DOCSLIB.ORG

Diamandis Thesis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Diamandis Thesis !"!#$ CHEMICAL GENETIC INTERROGATION OF NEURAL STEM CELLS: PHENOTYPE AND FUNCTION OF NEUROTRANSMITTER PATHWAYS IN NORMAL AND BRAIN TUMOUR INITIATING NEURAL PRECUSOR CELLS by Phedias Diamandis A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy. Department of Molecular Genetics University of Toronto © Copyright by Phedias Diamandis 2010 Phenotype and Function of Neurotransmitter Pathways in Normal and Brain Tumor Initiating Neural Precursor Cells Phedias Diamandis Doctor of Philosophy Department of Molecular Genetics University of Toronto 2010 &'(!)&*!% The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain brings promise for the treatment of neurological diseases and has yielded new insight into brain cancer. The complete repertoire of signaling pathways that governs these cells however remains largely uncharacterized. This thesis describes how chemical genetic approaches can be used to probe and better define the operational circuitry of the NSC. I describe the development of a small molecule chemical genetic screen of NSCs that uncovered an unappreciated precursor role of a number of neurotransmitter pathways commonly thought to operate primarily in the mature central nervous system (CNS). Given the similarities between stem cells and cancer, I then translated this knowledge to demonstrate that these neurotransmitter regulatory effects are also conserved within cultures of cancer stem cells. I then provide experimental and epidemiologically support for this hypothesis and suggest that neurotransmitter signals may also regulate the expansion of precursor cells that drive tumor growth in the brain. Specifically, I first evaluate the effects of neurochemicals in mouse models of brain tumors. I then outline a retrospective meta-analysis of brain tumor incidence rates in psychiatric patients presumed to be chronically taking neuromodulators similar to those identified in the initial screen. Lastly, by further exploring the phenotype and function of neurotransmitter pathways in purified populations of human NSCs, I determined that neurotransmitter pathway gene expression exists in a functionally heterogeneous phase-varying state that restricts the responsiveness of these populations to various stimuli. Taken together, this research provides novel insights into the phenotypic and functional landscape of neurotransmitter pathways in both normal and cancer-derived NSCs. In additional to a better fundamental understanding of NSC biology, these results suggest how clinically approved neuromodulators can be used to remodel the mature CNS and find application in the treatment of brain cancer. ! ""% "!+&,&% % When you set out on your journey to Ithaca, pray that the road is long, full of adventure, full of knowledge. The Lestrygonians and the Cyclops, the angry Poseidon -- do not fear them: You will never find such as these on your path, if your thoughts remain lofty, if a fine emotion touches your spirit and your body. The Lestrygonians and the Cyclops, the fierce Poseidon you will never encounter, if you do not carry them within your soul, if your soul does not set them up before you. Pray that the road is long. That the summer mornings are many, when, with such pleasure, with such joy you will enter ports seen for the first time; stop at Phoenician markets, and purchase fine merchandise, mother-of-pearl and coral, amber and ebony, and sensual perfumes of all kinds, as many sensual perfumes as you can; visit many Egyptian cities, to learn and learn from scholars. Always keep Ithaca in your mind. To arrive there is your ultimate goal. But do not hurry the voyage at all. It is better to let it last for many years; and to anchor at the island when you are old, rich with all you have gained on the way, not expecting that Ithaca will offer you riches. Ithaca has given you the beautiful voyage. Without her you would have never set out on the road. She has nothing more to give you. And if you find her poor, Ithaca has not deceived you. Wise as you have become, with so much experience, you must already have understood what Ithacas mean. - Constantine P. Cavafy (1911) ! """% &*,-./#$01$2$-!( I thank God for guiding me down the long and laborious journey of graduate studies. For what started off as a simple pursuit of a diploma and future career, soon became a voyage full of adventure, knowledge and perhaps the most significant part of my personal development. I would like to thank my supervisors Dr. Mike Tyers and Dr. Peter Dirks for the years of quality co-supervision. I truly feel you have both shaped the way I think not only about science, but also the way I see the world around me. Thank you for giving me freedom, independence and guidance when I needed it. I am more creative, efficient and a better self-critic because of you two. I hope that in the spirit of mentoring, I too can one day pass these skills down to my own students and that our collaborations and friendship continue to flourish. To my committee members Dr. Peter Roy and Dr. James Ellis, thank you for your valuable time and thoughts. Although our time together was short, your ideas and constructive criticism have left a forever-lasting improvement to this document. To Ian, you have been a model citizen, taking the time to share your endless wealth of patience and knowledge with us graduates students. You’ve been like a father figure in the lab to so many of us and have always led by good example. Thank you for consistently being there for both the good and bad times. You are a “true” team player and role model. To Kevin and Jenny, I also thank you for your constant support in my science and personal life. I consider you both true friends. To Caroline, Erick and Ryan, I have enjoyed embarking on this long PhD journey with you. I hope your graduate training has also brought you more riches that you could ever imagine. And to the remainder of the Dirks Lab, thank you all for your contributions to this work and for your friendship. You have all made coming to work enjoyable the last few years. Lastly, thank you to my mother Anastasia, my father Eleftherios and my sister Maria. I may have encountered many marvels and wonderful people during this long and difficult voyage, but perhaps the most wonderful realization it has brought me is the magnitude of love you have in your hearts. You have all proven that people can unselfishly provide unlimited belief, support and love to help another succeed. You have ! "#% taken a once troubled adolescent and helped him already surpass the expectations of his given abilities. There are many problems in this world, but if every child had the love you have given me, the earth would be a much better place. I hope that the completion of this journey has given me the insight, skills and experience needed to one day find a more sufficient way to honor the sacrifices you have made for my life. Until then, I dedicate this thesis, the most significant accomplishment of my life so far, to you. Thank you. Phedias Diamandis (2010) ! #% #"(!%.3%&'')$4"&!".-(% (±)-PPHT (±)-2-(N-Phenethyl-N- EGR Early growth response propyl)amino-5-hydroxytetralin 5-HT 5-Hydroxytryptamine (serotonin) Emx2 empty spiracles homeobox 2 5-HTR1A 5-Hydroxytryptamine (serotonin) ENU N-ethyl-N-nitrosourea receptor, 1A AC Adenylate cyclase ER endoplasmic reticulum Ach Acetylcholine ES Embryonic stem ACSF Artificial cerebral spinal fluid FACS fluorescence activated cell sorting AML Acute myeloid leukemia FGF basic fibroblast growth factor (bFGF) AMP adenosine monophosphate FITC fluorescein isothiocyanate B2M beta-2-microglobulin GABA !-aminobutyric acid BDNF Brain-derived neurotrophic factor GABRB1 !-aminobutyric acid receptor, beta 1 BMPs Bone Morphogenetic Proteins GABRB2 !-aminobutyric acid receptor, beta 2 BSA Bovine serum albumin GAD67 Glutamate decarboxylase, 67-kD BTSC brain tumor stem cell GBM glioblastoma multiforme BTX "-bungarotoxin GFAP glial fibrillary acidic protein 2+ CaMK Ca /calmodulin-dependent protein Gi G protein, inhibitory kinases cAMP cyclic adenosine monophosphate GluR Glutamate receptor, metabotropic (mGlu) CD cluster of differentiation GPCR Guanine nucleotide binding protein (G protein), coupled receptor CHRM3 Cholinergic receptor, muscarinic 3 Gq/11 G protein, q polypeptide (M3) CHRNA7 Cholinergic receptor, neuronal GRIN2B glutamate receptor, ionotropic, N- ("7nAChR) nicotinic, "-polypeptide 7 Methyl-D-Aspartate, subunit 2B CNTF ciliary neurotrophic factor GRIA1 glutamate receptor, ionotropic, AMPA-1 CpG cytosine and guanine separated by a Gs G Protein, stimulatory phosphate CREB cAMP response element binding GSK-3 Glycogen synthase kinase 3 CSC cancer stem cell h Human CNS central nervous system HDACS Histone deacetylases DAG Diacylglycerol HEPES N-2-Hydroxyethelypiperazine-N’-2- ethanesulfonic acid DAPI 4’,6’-diamidino-2-phenylindole Hh Hedgehog hydrochloride Dlk6 Delta-like 1 homolog HRP horseradish peroxidase Dlx5 Distal-less homeobox 5 HSCs Hematopoietic stem cells DMEM Dulbecco’s Modified Essential HTS high throughput screening Medium DMSO Dimethyl sulfoxide IP3 inositol 1,4,5-trisphosphate dNTPs Deoxynucleotide triphosphates JAK Janus kinase 3 DPAT (dipropylamino)tetralin Ki-67 Antigen identified by monoclonal antibody Ki-67 DRD2 Dopamine receptor D2 LIF Leukemia inhibitory factor E Embryonic day Lin Lineage EC# effective concentration needed to LOPAC library of pharmacologically active decrease proliferation by #% compounds ECT electroconvulsive therapy m Mouse
Load more

Recommended publications
  • (Danio Rerio Hamilton 1822) Adulto: Diferenças Entre Modelos Comportamentais, Linhagens E Efeitos Do Estresse Predatório Agudo
    I CAIO MAXIMINO DE OLIVEIRA Papel da serotonina no comportamento defensivo do paulistinha (Danio rerio Hamilton 1822) adulto: Diferenças entre modelos comportamentais, linhagens e efeitos do estresse predatório agudo Tese apresentada ao Programa de Pós- Graduação em Neurociências e Biologia Celular do Instituto de Ciências Biológicas da Universidade Federal do Pará, como requisito parcial para obtenção do título de Doutor em Neurociências e Biologia Celular Área de concentração: Neurociências Orientador: Prof. Dr. Anderson Manoel Herculano Belém/PA 2014 CIP – Catalogação na Publicação OL48p Oliveira, Caio Maximino de, 1983- Papel da serotonina no comportamento defensivo do paulistinha (Danio rerio Hamilton 1822) adulto: Diferenças entre modelos comportamentais, linhagens, e efeitos do estresse predatório agudo / Caio Maximino de Oliveira ± 2014 Orientador: Anderson Manoel Herculano Tese (Doutorado) ± Universidade Federal do Pará, Programa de Pós- Graduação em Neurociências e Biologia Celular, Belém/PA, 2014 1. Neuropsicofarmacologia. 2. Neurociências. 3. Psicopatologia. I. Herculano, Anderson Manoel, orient. II. Título CDD: 610 CDU: 615 III CAIO MAXIMINO DE OLIVEIRA Papel da serotonina no comportamento defensivo do paulistinha (Danio rerio Hamilton 1822) adulto: Diferenças entre modelos comportamentais, linhagens e efeitos do estresse predatório agudo Tese apresentada ao Programa de Pós-Graduação em Neurociências e Biologia Celular do Instituto de Ciências Biológicas da Universidade Federal do Pará, como requisito parcial para obtenção do título de Doutor em Neurociências e Biologia Celular (Ênfase em Neurociências) pela Comissão Julgadora composta pelos membros: COMISSÃO JULGADORA ___________________________________ Prof. Dr. Anderson Manoel Herculano Universidade Federal do Pará (Presidente) ___________________________________ Prof. Dr. Amauri Gouveia Jr. Universidade Federal do Pará ___________________________________ Prof. Dr. Fernando Allan Rocha Universidade Federal do Pará ___________________________________ Prof.
    [Show full text]
  • TABLE 1 Studies of Antagonist Activity in Constitutively Active
    TABLE 1 Studies of antagonist activity in constitutively active receptors systems shown to demonstrate inverse agonism for at least one ligand Targets are natural Gs and constitutively active mutants (CAM) of GPCRs. Of 380 antagonists, 85% of the ligands demonstrate inverse agonism. Receptor Neutral Antagonist Inverse Agonist Reference Human β2-adrenergic Dichloroisoproterenol, pindolol, labetolol, timolol, Chidiac et al., 1996; Azzi et alprenolol, propranolol, ICI 118,551, cyanopindolol al., 2001 Turkey erythrocyte β-adrenergic Propranolol, pindolol Gotze et al., 1994 Human β2-adrenergic (CAM) Propranolol Betaxolol, ICI 118,551, sotalol, timolol Samama et al., 1994; Stevens and Milligan, 1998 Human/guinea pig β1-adrenergic Atenolol, propranolol Mewes et al., 1993 Human β1-adrenergic Carvedilol CGP20712A, metoprolol, bisoprolol Engelhardt et al., 2001 Rat α2D-adrenergic Rauwolscine, yohimbine, WB 4101, idazoxan, Tian et al., 1994 phentolamine, Human α2A-adrenergic Napthazoline, Rauwolscine, idazoxan, altipamezole, levomedetomidine, Jansson et al., 1998; Pauwels MPV-2088 (–)RX811059, RX 831003 et al., 2002 Human α2C-adrenergic RX821002, yohimbine Cayla et al., 1999 Human α2D-adrenergic Prazosin McCune et al., 2000 Rat α2-adrenoceptor MK912 RX821002 Murrin et al., 2000 Porcine α2A adrenoceptor (CAM- Idazoxan Rauwolscine, yohimbine, RX821002, MK912, Wade et al., 2001 T373K) phentolamine Human α2A-adrenoceptor (CAM) Dexefaroxan, (+)RX811059, (–)RX811059, RS15385, yohimbine, Pauwels et al., 2000 atipamezole fluparoxan, WB 4101 Hamster α1B-adrenergic
    [Show full text]
  • Dosing Time Matters
    bioRxiv preprint doi: https://doi.org/10.1101/570119; this version posted March 21, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Dosing Time Matters 1 2,3 4,5,6 1* Marc D. Ruben ,​ David F. Smith ,​ Garret A. FitzGerald ,​ and John B. Hogenesch ​ ​ ​ ​ 1 Division​ of Human Genetics, Center for Chronobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH, 45229 2 Divisions​ of Pediatric Otolaryngology and Pulmonary and Sleep Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229 3 Department​ of Otolaryngology-Head and Neck Surgery, University of Cincinnati School of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267 4 Department​ of Systems Pharmacology and Translational Therapeutics, at the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 USA 5 Department​ of Medicine, at the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 USA 6 ​ Institute for Translational Medicine and Therapeutics (ITMAT), at the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 USA *Corresponding Author. Email: [email protected] Abstract Trainees in medicine are taught to diagnose and administer treatment as needed; time-of-day is rarely considered. Yet accumulating evidence shows that ~half of human genes and physiologic functions follow daily rhythms. Circadian medicine aims to incorporate knowledge of these rhythms to enhance diagnosis and treatment.
    [Show full text]
  • Infiltrating Myeloid Cells Drive Osteosarcoma Progression Via GRM4 Regulation of IL23
    Published OnlineFirst September 16, 2019; DOI: 10.1158/2159-8290.CD-19-0154 RESEARCH BRIEF Infi ltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23 Maya Kansara 1 , 2 , Kristian Thomson 1 , Puiyi Pang 1 , Aurelie Dutour 3 , Lisa Mirabello 4 , Francine Acher5 , Jean-Philippe Pin 6 , Elizabeth G. Demicco 7 , Juming Yan 8 , Michele W.L. Teng 8 , Mark J. Smyth 9 , and David M. Thomas 1 , 2 ABSTRACT The glutamate metabotropic receptor 4 (GRM4 ) locus is linked to susceptibility to human osteosarcoma, through unknown mechanisms. We show that Grm4 − / − gene– targeted mice demonstrate accelerated radiation-induced tumor development to an extent comparable with Rb1 +/ − mice. GRM4 is expressed in myeloid cells, selectively regulating expression of IL23 and the related cytokine IL12. Osteosarcoma-conditioned media induce myeloid cell Il23 expression in a GRM4-dependent fashion, while suppressing the related cytokine Il12 . Both human and mouse osteosarcomas express an increased IL23:IL12 ratio, whereas higher IL23 expression is associated with worse survival in humans. Con- sistent with an oncogenic role, Il23−/− mice are strikingly resistant to osteosarcoma development. Agonists of GRM4 or a neutralizing antibody to IL23 suppressed osteosarcoma growth in mice. These fi ndings identify a novel, druggable myeloid suppressor pathway linking GRM4 to the proinfl ammatory IL23/IL12 axis. SIGNIFICANCE: Few novel systemic therapies targeting osteosarcoma have emerged in the last four decades. Using insights gained from a genome-wide association study and mouse modeling, we show that GRM4 plays a role in driving osteosarcoma via a non–cell-autonomous mechanism regulating IL23, opening new avenues for therapeutic intervention.
    [Show full text]
  • Metabotropic Glutamate Receptors
    mGluR Metabotropic glutamate receptors mGluR (metabotropic glutamate receptor) is a type of glutamate receptor that are active through an indirect metabotropic process. They are members of thegroup C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatoryneurotransmitter. The mGluRs perform a variety of functions in the central and peripheral nervous systems: mGluRs are involved in learning, memory, anxiety, and the perception of pain. mGluRs are found in pre- and postsynaptic neurons in synapses of the hippocampus, cerebellum, and the cerebral cortex, as well as other parts of the brain and in peripheral tissues. Eight different types of mGluRs, labeled mGluR1 to mGluR8, are divided into groups I, II, and III. Receptor types are grouped based on receptor structure and physiological activity. www.MedChemExpress.com 1 mGluR Agonists, Antagonists, Inhibitors, Modulators & Activators (-)-Camphoric acid (1R,2S)-VU0155041 Cat. No.: HY-122808 Cat. No.: HY-14417A (-)-Camphoric acid is the less active enantiomer (1R,2S)-VU0155041, Cis regioisomer of VU0155041, is of Camphoric acid. Camphoric acid stimulates a partial mGluR4 agonist with an EC50 of 2.35 osteoblast differentiation and induces μM. glutamate receptor expression. Camphoric acid also significantly induced the activation of NF-κB and AP-1. Purity: ≥98.0% Purity: ≥98.0% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10 mM × 1 mL, 100 mg Size: 10 mM × 1 mL, 5 mg, 10 mg, 25 mg (2R,4R)-APDC (R)-ADX-47273 Cat. No.: HY-102091 Cat. No.: HY-13058B (2R,4R)-APDC is a selective group II metabotropic (R)-ADX-47273 is a potent mGluR5 positive glutamate receptors (mGluRs) agonist.
    [Show full text]
  • Use of Compounds Binding to the Sigma Receptor Ligands for the Treatment of Neuropathic Pain Developing As a Consequence of Chemotherapy
    (19) & (11) EP 2 090 311 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 19.08.2009 Bulletin 2009/34 A61K 31/495 (2006.01) A61P 25/02 (2006.01) A61P 29/02 (2006.01) (21) Application number: 08384001.7 (22) Date of filing: 18.02.2008 (84) Designated Contracting States: • Vela Hernàndez, José Miguel AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 08028 Barcelona (ES) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT • Zamanillo-Castanedo, Daniel RO SE SI SK TR 08041 Barcelona (ES) Designated Extension States: • Nieto-López, Francisco Rafael AL BA MK RS Dpt. Farmacia, Facultad de Medicina 18012 Granada (ES) (71) Applicant: Laboratorios Del. Dr. Esteve, S.A. 08041 Barcelona (ES) (74) Representative: Peters, Hajo et al Graf von Stosch (72) Inventors: Patentanwaltsgesellschaft mbH • Baeyens-Cabrera, José Manuel Prinzregentenstrasse 22 Dpt. Farmacia, F. Medicina 80538 München (DE) 18012 Granada (ES) • Buschmann, Helmut H. Remarks: 08960 Sant Just Desvern (ES) The references to the drawing(s) no. 6 are deemed to be deleted (Rule 56(4) EPC). (54) Use of compounds binding to the sigma receptor ligands for the treatment of neuropathic pain developing as a consequence of chemotherapy (57) The present invention refers to the use of compounds binding to the sigma receptor for the treatment or prevention of neuropathic pain resulting from chemotherapy. EP 2 090 311 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 090 311 A1 Description Field of the invention 5 [0001] The present invention refers to the use of compounds binding to the sigma receptor for the treatment or prevention of neuropathic pain resulting from chemotherapy.
    [Show full text]
  • Neurotransmitters-Drugs Andbrain Function.Pdf
    Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Edited by R. A. Webster Department of Pharmacology, University College London, UK JOHN WILEY & SONS, LTD Chichester Á New York Á Weinheim Á Brisbane Á Singapore Á Toronto Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Copyright # 2001 by John Wiley & Sons Ltd. Bans Lane, Chichester, West Sussex PO19 1UD, UK National 01243 779777 International ++44) 1243 779777 e-mail +for orders and customer service enquiries): [email protected] Visit our Home Page on: http://www.wiley.co.uk or http://www.wiley.com All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1P0LP,UK, without the permission in writing of the publisher. Other Wiley Editorial Oces John Wiley & Sons, Inc., 605 Third Avenue, New York, NY 10158-0012, USA WILEY-VCH Verlag GmbH, Pappelallee 3, D-69469 Weinheim, Germany John Wiley & Sons Australia, Ltd.
    [Show full text]
  • GABA Receptors
    D Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews Review No.7 / 1-2011 GABA receptors Wolfgang Froestl , CNS & Chemistry Expert, AC Immune SA, PSE Building B - EPFL, CH-1015 Lausanne, Phone: +41 21 693 91 43, FAX: +41 21 693 91 20, E-mail: [email protected] GABA Activation of the GABA A receptor leads to an influx of chloride GABA ( -aminobutyric acid; Figure 1) is the most important and ions and to a hyperpolarization of the membrane. 16 subunits with γ most abundant inhibitory neurotransmitter in the mammalian molecular weights between 50 and 65 kD have been identified brain 1,2 , where it was first discovered in 1950 3-5 . It is a small achiral so far, 6 subunits, 3 subunits, 3 subunits, and the , , α β γ δ ε θ molecule with molecular weight of 103 g/mol and high water solu - and subunits 8,9 . π bility. At 25°C one gram of water can dissolve 1.3 grams of GABA. 2 Such a hydrophilic molecule (log P = -2.13, PSA = 63.3 Å ) cannot In the meantime all GABA A receptor binding sites have been eluci - cross the blood brain barrier. It is produced in the brain by decarb- dated in great detail. The GABA site is located at the interface oxylation of L-glutamic acid by the enzyme glutamic acid decarb- between and subunits. Benzodiazepines interact with subunit α β oxylase (GAD, EC 4.1.1.15). It is a neutral amino acid with pK = combinations ( ) ( ) , which is the most abundant combi - 1 α1 2 β2 2 γ2 4.23 and pK = 10.43.
    [Show full text]
  • Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: a PET Study in Conscious Monkeys
    Neuropsychopharmacology (2013) 38, 2666–2674 & 2013 American College of Neuropsychopharmacology. All rights reserved 0893-133X/13 www.neuropsychopharmacology.org Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys 1 1 1 1 1 Shigeyuki Yamamoto , Hiroyuki Ohba , Shingo Nishiyama , Norihiro Harada , Takeharu Kakiuchi , 1 ,2 Hideo Tsukada and Edward F Domino* 1 2 Central Research Laboratory, Hamamatsu Photonics KK, Hamakita, Japan; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA Subanesthetic doses of ketamine, an N-methyl-D-aspartic acid (NMDA) antagonist, have a rapid antidepressant effect which lasts for up to 2 weeks. However, the neurobiological mechanism regarding this effect remains unclear. In the present study, the effects of subanesthetic doses of ketamine on serotonergic systems in conscious monkey brain were investigated. Five young monkeys 11 underwent four positron emission tomography measurements with [ C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzoni- 11 trile ([ C]DASB) for the serotonin transporter (SERT), during and after intravenous infusion of vehicle or ketamine hydrochloride in a 11 dose of 0.5 or 1.5 mg/kg for 40 min, and 24 h post infusion. Global reduction of [ C]DASB binding to SERT was observed during ketamine infusion in a dose-dependent manner, but not 24 h later. The effect of ketamine on the serotonin 1A receptor (5-HT1A-R) and dopamine transporter (DAT) was also investigated in the same subjects studied with [11C]DASB. No significant changes were observed in either 5-HT -R or DAT binding after ketamine infusion. Microdialysis analysis indicated that ketamine infusion transiently increased 1A serotonin levels in the extracellular fluid of the prefrontal cortex.
    [Show full text]
  • Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation
    www.sciencemag.org/cgi/content/full/327/5963/348/DC1 Supporting Online Material for Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation Jason Rihel,* David A. Prober, Anthony Arvanites, Kelvin Lam, Steven Zimmerman, Sumin Jang, Stephen J. Haggarty, David Kokel, Lee L. Rubin, Randall T. Peterson, Alexander F. Schier* *To whom correspondence should be addressed. E-mail: [email protected] (A.F.S.); [email protected] (J.R.) Published 15 January 2010, Science 327, 348 (2010) DOI: 10.1126/science.1183090 This PDF file includes: Materials and Methods SOM Text Figs. S1 to S18 Table S1 References Supporting Online Material Table of Contents Materials and Methods, pages 2-4 Supplemental Text 1-7, pages 5-10 Text 1. Psychotropic Drug Discovery, page 5 Text 2. Dose, pages 5-6 Text 3. Therapeutic Classes of Drugs Induce Correlated Behaviors, page 6 Text 4. Polypharmacology, pages 6-7 Text 5. Pharmacological Conservation, pages 7-9 Text 6. Non-overlapping Regulation of Rest/Wake States, page 9 Text 7. High Throughput Behavioral Screening in Practice, page 10 Supplemental Figure Legends, pages 11-14 Figure S1. Expanded hierarchical clustering analysis, pages 15-18 Figure S2. Hierarchical and k-means clustering yield similar cluster architectures, page 19 Figure S3. Expanded k-means clustergram, pages 20-23 Figure S4. Behavioral fingerprints are stable across a range of doses, page 24 Figure S5. Compounds that share biological targets have highly correlated behavioral fingerprints, page 25 Figure S6. Examples of compounds that share biological targets and/or structural similarity that give similar behavioral profiles, page 26 Figure S7.
    [Show full text]
  • NINDS Custom Collection II
    ACACETIN ACEBUTOLOL HYDROCHLORIDE ACECLIDINE HYDROCHLORIDE ACEMETACIN ACETAMINOPHEN ACETAMINOSALOL ACETANILIDE ACETARSOL ACETAZOLAMIDE ACETOHYDROXAMIC ACID ACETRIAZOIC ACID ACETYL TYROSINE ETHYL ESTER ACETYLCARNITINE ACETYLCHOLINE ACETYLCYSTEINE ACETYLGLUCOSAMINE ACETYLGLUTAMIC ACID ACETYL-L-LEUCINE ACETYLPHENYLALANINE ACETYLSEROTONIN ACETYLTRYPTOPHAN ACEXAMIC ACID ACIVICIN ACLACINOMYCIN A1 ACONITINE ACRIFLAVINIUM HYDROCHLORIDE ACRISORCIN ACTINONIN ACYCLOVIR ADENOSINE PHOSPHATE ADENOSINE ADRENALINE BITARTRATE AESCULIN AJMALINE AKLAVINE HYDROCHLORIDE ALANYL-dl-LEUCINE ALANYL-dl-PHENYLALANINE ALAPROCLATE ALBENDAZOLE ALBUTEROL ALEXIDINE HYDROCHLORIDE ALLANTOIN ALLOPURINOL ALMOTRIPTAN ALOIN ALPRENOLOL ALTRETAMINE ALVERINE CITRATE AMANTADINE HYDROCHLORIDE AMBROXOL HYDROCHLORIDE AMCINONIDE AMIKACIN SULFATE AMILORIDE HYDROCHLORIDE 3-AMINOBENZAMIDE gamma-AMINOBUTYRIC ACID AMINOCAPROIC ACID N- (2-AMINOETHYL)-4-CHLOROBENZAMIDE (RO-16-6491) AMINOGLUTETHIMIDE AMINOHIPPURIC ACID AMINOHYDROXYBUTYRIC ACID AMINOLEVULINIC ACID HYDROCHLORIDE AMINOPHENAZONE 3-AMINOPROPANESULPHONIC ACID AMINOPYRIDINE 9-AMINO-1,2,3,4-TETRAHYDROACRIDINE HYDROCHLORIDE AMINOTHIAZOLE AMIODARONE HYDROCHLORIDE AMIPRILOSE AMITRIPTYLINE HYDROCHLORIDE AMLODIPINE BESYLATE AMODIAQUINE DIHYDROCHLORIDE AMOXEPINE AMOXICILLIN AMPICILLIN SODIUM AMPROLIUM AMRINONE AMYGDALIN ANABASAMINE HYDROCHLORIDE ANABASINE HYDROCHLORIDE ANCITABINE HYDROCHLORIDE ANDROSTERONE SODIUM SULFATE ANIRACETAM ANISINDIONE ANISODAMINE ANISOMYCIN ANTAZOLINE PHOSPHATE ANTHRALIN ANTIMYCIN A (A1 shown) ANTIPYRINE APHYLLIC
    [Show full text]
  • Cholecystokinin Octapeptide Antagonized Opioid Analgesia Mediated by /T- and R- but Not Cs-Receptors in the Spinal Cord of the Rat
    Brain Research, 523 (1990) 5-10 5 Elsevier BRES 15696 Cholecystokinin octapeptide antagonized opioid analgesia mediated by /t- and r- but not cS-receptors in the spinal cord of the rat Xiao-Jing Wang, Xiao-Hong Wang and Ji-Sheng Han Department of Physiology, Beijing Medical University, Beijing (People's Republic of China) (Accepted 23 January 1990) Key words: Cholecystokinin octapeptide; (N-MePhea,o-Pro4) Morphiceptin; (N-MeTyrl,N-MeArg7,D-Leu 8) Dynorphin(1-8) ethylamide; (D-Pen 2'5) Enkephalin; Proglumide; Intrathecal injection; Opioid analgesia; Antiopioid effect Intrathecal (ith) injection of cholecystokinin octapeptide (CCK-8) to the rat with single dose of 4 or 40 ng, or successive doses from 0.1 to 1/ag at 10 rain intervals produced neither analgesia nor hyperalgesia. However, the analgesia produced by ith injection of PL017, a specific /~-reeeptor agonist or 66A-078, a specific r-receptor agonist could be markedly antagonized by CCK-8 at a dose as small as 4 ng. In contrast, analgesia produced by ith injection of 6-agonist DPDPE could not be blocked by CCK-8 even at a dose as high as 40 ng. Since the effect of CCK-8 could be totally reversed by the CCK receptor antagonist proglumide, this effect is most probably mediated by CCK receptors. INTRODUCTION MATERIALS AND METHODS Cholecystokinin octapeptide (CCK-8) has been known Surgical procedures and intrathecal injection of drugs Male Wistar rats weighing 200-250 g were anesthetized with as a neuropeptide of abundant and wide distribution in chlorohydrate (0.4 g/kg, i.p.). PE-10 polyethiene catheter of 7.5 cm CNS 1 with some important physiological functions in- long was implanted through the atlanto-occipital membrane down to cluding the anti-opioid effect4'9.
    [Show full text]