douglas Sheffler, Ryan Morrison, Colleen Niswender, Jerri Rook, and Kyle Emmitte. Finally, I thank my friends and family, both old and new, for their unwavering faith in my success and their unfathomable ability to improve my life with every passing day. While no mere acknowledgment can suffice for any of the contributions mentioned on this page, all of my attempts to quantify the specific ways in which these individuals have enriched my existence seem especially inadequate. So to my parents, grandparents, brothers, cousins, aunts, uncles, in-laws, brunch-eaters, band-players, cast-mates and soul-mate, I will simply thank you for everything and hope that it is enough. iv PREFACE Note Regarding the Numbering of Figures, Tables, Schemes and Compounds All figures, tables and schemes listed in this document are given a unique ID following the convention Object type [Chapter number].[object number] (e.g. Figure II.3 or Scheme III.1). All chemical structures listed in this document are given a unique ID upon their first appearance in this document, following the convention [Chapter number].[compound number] (e.g. IV.22). Compounds generated during the course of this work are referred to in the text by this convention; the corresponding identifier generated by Vanderbilt University will be referenced alongside this numbering system for key compounds where further clarification is required. Commercially available materials that were purchased for use in this work are referred to by the name they are sold under (e.g. LY341495). Note Regarding Animal Care and Use All animal studies described in this document were performed under protocols that had been reviewed and approved by the Vanderbilt University Institutional Animal Care and Use Committee (IACUC), and all experiments are performed in strict accordance with the NIH Guide for the Care and Use of Laboratory Animals. Such studies were conducted in the vivarium facility or the mouse neurobehavioral core of v Vanderbilt University Medical Center, which operates under guidelines set forth by the NIH and is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). Animals used were under the care of veterinary and vivarium staff with extensive experience in the care of rodents. Note Regarding Human Subjects Protection All studies described in this document that use human DNA and medical records were conducted under a protocol that had been reviewed and approved by the Vanderbilt University Human Research Protections Program / Institutional Review Board (HRPP / IRB). All records and samples were obtained with patient consent using the opt- out policy of the Vanderbilt BioVU database, and were fully de-identified in compliance with the Health Insurance Portability and Accountability Act (HIPAA). Note Regarding Copyright Permissions Some portions of this document are reproduced from works previously published by the author. All necessary copyright permissions have been obtained for the use of text and figures from these document. Where necessary, such permissions are noted at the conclusion of the chapter where they are presented. vi TABLE OF CONTENTS Page DEDICATION ....................................................................................................................... ii ACKNOWLEDGEMENTS ..................................................................................................... iii PREFACE ............................................................................................................................. v LIST OF TABLES .................................................................................................................. xi LIST OF FIGURES ............................................................................................................... xiii LIST OF EQUATIONS AND SCHEMES .................................................................................xv LIST OF ABBREVIATIONS .................................................................................................. xvi Chapter I. BACKGROUND AND INTRODUCTION .............................................................................. 1 Metabotropic Glutamate Receptors 2 and 3 ............................................................... 1 The glutamatergic nervous system and the neurotransmitter glutamate ............ 1 Structure and function of the group II metabotropic glutamate receptors .......... 6 Ligands for Metabotropic Glutamate Receptors 2 and 3 ............................................ 9 Orthosteric versus allosteric regulation ................................................................ 9 Allosteric regulation in drug discovery ................................................................ 12 Orthosteric ligands for the group II metabotropic glutamate receptors ............ 14 Allosteric ligands for the group II metabotropic glutamate receptors ................ 17 Role of the Metabotropic Glutamate Receptors 2 and 3 in Psychiatric Illnesses ..... 19 The group II metabotropic glutamate receptors and schizophrenia ................... 19 The group II metabotropic glutamate receptors and depression ....................... 21 The group II metabotropic glutamate receptors and anxiety disorders ............. 23 The group II metabotropic glutamate receptors and substance dependence .... 25 The group II metabotropic glutamate receptors and other neuropsychiatric illnesses ................................................................................................................ 26 Conclusions ................................................................................................................ 27 II. MATERIALS AND METHODS ......................................................................................... 28 Chemical Synthesis, Analysis, and Purification Techniques ...................................... 28 vii Iterative, parallel, multidimensional synthesis .................................................... 28 General methods and instrumentation ............................................................... 29 Molecular Pharmacology Techniques ........................................................................ 32 Cell culture ..........................................................................................................
Load more

Recommended publications
  • Mglu2 Receptor Agonism, but Not Positive Allosteric Modulation, Elicits Rapid Tolerance Towards Their Primary Efficacy on Sleep Measures in Rats
    RESEARCH ARTICLE mGlu2 Receptor Agonism, but Not Positive Allosteric Modulation, Elicits Rapid Tolerance towards Their Primary Efficacy on Sleep Measures in Rats Abdallah Ahnaou1*, Hilde Lavreysen1, Gary Tresadern2, Jose M. Cid2, Wilhelmus H. Drinkenburg1 1 Dept. of Neuroscience, Janssen Research & Development, A Division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340, Beerse, Belgium, 2 Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A., Jarama 75, Polígono Industrial, 45007, Toledo, Spain * [email protected] Abstract OPEN ACCESS G-protein-coupled receptor (GPCR) agonists are known to induce both cellular adaptations Citation: Ahnaou A, Lavreysen H, Tresadern G, Cid resulting in tolerance to therapeutic effects and withdrawal symptoms upon treatment dis- JM, Drinkenburg WH (2015) mGlu2 Receptor continuation. Glutamate neurotransmission is an integral part of sleep-wake mechanisms, Agonism, but Not Positive Allosteric Modulation, Elicits Rapid Tolerance towards Their Primary which processes have translational relevance for central activity and target engagement. Efficacy on Sleep Measures in Rats. PLoS ONE 10 Here, we investigated the efficacy and tolerance potential of the metabotropic glutamate (12): e0144017. doi:10.1371/journal.pone.0144017 receptors (mGluR2/3) agonist LY354740 versus mGluR2 positive allosteric modulator Editor: James Porter, University of North Dakota, (PAM) JNJ-42153605 on sleep-wake organisation in rats. In vitro, the selectivity and UNITED STATES potency of JNJ-42153605 were characterized. In vivo, effects on sleep measures were Received: July 12, 2015 investigated in rats after once daily oral repeated treatment for 7 days, withdrawal and con- Accepted: November 12, 2015 secutive re-administration of LY354740 (1–10 mg/kg) and JNJ-42153605 (3–30 mg/kg).
    [Show full text]
  • Selective Blockade of the Metabotropic Glutamate Receptor Mglur5 Protects Mouse Livers in in Vitro and Ex Vivo Models of Ischemia Reperfusion Injury
    International Journal of Molecular Sciences Article Selective Blockade of the Metabotropic Glutamate Receptor mGluR5 Protects Mouse Livers in In Vitro and Ex Vivo Models of Ischemia Reperfusion Injury Andrea Ferrigno 1,* ID , Clarissa Berardo 1, Laura Giuseppina Di Pasqua 1, Veronica Siciliano 1, Plinio Richelmi 1, Ferdinando Nicoletti 2,3 and Mariapia Vairetti 1 ID 1 Department of Internal Medicine and Therapeutics, Cellular and Molecular Pharmacology and Toxicology Unit, University of Pavia, 27100 Pavia, Italy; [email protected] (C.B.); [email protected] (L.G.D.P.); [email protected] (V.S.); [email protected] (P.R.); [email protected] (M.V.) 2 Department of Physiology and Pharmacology, Sapienza University, 00185 Roma, Italy; [email protected] 3 I.R.C.C.S. Neuromed, 86077 Pozzilli, Italy * Correspondence: [email protected]; Tel.: +39-0382-986451 Received: 20 November 2017; Accepted: 22 January 2018; Published: 23 January 2018 Abstract: 2-Methyl-6-(phenylethynyl)pyridine (MPEP), a negative allosteric modulator of the metabotropic glutamate receptor (mGluR) 5, protects hepatocytes from ischemic injury. In astrocytes and microglia, MPEP depletes ATP. These findings seem to be self-contradictory, since ATP depletion is a fundamental stressor in ischemia. This study attempted to reconstruct the mechanism of MPEP-mediated ATP depletion and the consequences of ATP depletion on protection against ischemic injury. We compared the effects of MPEP and other mGluR5 negative modulators on ATP concentration when measured in rat hepatocytes and acellular solutions. We also evaluated the effects of mGluR5 blockade on viability in rat hepatocytes exposed to hypoxia. Furthermore, we studied the effects of MPEP treatment on mouse livers subjected to cold ischemia and warm ischemia reperfusion.
    [Show full text]
  • The G Protein-Coupled Glutamate Receptors As Novel Molecular Targets in Schizophrenia Treatment— a Narrative Review
    Journal of Clinical Medicine Review The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment— A Narrative Review Waldemar Kryszkowski 1 and Tomasz Boczek 2,* 1 General Psychiatric Ward, Babinski Memorial Hospital in Lodz, 91229 Lodz, Poland; [email protected] 2 Department of Molecular Neurochemistry, Medical University of Lodz, 92215 Lodz, Poland * Correspondence: [email protected] Abstract: Schizophrenia is a severe neuropsychiatric disease with an unknown etiology. The research into the neurobiology of this disease led to several models aimed at explaining the link between perturbations in brain function and the manifestation of psychotic symptoms. The glutamatergic hypothesis postulates that disrupted glutamate neurotransmission may mediate cognitive and psychosocial impairments by affecting the connections between the cortex and the thalamus. In this regard, the greatest attention has been given to ionotropic NMDA receptor hypofunction. However, converging data indicates metabotropic glutamate receptors as crucial for cognitive and psychomotor function. The distribution of these receptors in the brain regions related to schizophrenia and their regulatory role in glutamate release make them promising molecular targets for novel antipsychotics. This article reviews the progress in the research on the role of metabotropic glutamate receptors in schizophrenia etiopathology. Citation: Kryszkowski, W.; Boczek, T. The G Protein-Coupled Glutamate Keywords: schizophrenia; metabotropic glutamate receptors; positive allosteric modulators; negative Receptors as Novel Molecular Targets allosteric modulators; drug development; animal models of schizophrenia; clinical trials in Schizophrenia Treatment—A Narrative Review. J. Clin. Med. 2021, 10, 1475. https://doi.org/10.3390/ jcm10071475 1. Introduction Academic Editors: Andreas Reif, Schizophrenia is a common debilitating disease affecting about 0.3–1% of the human Blazej Misiak and Jerzy Samochowiec population worldwide [1].
    [Show full text]
  • Dynamic L-Glutamate Signaling in the Prefrontal Cortex and the Effects of Methylphenidate Treatment
    University of Kentucky UKnowledge Theses and Dissertations--Neuroscience Neuroscience 2012 DYNAMIC L-GLUTAMATE SIGNALING IN THE PREFRONTAL CORTEX AND THE EFFECTS OF METHYLPHENIDATE TREATMENT Catherine Elizabeth Mattinson University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Mattinson, Catherine Elizabeth, "DYNAMIC L-GLUTAMATE SIGNALING IN THE PREFRONTAL CORTEX AND THE EFFECTS OF METHYLPHENIDATE TREATMENT" (2012). Theses and Dissertations--Neuroscience. 4. https://uknowledge.uky.edu/neurobio_etds/4 This Doctoral Dissertation is brought to you for free and open access by the Neuroscience at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Neuroscience by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained and attached hereto needed written permission statements(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine). I hereby grant to The University of Kentucky and its agents the non-exclusive license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless a preapproved embargo applies.
    [Show full text]
  • Effects of N-Acetylcysteine on Brain Glutamate Levels and Resting Perfusion in Schizophrenia
    Psychopharmacology https://doi.org/10.1007/s00213-018-4997-2 ORIGINAL INVESTIGATION Effects of N-acetylcysteine on brain glutamate levels and resting perfusion in schizophrenia Grant McQueen1 & John Lally1,2 & Tracy Collier1 & Fernando Zelaya3 & David J. Lythgoe3 & Gareth J. Barker3 & James M. Stone1,4 & Philip McGuire1 & James H. MacCabe1 & Alice Egerton1 Received: 6 March 2018 /Accepted: 6 August 2018 # The Author(s) 2018 Abstract Rationale N-Acetylcysteine (NAC) is currently under investigation as an adjunctive treatment for schizophrenia. The therapeutic potential of NAC may involve modulation of brain glutamate function, but its effects on brain glutamate levels in schizophrenia have not been evaluated. Objectives The aim of this study was to examine whether a single dose of NAC can alter brain glutamate levels. A secondary aim was to characterise its effects on regional brain perfusion. Methods In a double-blind placebo-controlled crossover study, 19 patients with a diagnosis of schizophrenia underwent two MRI scans, following oral administration of 2400 mg NAC or matching placebo. Proton magnetic resonance spectroscopy was used to investigate the effect of NAC on glutamate and Glx (glutamate plus glutamine) levels scaled to creatine (Cr) in the anterior cingulate cortex (ACC) and in the right caudate nucleus. Pulsed continuous arterial spin labelling was used to assess the effects of NAC on resting cerebral blood flow (rCBF) in the same regions. Results Relative to the placebo condition, the NAC condition was associated with lower levels of Glx/Cr, in the ACC (P <0.05), but not in the caudate nucleus. There were no significant differences in CBF in the NAC compared to placebo condition.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9,114,138 B2 Cid-Nunez Et Al
    USOO9114138B2 (12) United States Patent (10) Patent No.: US 9,114,138 B2 Cid-Nunez et al. (45) Date of Patent: Aug. 25, 2015 (54) 1',3'-DISUBSTITUTED-4-PHENYL-3,4,5,6- (58) Field of Classification Search TETRAHYDRO-2H, 1'H-14' CPC .......................... A61K 31/4545; CO7D 401/04 BPYRIDINYL-2'-ONES USPC ........................................... 546/194; 514/318 (75) Inventors: Jose Maria Cid-Nunez, Toledo (ES); See application file for complete search history. Andres Avelino Trabanco-Suarez, (56) References Cited Toledo (ES); Gregor James MacDonald, Beerse (BE); Guillaume U.S. PATENT DOCUMENTS Albert Jacques Duvey, Geneva (CH): 4,051,244. A 9/1977 Mattioda et al. Robert Johannes Lutjens, Geneva 4,066,651 A 1/1978 Brittain et al. (CH); Terry Patrick Finn, Geneva (CH) (Continued) (73) Assignees: Janssen Pharmaceuticals, Inc., FOREIGN PATENT DOCUMENTS Titusville, NJ (US); Addex Pharma SA, BE 841390 11, 1976 Geneva (CH) CA 1019323 1Of 1977 (*) Notice: Subject to any disclaimer, the term of this (Continued) patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 287 days. Adam, Octavian R. “Symptomatic Treatment of Huntington Dis (21) Appl. No.: 12/677,618 ease” Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Apr. 2008, vol. 5, 181-197.* (22) PCT Filed: Sep. 12, 2008 Hook V. Y.H. “Neuroproteases in Peptide Neurotransmission and Neurodegenerative Diseases Applications to Drug Discovery (86). PCT No.: PCT/EP2008/007551 Research” Biodrugs 2006, 20, 105-119.* 371 1 Conn, P.J. “Activation of metabotropic glutamate receptors as a novel S (c)(1), approach for the treatment of schizophrenia.” Trends in Pharmaco (2), (4) Date: Jun.
    [Show full text]
  • Treatment of Schizophrenia Course Director: Philip Janicak, M.D
    S6735- Treatment of Schizophrenia Course Director: Philip Janicak, M.D. #APAAM2016 Saturday, May 14, 2016 Marriott Marquis - Marquis Ballroom D psychiatry.org/ annualmeetingS4637 ANNUAL MEETING May 14-18, 2016 • Atlanta Reference • Janicak PG, Marder SR, Tandon R, Goldman M (Eds.). Schizophrenia: Recent Advances in Diagnosis and Treatment. New York, NY: Springer; 2014. Schizophrenia: Recent Diagnostic Advances, Neurobiology, and the Neuropharmacology of Antipsychotic Drug Therapy Rajiv Tandon, MD Professor of Psychiatry University of Florida College of Medicine Gainesville, Florida Annual Meeting of the American Psychiatric Association New York, New York May 3–7, 2014 Disclosure Information MEMBER, WPA PHARMACOPSYCHIATRY SECTION MEMBER, DSM-5 WORKGROUP ON PSYCHOTIC DISORDERS A CLINICIAN AND CLINICAL RESEARCHER Pharmacological Treatment of Any Disease • Know the Disease that you are treating • Nature; Treatment targets; Treatment goals; • Know the Treatments at your disposal • What they do; How they compare; Costs; • Principles of Treatment • Measurement-based; Targeted; Individualized Program Outline • Nature and Definition of psychosis? • Clinical description • What is wrong in psychotic illness • Dimensions of Psychopathology • Neurobiological Abnormalities • Mechanisms underlying antipsychotic effects? • What contributes to Efficacy • Basis of Side-effect differences 5 Challenges in DSM-IV Construct of Psychotic Disorders ♦ Indistinct Boundaries ♦ With Other Disorders (eg., with OCD) ♦ Within Group of Psychotic Disorders (eg. between
    [Show full text]
  • Conformational Dynamics Between Transmembrane Domains And
    RESEARCH ARTICLE Conformational dynamics between transmembrane domains and allosteric modulation of a metabotropic glutamate receptor Vanessa A Gutzeit1, Jordana Thibado2, Daniel Starer Stor2, Zhou Zhou3, Scott C Blanchard2,3,4, Olaf S Andersen2,3, Joshua Levitz2,4,5* 1Neuroscience Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, United States; 2Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, United States; 3Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States; 4Tri-Institutional PhD Program in Chemical Biology, New York, United States; 5Department of Biochemistry, Weill Cornell Medicine, New York, United States Abstract Metabotropic glutamate receptors (mGluRs) are class C, synaptic G-protein-coupled receptors (GPCRs) that contain large extracellular ligand binding domains (LBDs) and form constitutive dimers. Despite the existence of a detailed picture of inter-LBD conformational dynamics and structural snapshots of both isolated domains and full-length receptors, it remains unclear how mGluR activation proceeds at the level of the transmembrane domains (TMDs) and how TMD-targeting allosteric drugs exert their effects. Here, we use time-resolved functional and conformational assays to dissect the mechanisms by which allosteric drugs activate and modulate mGluR2. Single-molecule subunit counting and inter-TMD fluorescence resonance energy transfer *For correspondence: measurements in living cells
    [Show full text]
  • The Effect of Intrahippocampal Injection of Group II and III Metobotropic Glutamate Receptor Agonists on Anxiety; the Role of Neuropeptide Y
    Neuropsychopharmacology (2007) 32, 1242–1250 & 2007 Nature Publishing Group All rights reserved 0893-133X/07 $30.00 www.neuropsychopharmacology.org The Effect of Intrahippocampal Injection of Group II and III Metobotropic Glutamate Receptor Agonists on Anxiety; the Role of Neuropeptide Y ´ ,1 1 1 1 Maria Smiałowska* , Joanna M Wieron´ska , Helena Domin and Barbara Zie˛ba 1Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Krako´w, Poland Earlier studies conducted by our group and by other authors indicated that metabotropic glutamatergic receptor (mGluR) ligands might have anxiolytic activity and that amygdalar neuropeptide Y (NPY) neurons were engaged in that effect. Apart from the amygdala, the hippocampus, another limbic structure, also seems to be engaged in regulation of anxiety. It is rich in mGluRs and contains numerous NPY interneurons. In the present study, we investigated the anxiolytic activity of group II and III mGluR agonists after injection into the hippocampus, and attempted to establish whether hippocampal NPY neurons and receptors were engaged in the observed effects. Male Wistar rats were bilaterally microinjected with the group II mGluR agonist (2S,10S,20S)-2-(carboxycyclopropyl)glycine (L-CCG-I), group III mGluR agonist O-Phospho-L-serine (L-SOP), NPY, the Y1 receptor antagonist BIBO 3304, and the Y2 receptor antagonist BIIE 0246 into the CA1 or dentate area (DG). The effect of those compounds on anxiety was tested in the elevated plus-maze. Moreover, the effects of L-CCG-I and L-SOP on the expression of NPYmRNA in the hippocampus were studied using in situ hybridization method. It was found that a significant anxiolytic effect was induced by L-SOP injection into the CA1 region or by L-CCG-I injection into the DG.
    [Show full text]
  • Hippocampal Dysfunction in the Pathophysiology of Schizophrenia: a Selective Review and Hypothesis for Early Detection and Intervention
    OPEN Molecular Psychiatry (2018) 23, 1764–1772 www.nature.com/mp ORIGINAL ARTICLE Hippocampal dysfunction in the pathophysiology of schizophrenia: a selective review and hypothesis for early detection and intervention JA Lieberman1,2, RR Girgis1,2, G Brucato1,2, H Moore1,2, F Provenzano3, L Kegeles1,2, D Javitt1,2, J Kantrowitz1,2, MM Wall1,2,4, CM Corcoran1, SA Schobel1 and SA Small1,3,5 Scientists have long sought to characterize the pathophysiologic basis of schizophrenia and develop biomarkers that could identify the illness. Extensive postmortem and in vivo neuroimaging research has described the early involvement of the hippocampus in the pathophysiology of schizophrenia. In this context, we have developed a hypothesis that describes the evolution of schizophrenia—from the premorbid through the prodromal stages to syndromal psychosis—and posits dysregulation of glutamate neurotransmission beginning in the CA1 region of the hippocampus as inducing attenuated psychotic symptoms and initiating the transition to syndromal psychosis. As the illness progresses, this pathological process expands to other regions of the hippocampal circuit and projection fields in other anatomic areas including the frontal cortex, and induces an atrophic process in which hippocampal neuropil is reduced and interneurons are lost. This paper will describe the studies of our group and other investigators supporting this pathophysiological hypothesis, as well as its implications for early detection and therapeutic intervention. Molecular Psychiatry advance online publication, 9 January 2018; doi:10.1038/mp.2017.249 INTRODUCTION between dementia praecox and manic-depressive illness by Background and historical context painstaking description of symptoms and illness course. Since Scientists have been challenged to elucidate the pathological then, researchers have continued to search for the neuropatho- basis of mental illness.
    [Show full text]
  • Group II/III Metabotropic Glutamate Receptors Exert Endogenous Activity-Dependent Modulation of TRPV1 Receptors on Peripheral Nociceptors
    The Journal of Neuroscience, September 7, 2011 • 31(36):12727–12737 • 12727 Behavioral/Systems/Cognitive Group II/III Metabotropic Glutamate Receptors Exert Endogenous Activity-Dependent Modulation of TRPV1 Receptors on Peripheral Nociceptors Susan M. Carlton, Shengtai Zhou, Rosann Govea, and Junhui Du Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-1069 There is pharmacological evidence that group II and III metabotropic glutamate receptors (mGluRs) function as activity-dependent autoreceptors, inhibiting transmission in supraspinal sites. These receptors are expressed by peripheral nociceptors. We investigated whether mGluRs function as activity-dependent autoreceptors inhibiting pain transmission to the rat CNS, particularly transient recep- tor potential vanilloid 1 (TRPV1)-induced activity. Blocking peripheral mGluR activity by intraplantar injection of antagonists LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid] (LY) (20, 100 ␮M, group II/III), APICA [(RS)-1- amino-5-phosphonoindan-1-carboxylic acid] (100 ␮M, group II), or UBP1112 (␣-methyl-3-methyl-4-phosphonophenylglycine) (30 ␮M, groupIII)increasedcapsaicin(CAP)-inducednociceptivebehaviorsandnociceptoractivity.Incontrast,groupIIagonistAPDC[(2R,4R)- 4-aminopyrrolidine-2,4-dicarboxylate] (0.1 ␮M) or group III agonist L-(ϩ)-2-amino-4-phosphonobutyric acid (L-AP-4) (10 ␮M) blocked the LY-induced increase. Ca 2ϩ imaging in dorsal root ganglion (DRG) cells confirmed LY enhanced CAP-induced Ca 2ϩ mobilization, which was blocked by APDC and L-AP-4. We hypothesized that excess glutamate (GLU) released by high intensity and/or prolonged stimulation endogenously activated group II/III, dampening nociceptor activation. In support of this, intraplantar GLU ϩ LY produced heat hyperalgesia, and exogenous GLU ϩ LY applied to nociceptors produced enhanced nociceptor activity and thermal sensitization.
    [Show full text]
  • G Protein-Coupled Receptors
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading.
    [Show full text]