DOCSLIB.ORG

Structural Determinants for Substrate and Inhibitor Recognition by the Dopamine Transporter Okechukwu T

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Structural Determinants for Substrate and Inhibitor Recognition by the Dopamine Transporter Okechukwu T Duquesne University Duquesne Scholarship Collection Electronic Theses and Dissertations Fall 2005 Structural Determinants for Substrate and Inhibitor Recognition by the Dopamine Transporter Okechukwu T. Ukairo Follow this and additional works at: https://dsc.duq.edu/etd Recommended Citation Ukairo, O. (2005). Structural Determinants for Substrate and Inhibitor Recognition by the Dopamine Transporter (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/etd/1297 This Immediate Access is brought to you for free and open access by Duquesne Scholarship Collection. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of Duquesne Scholarship Collection. For more information, please contact [email protected]. STRUCTURAL DETERMINANTS FOR SUBSTRATE AND INHIBITOR RECOGNITION BY THE DOPAMINE TRANSPORTER A Dissertation Presented to the Graduate School of Pharmaceutical Sciences Of Duquesne University In Partial Fulfillment of the Requirements for the Degree Of Doctor of Philosophy Pharmacology and Toxicology By Okechukwu T. Ukairo December 9, 2005 ii COPYRIGHT NOTICE The information contained within this document is protected under the copyright laws of the United States of America. Duplication of this document is prohibited without the written permission of the copyright holder. iii ACKNOWLEDGEMENTS I would like to express my sincere gratitude to Dr. Chris Surratt, my thesis advisor, for his years of support and guidance. Dr. Surratt has been a great mentor and I’ve become a better scientist under his guidance. I am also deeply grateful to members of my dissertation committee, Drs. Paula Witt-Enderby, Wilson Meng, David Johnson and John Pollock for their invaluable suggestions and continued encouragement throughout the course of my research. I am particularly indebted to Dr Pollock for his help with confocal microscopy experiments. Dr. Pollock was unstinting in his help and I have constantly drawn from his expert knowledge and good advice. I extend special thanks to Dr. Simon Watkins of the University of Pittsburgh, PA for allowing me the use of his laboratory facilities. I gratefully acknowledge the help I received from Suneetha Ramanujapuram, Corry Bondi, Stephen Pan, and Mike Schmidt in carrying out some of the experiments. Drs. Doug Bricker, Fred Fotchman, Thomas Mattei, and Wilson Meng have been a source of good counsel and encouragement and I am deeply grateful to them. My sojourn at Duquesne University has been a wonderful and rewarding experience due to the love and support of great friends such as Nick and Lisa Radio, Dr. Viji Pokala, and Jeff Kovacs. They continuously challenged me in their respective ways to become a better and more focused graduate student. My sincere and heartfelt thanks to my wife, Stella, and our kids, Lulu and Toby, for their selfless understanding and patience and without whom all these wouldn’t have been possible. iv TABLE OF CONTENTS PAGES I. INTRODUCTION ..............................................................................................1 A. Overview......................................................................................................1 B. Statement of the problem.............................................................................4 C. Literature Survey .........................................................................................7 1. Structure of the Dopamine Transporter ....................................................7 2. Substrate and Inhibitor Selectivity of the DAT.........................................10 Benztropines ............................................................................................11 GBR Compounds .....................................................................................12 Mazindol...................................................................................................13 WIN-type of compounds...........................................................................13 4-ARA-127 ...............................................................................................14 3. Structure-Function Analysis of the Dopamine Transporter .....................15 a. Transmembrane (TM) domains...........................................................15 b. Extracellular loops (ECL).....................................................................24 c. Intracellular loops (ICL) .......................................................................26 4. Regulation of DAT Function....................................................................27 a. Post-translational modification ............................................................27 b. Protein-protein interactions .................................................................29 c. Transporter oligomerization.................................................................31 II. MATERIALS AND METHODS ......................................................................33 A. Materials and Equipment ...........................................................................33 1. Facilities..................................................................................................33 v 2. Cell lines...............................................................................................33 3. Chemicals and Drugs ...........................................................................33 4. Materials...............................................................................................37 5. Equipment ............................................................................................38 6. Computer Software...............................................................................39 B. Methodology and Procedures ....................................................................40 1. Cell culture..............................................................................................40 2. Site- directed mutagenesis .....................................................................41 3. Cell Transfections ...................................................................................43 4. Immunocytochemistry and confocal microscopy.....................................45 5. [3H]-Dopamine saturation uptake assays................................................46 6. [3H]-Dopamine uptake inhibition assays .................................................47 7. [3H]WIN35,428 saturation binding assays...............................................48 8. [3H]WIN35,428 binding inhibition assays ................................................48 9. Protein assays ........................................................................................50 III. RESULTS AND DISCUSSION .....................................................................52 A. Results.......................................................................................................52 1. Expression, localization and function of WT DAT and D79 mutant DATs .....................................................................................................................52 2. Assessing the role of DAT TM 1 D79 residue in dopamine uptake.........56 3. Effect of DAT inhibitors on CHO cells stably expressing WT or D79E DAT .....................................................................................................................60 vi 4. Effects of cell age, density and DAT cell surface expression on the DUIPs of classical DAT inhibitors............................................................................67 B. Discussion..................................................................................................74 IV. CONCLUSIONS ...........................................................................................86 V. APPENDICES ...............................................................................................87 VI. REFERENCES.............................................................................................91 VII. ABSTRACT...............................................................................................101 vii LIST OF TABLES PAGES Table 1. Effect of DAT substrates on CHO cells stably expressing WT and D79E DAT. ................................................................................................................................. 59 Table 2. Dopamine uptake inhibition potencies and binding affinities of structurally diverse DAT inhibitors at CHO cells stably expressing WT or D79E DAT. ................................................................................................................................. 65 Table 3. Dopamine uptake inhibition potencies and binding affinities of benztropine and its analogs at CHO cells stably expressing WT or D79E DAT.. 66 Table 4. Effect of DAT blockers on WT DAT-CHO cells of different passage numbers........................................................................................................................... 69 Table 5. Effect of cell density on the DUIP and binding affinity of cocaine at WT DAT-CHO cells. .............................................................................................................. 70 Table 6. Effects of DAT cell surface expression on the DUIP of cocaine ............ 71 Table 7. Kinetic and binding characteristics of rDAT wild-type in CHO cells of different passage numbers. .......................................................................................... 73 viii LIST OF FIGURES PAGES
Load more

Recommended publications
  • Dopamine Reuptake Transporter (DAT) “Inverse Agonism” E Anovel 66 2 67 3 Hypothesis to Explain the Enigmatic Pharmacology of Cocaine 68 4 * 69 5 Q5 David J
    NP5526_proof ■ 24 June 2014 ■ 1/22 Neuropharmacology xxx (2014) 1e22 55 Contents lists available at ScienceDirect 56 57 Neuropharmacology 58 59 60 journal homepage: www.elsevier.com/locate/neuropharm 61 62 63 64 65 1 Dopamine reuptake transporter (DAT) “inverse agonism” e Anovel 66 2 67 3 hypothesis to explain the enigmatic pharmacology of cocaine 68 4 * 69 5 Q5 David J. Heal , Jane Gosden, Sharon L. Smith 70 6 71 RenaSci Limited, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK 7 72 8 73 9 article info abstract 74 10 75 11 76 Article history: The long held view is cocaine's pharmacological effects are mediated by monoamine reuptake inhibition. 12 Available online xxx However, drugs with rapid brain penetration like sibutramine, bupropion, mazindol and tesofensine, 77 13 which are equal to or more potent than cocaine as dopamine reuptake inhibitors, produce no discernable 78 14 Keywords: subjective effects such as drug “highs” or euphoria in drug-experienced human volunteers. Moreover 79 15 Cocaine they are dysphoric and aversive when given at high doses. In vivo experiments in animals demonstrate 80 16 Dopamine reuptake inhibitor that cocaine's monoaminergic pharmacology is profoundly different from that of other prescribed 81 Dopamine releasing agent 17 monoamine reuptake inhibitors, with the exception of methylphenidate. These findings led us to 82 Dopamine transporter fi 18 Inverse agonist conclude that the highly unusual, stimulant pro le of cocaine and related compounds, eg methylphe- 83 19 DAT inverse agonist nidate, is not mediated by monoamine reuptake inhibition alone. 84 We describe the experimental findings which suggest cocaine serves as a negative allosteric 20 Novel mechanism 85 21 modulator to alter the function of the dopamine reuptake transporter (DAT) and reverse its direction of fi 86 22 transport.
    [Show full text]
  • World of Cognitive Enhancers
    ORIGINAL RESEARCH published: 11 September 2020 doi: 10.3389/fpsyt.2020.546796 The Psychonauts’ World of Cognitive Enhancers Flavia Napoletano 1,2, Fabrizio Schifano 2*, John Martin Corkery 2, Amira Guirguis 2,3, Davide Arillotta 2,4, Caroline Zangani 2,5 and Alessandro Vento 6,7,8 1 Department of Mental Health, Homerton University Hospital, East London Foundation Trust, London, United Kingdom, 2 Psychopharmacology, Drug Misuse, and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom, 3 Swansea University Medical School, Institute of Life Sciences 2, Swansea University, Swansea, United Kingdom, 4 Psychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy, 5 Department of Health Sciences, University of Milan, Milan, Italy, 6 Department of Mental Health, Addictions’ Observatory (ODDPSS), Rome, Italy, 7 Department of Mental Health, Guglielmo Marconi” University, Rome, Italy, 8 Department of Mental Health, ASL Roma 2, Rome, Italy Background: There is growing availability of novel psychoactive substances (NPS), including cognitive enhancers (CEs) which can be used in the treatment of certain mental health disorders. While treating cognitive deficit symptoms in neuropsychiatric or neurodegenerative disorders using CEs might have significant benefits for patients, the increasing recreational use of these substances by healthy individuals raises many clinical, medico-legal, and ethical issues. Moreover, it has become very challenging for clinicians to Edited by: keep up-to-date with CEs currently available as comprehensive official lists do not exist. Simona Pichini, Methods: Using a web crawler (NPSfinder®), the present study aimed at assessing National Institute of Health (ISS), Italy Reviewed by: psychonaut fora/platforms to better understand the online situation regarding CEs.
    [Show full text]
  • DOPAMINE TRANSPORTER in ALCOHOLISM a SPET Study
    DOPAMINE TRANSPORTER IN PEKKA ALCOHOLISM LAINE A SPET study Departments of Psychiatry and Clinical Chemistry, University of Oulu Department of Forensic Psychiatry, University of Kuopio Department of Clinical Physiology and Nuclear Medicine, University of Helsinki OULU 2001 PEKKA LAINE DOPAMINE TRANSPORTER IN ALCOHOLISM A SPET study Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in the Väinö Pääkkönen Hall of the Department of Psychiatry (Peltolantie 5), on November 30th, 2001, at 12 noon. OULUN YLIOPISTO, OULU 2001 Copyright © 2001 University of Oulu, 2001 Manuscript received 12 October 2001 Manuscript accepted 16 October 2001 Communicated by Professor Esa Korpi Professor Matti Virkkunen ISBN 951-42-6527-0 (URL: http://herkules.oulu.fi/isbn9514265270/) ALSO AVAILABLE IN PRINTED FORMAT ISBN 951-42-6526-2 ISSN 0355-3221 (URL: http://herkules.oulu.fi/issn03553221/) OULU UNIVERSITY PRESS OULU 2001 Laine, Pekka, Dopamine transporter in alcoholism A SPET study Department of Clinical Chemistry, Division of Nuclear Medicine, University of Oulu, P.O.Box 5000, FIN-90014 University of Oulu, Finland, Department of Forensic Psychiatry, University of Kuopio, , FIN-70211 University of Kuopio, Finland, Department of Clinical Physiology and Nuclear Medicine, Division of Nuclear Medicine, University of Helsinki, P.O. Box 340, FIN-00029 Helsinki, Finland, Department of Psychiatry, University of Oulu, P.O.Box 5000, FIN-90014 University of Oulu, Finland 2001 Oulu, Finland (Manuscript received 12 October 2001) Abstract A large body of animal studies indicates that reinforcement from alcohol is associated with dopaminergic neurotransmission in the mesocorticolimbic pathway. However, as most psychiatric phenomena cannot be studied with animals, human studies are needed.
    [Show full text]
  • The Pharmacology of an Agonist Medication to Treat Stimulant Use Disorder
    Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2017 The Pharmacology of an Agonist Medication to Treat Stimulant Use Disorder Amy Johnson johnsonar24 Follow this and additional works at: https://scholarscompass.vcu.edu/etd © Amy Johnson Downloaded from https://scholarscompass.vcu.edu/etd/5177 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. © Amy R. Johnson 2017 All Rights Reserved The Pharmacology of an Agonist Medication to Treat Stimulant Use Disorder A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University by Amy R. Johnson Bachelor of Science, University of Wisconsin - Eau Claire, 2013 Advisor: S. Stevens Negus, PhD Professor of Pharmacology and Toxicology Virginia Commonwealth University Virginia Commonwealth University Richmond, VA November, 2017 Acknowledgements Thank you to all the people who made this dissertation possible. I would like to thank my family for their support and belief in me. Many thanks to my dissertation advisor, Steve Negus, for his guidance, knowledge, patience, and encouragement. Thank you to Katherine Nicholson and Matthew Banks, each of whom guided me through a different procedure through the course of my research and served on my committee. Thanks to my remaining committee members, Lori Keyser-Marcus and Jose Eltit, for their time and commitment to my project. Thank you to my entire committee for helping to develop and mold me as a scientist.
    [Show full text]
  • Mechanisms of Cocaine Abuse and Toxicity
    Mechanisms of Cocaine Abuse and Toxicity U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol, Drug Abuse, and Mental Health Administration I Mechanisms of Cocaine Abuse and Toxicity Editors: Doris Clouet, Ph.D. Khursheed Asghar, Ph.D. Roger Brown, Ph.D. Division of Preclinical Research National Institute on Drug Abuse NIDA Research Monograph 88 1988 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, DC 20402 NIDA Research Monographs are prepared by the research divisions of the National Institute on Drug Abuse and published by its Office of Science. The primary objective of the series is to provide critical reviews of research problem areas and techniques, the content of state-of-the-art conferences, and integrative research reviews. Its dual publication emphasis is rapid and targeted dissemination to the scientific and professional community. Editorial Advisors MARTIN W. ADLER, Ph.D. MARY L. JACOBSON Temple University School of Medicine National Federation of Parents for Philadelphia,Pennsylvania Drug-Free Youth Omaha, Nebraska SYDNEY ARCHER, Ph.D. Rensselaer Polytechnic lnstitute Troy, New York REESE T. JONES, M.D. Langley Porter Neuropsychiatric lnstitute RICHARD E. BELLEVILLE, Ph.D. San Francisco, California NB Associates, Health Sciences RockviIle, Maryland DENISE KANDEL, Ph.D. KARST J. BESTEMAN College of Physicians and Surgeons of Alcohol and Drug Problems Association Columbia University of North America New York, New York Washington, D.C. GILBERT J.
    [Show full text]
  • List of SSRI Effects Spirits for MD Widespread Use of Antidepressants
    List of SSRI Effects Spirits for MD widespread use of antidepressants in new SSRI-era, 2C family, 5-HT2Ay overactivity, 5-HT pro-drugs, abdominal distension, abnormal brain states, Abnormal Dreams, abnormal personalities, Abnormal Thinking, abnormally extreme emotions, abrupt cessation, abrupt interruption therapy, Acting aggressive, acting on dangerous impulses, active metabolite, acute pharma- cological action of meds, adaptation phase, & theory, addictions, Adhyperforin, adverse drug reaction, adverse effects, Advil, affect newborns, affect reuptake inhibition of serotonin & norepinephrine, aggression, aggressiveness, agitation, agomelatine, agoraphobia, akathisia, Alaproclate, alcohol use, alcohol Abuse, alcohol mixed with meds, alcoholism, Aleve, Allosteric serotonin reuptake inhibitor, alprazolam, altering hormones, alteration of neuronal activity in central nervous system, altered brain, altered mind, altered thinking, ambien, Amitifadine, amitriptyline, Amnesia, Amoxapine, Anafranil, analgesic, anorexia nervosa, anorgasmia, anti- depressant withdrawal aids, Anti-inflammatory, antiarrhythmic agents, antidepressant activity, Antidepressant Nightmares, antidepressant withdrawal symptoms, antidepressant-associated mania, antidepressant- associated psychosis, antidepressants, antipsychotic diphenylbutylpiperidine derivative, anxiety, anxiety related disorders, appetite changes, Aropax, arson, Asentra, Aspirin, ASA, Attempted Murder, Attempted suicide, auditory hallucinations, autism, autoimmune hypersensitivity, autonomic dysfunctions,
    [Show full text]
  • Cocaine Addiction: Changes in Excitatory and Inhibitory Neurotransmission
    4 Cocaine Addiction: Changes in Excitatory and Inhibitory Neurotransmission Edgar Antonio Reyes-Montaño and Edwin Alfredo Reyes-Guzmán Protein Research Group (Grupo de Investigación en Proteínas, GRIP) Universidad Nacional de Colombia, Sede Bogotá Colombia 1. Introduction The principal routes of cocaine administration are oral, intranasal, intravenous, and inhalation. The slang terms for these routes are, respectively, "chewing," "snorting," "mainlining," "injecting," and "smoking" (including freebase and crack cocaine). Cocaine use ranges from occasional use to repeated or compulsive use, with a variety of patterns between these extremes. There is no safe way to use cocaine. Any route of administration can lead to absorption of toxic amounts of cocaine, allowing to acute cardiovascular or cerebrovascular emergencies that could result in sudden death. Repeated cocaine use by any route of administration can produce addiction and other adverse health consequences. Those who snort or sniff cocaine through their noses suffer damage to their nasal and sinus passages. These include nasal crusting, nosebleeds, nasal congestion, irritation, facial pain caused by sinusitis and hoarseness. Cocaine addiction changes the responsiveness of the brain to various neurotransmitters or chemicals. The development of drug addiction involves persistent cellular and molecular changes in the Central Nervious System. The brain dopamine, GABA and glutamate systems play key roles in mediating drug-induced neuroadaptation. We show some physiological changes that can occur in some key pathways in which glutamate, dopamine and GABA receptors are involved. These chemical changes cause different effects in users, including: anxiety, confusion, dizziness, psychosis, headaches and nausea. Cocaine use and addiction affects the sympathetic nervous system (which controls automatic functions such as breathing, heartbeat, etc.).
    [Show full text]
  • Datscan, INN- Ioflupane (123I)
    SCIENTIFIC DISCUSSION This module reflects the initial scientific discussion and scientific discussion on procedures, which have been finalised before 1 February 2004. For scientific information on procedures after this date please refer to module 8B. I Introduction DaTSCAN is a diagnostic medicinal product containing the active substance ioflupane ( 123I) INN, (otherwise referred to as 123I-FP-CIT or 123I-β-CIT-FP) which is a radioiodinated cocaine analogue. This cocaine analogue is a ligand with high affinity to dopamine transporter (DaT) located on the presynaptic nerve endings (axon terminals) in the striatum. The axon terminals are projections of the dopamine neurones in the substantia nigra. Therefore, binding of DaTSCAN in the striatum is claimed to reflect the number of dopaminergic neurones in the substantia nigra. It has been developed as a dopamine transporter imaging agent for single photon emission computed tomography (SPECT). The technique is claimed to be sensitive enough to differentiate changes in the nigrostriatal dopaminergic system in patients with Parkinsonism and healthy controls. The indication is as follows: DaTSCAN is indicated for detecting loss of functional dopaminergic neuron terminals in the striatum of patients with clinically uncertain Parkinsonian Syndromes, in order to help differentiate Essential Tremor from Parkinsonian Syndromes related to idiopathic Parkinson’s Disease, Multiple System Atrophy and Progressive Supranuclear Palsy. DaTSCAN is unable to discriminate between Parkinson's Disease, Multiple System Atrophy and Progressive Supranuclear Palsy. Parkinson's disease is characterised by akinesia, rigidity and abnormal involuntary movements. True Parkinsonian syndrome includes conditions like multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), in addition to Parkinson's disease.
    [Show full text]
  • Synthesis and Evaluation of Novel Tropane Compounds As Potential Therapeutics for Drug Abuse
    University of New Orleans ScholarWorks@UNO University of New Orleans Theses and Dissertations Dissertations and Theses 8-8-2007 Synthesis And Evaluation Of Novel Tropane Compounds As Potential Therapeutics For Drug Abuse Harneet Kaur University of New Orleans Follow this and additional works at: https://scholarworks.uno.edu/td Recommended Citation Kaur, Harneet, "Synthesis And Evaluation Of Novel Tropane Compounds As Potential Therapeutics For Drug Abuse" (2007). University of New Orleans Theses and Dissertations. 586. https://scholarworks.uno.edu/td/586 This Dissertation is protected by copyright and/or related rights. It has been brought to you by ScholarWorks@UNO with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in University of New Orleans Theses and Dissertations by an authorized administrator of ScholarWorks@UNO. For more information, please contact [email protected]. Synthesis And Evaluation Of Novel Tropane Compounds As Potential Therapeutics For Drug Abuse A Dissertation Submitted to the Graduate Faculty of the University of New Orleans in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Chemistry by Harneet Kaur M.S. (Hons) Panjab University 2001 M.S. University of New Orleans 2004 August 2007 To my family, for their love and support Father: Dr.
    [Show full text]
  • Michael J. Kuhar, Ph.D Page 1 10/1/2014 CURRICULUM VITAE Michael Joseph Kuhar
    Michael J. Kuhar, Ph.D Page 1 10/1/2014 CURRICULUM VITAE Michael Joseph Kuhar Address: Yerkes National Primate Research Center of Emory University Division of Behavioral Neuroscience and Psychiatric Disorders 954 Gatewood Rd. NE Atlanta, GA 30329 Phone: (404) 727-3274 e-mail: [email protected]; [email protected]; [email protected] Web site: http://www.emory.edu/NEUROSCIENCE/Kuhar Education: 1965, B.S., University of Scranton, Scranton, Pennsylvania, Departments of Physics and Philosophy, Magna cum Laude 1970, Ph.D., The Johns Hopkins University, Baltimore, Maryland, Departments of Biophysics and Pharmacology Present Positions: November 1995-present, Professor, Emory Uinversity Charles Howard Candler Professor of Neuropharmacology Georgia Research Alliance Eminent Scholar Center for Ethics, Senior Fellow Division of Behavioral Neuroscience and Psychiatric Disorders (Chief of the Neuroscience Division, 1995-2010) Yerkes National Primate Research Center of Emory University, Department of Pharmacology, Emory University School of Medicine Previous Positions: July 1985-November 1995 Chief, Neuroscience Branch, Addiction Research Center National Institute on Drug Abuse Professor, Part-time, The Johns Hopkins University School of Medicine, Departments of Neuroscience, Pharmacology and Psychiatry July 1981, Professor, The Johns Hopkins University School of Medicine, Departments of Neuroscience, Pharmacology and Psychiatry July 1980, Associate Professor, The Johns Hopkins University School of Medicine, Departments of Neuroscience, Pharmacology and Psychiatry July 1976, Associate Professor, The Johns Hopkins University School of Medicine, Departments of Pharmacology and Psychiatry October 1972, Assistant Professor, The Johns Hopkins University School of Medicine, Departments of Pharmacology and Psychiatry October 1970, Postdoctoral Fellow, Yale University School of Medicine, Department of Psychiatry and Basic Biological Sciences Michael J.
    [Show full text]
  • Tuesday, December 13, 2005 Poster Session II
    Neuropsychopharmacology (2005) 30, S143-S209 © 2005 Nature Publishing Group All rights reserved 0893-133X/05 www.neuropsychopharmacology.org S143 Tuesday, December 13, 2005 the context of cocaine delivery can alter the neurochemical responses to Poster Session II - Tuesday the drug. In addition, increasing evidence suggests that stress can also in- fluence COC reinforcement through extrahypothalamic brain regions. The present study was designed to determine differences in the neuro- 1. Diffusion Tensor Imaging in Cocaine Dependence: Evidence for chemical and neuroendocrine responses to COC during response-con- Reduced Myelin in the Anterior Corpus Callosum tingent and response-independent COC administration in rats. F. Gerard Moeller*, Khader M Hassan, Joel L Steinberg, Ignacio Methods: Male Wistar rats were divided into triads of 3 rats each: Valdes, Larry Kramer, Ponnada A Narayana and Alan C Swann one rat was selected as the self-administration (SA) rat, while the Psychiatry and Behavioral Sciences, Univ. of Texas Health Sci. Center other two rats were designated as the yoked-cocaine (YC) and yoked- at Houston, Houston, TX, USA saline (YS) rats, respectively. Rats were implanted with jugular Sponsor: Alan Swann catheters and a microdialysis guide cannula aimed at the medial pre- frontal cortex (MPC). SA rats were trained to self-administer cocaine Background: Fractional anisotropy (FA) as measured by diffusion (0.25 mg/kg/inf) under a fixed-ratio 2 schedule of reinforcement; 20- tensor imaging (DTI) is becoming increasingly used as a measure min samples were collected 2 hrs prior to, during and after the SA of subtle white matter pathology in psychiatric populations. How- session.
    [Show full text]
  • 022454Orig1s000
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 022454Orig1s000 PHARMACOLOGY REVIEW(S) MEMORANDUM DaTSCAN (Ioflupane I123 injection) Date: September 4, 2009 To: File for NDA #22-454 From: John K. Leighton, PhD, DABT Associate Director for Pharmacology Office of Oncology Drug Products I have examined pharmacology/toxicology supporting review and labeling provided by Dr. Awe and discussed with his team leader, Dr. Laniyonu. I concur with their conclusions that DaTSCAN may be approved. No additional pharmacology or toxicology studies are necessary for the proposed indication. --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- JOHN K LEIGHTON 09/04/2009 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION NDA NUMBER: 22-454 SERIAL NUMBER: 000 DATE RECEIVED BY CENTER: 03/09/09 PRODUCT: DaTSCANTM: Ioflupane I 123 injection INTENDED CLINICAL POPULATION: Patients with symptoms and signs suggestive of dopaminergic neurodegeneration. SPONSOR: GE Healthcare Inc. DOCUMENTS REVIEWED: Electronic Submission REVIEW DIVISION: Division of Medical Imaging and Hematology
    [Show full text]