DOCSLIB.ORG

Structural and Functional Alterations in the Cortex in a Rodent Model of First-Episode Psychosis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Structural and Functional Alterations in the Cortex in a Rodent Model of First-Episode Psychosis From the Department of Neurophysiology of the Ruhr University Bochum Chair: Prof. Dr. phil. habil. Denise Manahan-Vaughan Structural and Functional Alterations in the Cortex in a Rodent Model of First-Episode Psychosis Inaugural Dissertation for the Attainment of a Doctor’s Degree in Medicine at the High Medical Faculty of the Ruhr University Bochum presented by Thomas Grüter from Lippstadt 2014 Dean: Prof. Dr. med. A. Bufe Referee: Prof. Dr. phil. habil. D. Manahan-Vaughan 1st Co-referee: Prof. Dr. med. M. Brüne 2nd Co-referee: Prof. Dr. rer. nat. T. Gloveli Date of oral examination: 17 November 2015 Abstract Problem: Schizophrenia is a common mental disorder that is characterised by positive and nega- tive symptoms, as well as cognitive and social deficits. To date, the origin and aetiology of schiz- ophrenia are still obscure and sufficient treatment for the negative and cognitive symptoms is unavailable. However, several studies indicate that early treatment results in a better outcome. Method: Dysfunctional glutamate receptors play a central role in schizophrenia pathology. This has led to the glutamate hypothesis of psychosis/ schizophrenia. In this study, an animal model of first-episode psychosis that implements a single high-dose treatment of the non-competitive N- methyl-D-aspartate receptor (NMDAR) antagonist MK801 in rats was used in order to examine resultant changes in neurotransmitter receptor expression. Due to the significance of glutama- tergic neurotransmission for synaptic plasticity, plasticity-relevant receptors were in focus. Alter- ations in expression of the NMDAR subunits GluN1, GluN2A, and GluN2B, the γ-aminobutyric acid (GABA) receptors GABAA and GABAB, the dopamine D1 and D2 receptors, as well as the metabotropic glutamate (mGlu) receptors 1, 2/3, and 5 were analysed via immunohistochemical labelling 1 and 4 weeks after antagonist treatment. Particular attention was paid to the prefrontal cortex (PFC) and hippocampus, as these structures are known to be affected in psychosis. By means of in-situ hybridisation, experience-dependent cellular activity was assessed 1 and 4 weeks after MK801-treatment by evaluating hippocampal expression of the immediate early gene Arc at rest and following spatial learning. Results: An increase of GABAA receptor expression and, in addition, a decrease of mGlu1 recep- tor expression were found 1 week after NMDAR antagonism, in both the PFC and hippocampus. At that time-point, GABAB receptor expression was up-regulated in the hippocampus and NMDAR subunit GluN2B was down-regulated in the PFC. Four weeks after treatment, GABAB and D1 receptors expressions were significantly increased in both PFC and hippocampus, GABAA receptor expression was decreased in the PFC, and GluN2B subunit expression was increased in the hippocampus. GluN1, GluN2A, mGlu2/3, mGlu5 and D2 receptors were unaf- fected at both time-points. Furthermore, basal hippocampal Arc gene expression was increased in MK801-treated animals. In contrast, no difference was detected between Arc gene expression in vehicle and MK801-treated rats after novel spatial exploration either 1 or 4 weeks after treatment. Conclusions: Long-term alterations in receptor distribution occur concurrently with enhanced basal cellular excitability in the hippocampus and PFC in an animal model of first-episode psy- chosis. These changes might underlie disturbances of synaptic plasticity, neuronal oscillations, and learning and memory that are known to occur in this animal model and provide novel in- sights into the dynamics of schizophrenia pathology. Table of contents: 1. Introduction .................................................................................................... 6 1.1. Schizophrenia ................................................................................................... 6 1.2. Brain regions affected by schizophrenia .......................................................... 8 1.2.1. Hippocampal formation .................................................................................... 8 1.2.2. Prefrontal cortex ............................................................................................. 11 1.3. Hypotheses for the occurrence of psychotic symptoms ................................. 13 1.4. Animal model of NMDA receptor antagonism .............................................. 15 1.5. Properties of significant receptors in schizophrenia....................................... 16 1.5.1. N-methyl-D-aspartate receptors ..................................................................... 17 1.5.2. γ-Aminobutyric acid receptors ....................................................................... 18 1.5.3. Dopamine receptors ........................................................................................ 19 1.5.4. Metabotropic glutamate receptors .................................................................. 20 1.6. Immediate early genes .................................................................................... 21 2. Objectives ..................................................................................................... 23 3. Materials and Methods ................................................................................ 24 3.1. Animals .......................................................................................................... 24 3.2. Drug treatment ................................................................................................ 24 3.3. Immunohistochemical labelling ..................................................................... 24 3.4. In situ-hybridisation ....................................................................................... 26 3.5. Brain slice assessment .................................................................................... 30 3.6. Analysis .......................................................................................................... 30 4. Results ........................................................................................................... 32 4.1. Immunohistochemistry ................................................................................... 32 4.1.1. Time-dependent alterations in the expression of GluN2B, but not GluN1 and GluN2A subunits in the hippocampus and prefrontal cortex after MK801-treatment ................................................................................... 32 4.1.2. Differences in the expression of GABAA and GABAB receptors in the hippocampus and prefrontal cortex after MK801-treatment ......................... 34 1 4.1.3. Dopamine D1 but not dopamine D2 receptor expression is chronically elevated in the hippocampus and prefrontal cortex after MK801- treatment ......................................................................................................... 37 4.1.4. The expression of metabotropic glutamate receptor mGlu1, but not mGlu5 or mGlu2/3 is transiently reduced in the hippocampus and prefrontal cortex after MK801-treatment ....................................................... 39 4.1.5. Synopsis of neurotransmitter receptor expression alterations after MK801-treatment ........................................................................................... 41 4.2. In situ-hybridisation ....................................................................................... 42 4.2.1. MK801-treatment alters basal Arc gene expression in the hippocampus and following spatial learning .................................................. 42 4.2.2. The exploratory behaviour of rats is not affected 1 and 4 weeks after MK801-treatment ........................................................................................... 45 5. Discussion ..................................................................................................... 46 5.1. MK801 - a valid model in schizophrenia research? ....................................... 46 5.2. Is the rodent prefrontal cortex comparable to the human prefrontal cortex? ............................................................................................................ 48 5.3. Impact of changed receptor expression on the course of psychotic symptoms ....................................................................................................... 49 5.3.1. The role of altered GluN2 subunit composition in synaptic plasticity and learning and memory ............................................................................... 50 5.3.2. Changes in neuronal activity by altered GABA receptors expression have consequences for synaptic plasticity and cognitive function ................ 53 5.3.3. Contribution of changed dopamine receptor expression to synaptic plasticity and learning and memory ............................................................... 58 5.3.4. Influence of changed metabotropic glutamate receptor expression on synaptic plasticity and learning and memory ................................................. 60 5.4. Enhanced neuronal activity in the animal model of psychosis ...................... 62 5.4.1. Connection of Arc gene expression to neuronal activity, synaptic plasticity, and learning and memory .............................................................. 62 5.4.2. Consequences of altered neuronal activity in the animal model and in schizophrenia patients .................................................................................... 64 2 5.5. The hippocampus and prefrontal cortex – key structures in the occurrence
Load more

Recommended publications
  • Comprehensive Review on the Interaction Between Natural Compounds and Brain Receptors: Benefits and Toxicity
    European Journal of Medicinal Chemistry 174 (2019) 87e115 Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech Review article Comprehensive review on the interaction between natural compounds and brain receptors: Benefits and toxicity * Ana R. Silva a, Clara Grosso b, , Cristina Delerue-Matos b,Joao~ M. Rocha a, c a Centre of Molecular and Environmental Biology (CBMA), Department of Biology (DB), University of Minho (UM), Campus Gualtar, P-4710-057, Braga, Portugal b REQUIMTE/LAQV, Instituto Superior de Engenharia do Instituto Politecnico do Porto, Rua Dr. Antonio Bernardino de Almeida, 431, P-4249-015, Porto, Portugal c REQUIMTE/LAQV, Grupo de investigaçao~ de Química Organica^ Aplicada (QUINOA), Laboratorio de polifenois alimentares, Departamento de Química e Bioquímica (DQB), Faculdade de Ci^encias da Universidade do Porto (FCUP), Rua do Campo Alegre, s/n, P-4169-007, Porto, Portugal article info abstract Article history: Given their therapeutic activity, natural products have been used in traditional medicines throughout the Received 6 December 2018 centuries. The growing interest of the scientific community in phytopharmaceuticals, and more recently Received in revised form in marine products, has resulted in a significant number of research efforts towards understanding their 10 April 2019 effect in the treatment of neurodegenerative diseases, such as Alzheimer's (AD), Parkinson (PD) and Accepted 11 April 2019 Huntington (HD). Several studies have shown that many of the primary and secondary metabolites of Available online 17 April 2019 plants, marine organisms and others, have high affinities for various brain receptors and may play a crucial role in the treatment of diseases affecting the central nervous system (CNS) in mammalians.
    [Show full text]
  • NIDA Drug Supply Program Catalog, 25Th Edition
    RESEARCH RESOURCES DRUG SUPPLY PROGRAM CATALOG 25TH EDITION MAY 2016 CHEMISTRY AND PHARMACEUTICS BRANCH DIVISION OF THERAPEUTICS AND MEDICAL CONSEQUENCES NATIONAL INSTITUTE ON DRUG ABUSE NATIONAL INSTITUTES OF HEALTH DEPARTMENT OF HEALTH AND HUMAN SERVICES 6001 EXECUTIVE BOULEVARD ROCKVILLE, MARYLAND 20852 160524 On the cover: CPK rendering of nalfurafine. TABLE OF CONTENTS A. Introduction ................................................................................................1 B. NIDA Drug Supply Program (DSP) Ordering Guidelines ..........................3 C. Drug Request Checklist .............................................................................8 D. Sample DEA Order Form 222 ....................................................................9 E. Supply & Analysis of Standard Solutions of Δ9-THC ..............................10 F. Alternate Sources for Peptides ...............................................................11 G. Instructions for Analytical Services .........................................................12 H. X-Ray Diffraction Analysis of Compounds .............................................13 I. Nicotine Research Cigarettes Drug Supply Program .............................16 J. Ordering Guidelines for Nicotine Research Cigarettes (NRCs)..............18 K. Ordering Guidelines for Marijuana and Marijuana Cigarettes ................21 L. Important Addresses, Telephone & Fax Numbers ..................................24 M. Available Drugs, Compounds, and Dosage Forms ..............................25
    [Show full text]
  • Implications of Dopamine D3 Receptor for Glaucoma: In-Silico and In-Vivo Studies
    International PhD Program in Neuropharmacology XXVI Cycle Implications of dopamine D3 receptor for glaucoma: in-silico and in-vivo studies PhD thesis Chiara Bianca Maria Platania Coordinator: Prof. Salvatore Salomone Tutor: Prof. Claudio Bucolo Department of Clinical and Molecular Biomedicine Section of Pharmacology and Biochemistry. University of Catania - Medical School December 2013 Copyright ©: Chiara B. M. Platania - December 2013 2 TABLE OF CONTENTS ACKNOWLEDGEMENTS............................................................................ 4 LIST OF ABBREVIATIONS ........................................................................ 5 ABSTRACT ................................................................................................... 7 GLAUCOMA ................................................................................................ 9 Aqueous humor dynamics .................................................................. 10 Pharmacological treatments of glaucoma............................................ 12 Pharmacological perspectives in treatment of glaucoma ..................... 14 Animal models of glaucoma ............................................................... 18 G PROTEIN COUPLED RECEPTORS ....................................................... 21 GPCRs functions and structure ........................................................... 22 Molecular modeling of GPCRs ........................................................... 25 D2-like receptors ...............................................................................
    [Show full text]
  • Activation of D1R/PKA/Mtor Signaling Cascade in Medial
    www.nature.com/scientificreports OPEN Activation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the Received: 17 November 2016 Accepted: 3 May 2017 antidepressant effects ofl -SPD Published: xx xx xxxx Bing Zhang1,2,3, Fei Guo1, Yuqin Ma1,2, Yingcai Song3, Rong Lin3, Fu-Yi Shen3, Guo-Zhang Jin1, Yang Li 1 & Zhi-Qiang Liu3 Major depressive disorder (MDD) is a common neuropsychiatric disorder characterized by diverse symptoms. Although several antidepressants can influence dopamine system in the medial prefrontal cortex (mPFC), but the role of D1R or D2R subtypes of dopamine receptor during anti-depression process is still vague in PFC region. To address this question, we investigate the antidepressant effect of levo-stepholidine (l-SPD), an antipsychotic medication with unique pharmacological profile of D1R agonism and D2R antagonism, and clarified its molecular mechanisms in the mPFC. Our results showed that l-SPD exerted antidepressant-like effects on the Sprague-Dawley rat CMS model of depression. Mechanism studies revealed that l-SPD worked as a specific D1R agonist, rather than D2 antagonist, to activate downstream signaling of PKA/mTOR pathway, which resulted in increasing synaptogenesis-related proteins, such as PSD 95 and synapsin I. In addition, l-SPD triggered long- term synaptic potentiation (LTP) in the mPFC, which was blocked by the inhibition of D1R, PKA, and mTOR, supporting that selective activation of D1R enhanced excitatory synaptic transduction in PFC. Our findings suggest a critical role of D1R/PKA/mTOR signaling cascade in the mPFC during thel -SPD mediated antidepressant process, which may also provide new insights into the role of mesocortical dopaminergic system in antidepressant effects.
    [Show full text]
  • Handbook of Schizophrenia Spectrum Disorders, Volume III
    Handbook of Schizophrenia Spectrum Disorders, Volume III Michael S. Ritsner Editor Handbook of Schizophrenia Spectrum Disorders, Volume III Therapeutic Approaches, Comorbidity, and Outcomes 123 Editor Michael S. Ritsner Technion – Israel Institute of Technology Rappaport Faculty of Medicine Haifa Israel [email protected] ISBN 978-94-007-0833-4 e-ISBN 978-94-007-0834-1 DOI 10.1007/978-94-007-0834-1 Springer Dordrecht Heidelberg London New York Library of Congress Control Number: 2011924745 © Springer Science+Business Media B.V. 2011 No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Foreword Schizophrenia Spectrum Disorders: Insights from Views Across 100 years Schizophrenia spectrum and related disorders such as schizoaffective and mood dis- orders, schizophreniform disorders, brief psychotic disorders, delusional and shared psychotic disorders, and personality (i.e., schizotypal, paranoid, and schizoid per- sonality) disorders are the most debilitating forms of mental illness, worldwide. There are 89,377 citations (including 10,760 reviews) related to “schizophrenia” and 2118 (including 296 reviews) related to “schizophrenia spectrum” in PubMed (accessed on August 12, 2010). The classification of these disorders, in particular, of schizophrenia, schizoaf- fective and mood disorders (referred to as functional psychoses), has been debated for decades, and its validity remains controversial.
    [Show full text]
  • Guidelines for Biological Treatment of Schizophrenia, Part 2
    The World Journal of Biological Psychiatry, 2013; 14: 2–44 GUIDELINES World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia, Part 2: Update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects ALKOMIET HASAN 1 , PETER FALKAI1 , THOMAS WOBROCK 2 , JEFFREY LIEBERMAN 3 , BIRTE GLENTHOJ 4 , WAGNER F. GATTAZ 5 , FLORENCE THIBAUT6 & HANS-JÜ RGEN M Ö LLER 1 , WFSBP Task force on Treatment Guidelines for Schizophrenia * 1 Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany, 2 Centre of Mental Health, Darmstadt-Dieburg Clinics, Darmstadt, Germany, 3 Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, Lieber Center for Schizophrenia Research, New York, USA, 4 Center for Neuropsychiatric Schizophrenia Research & Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Copenhagen University Hospital, Psychiatric Center Glostrup, Denmark, 5 Department of Psychiatry, University of Sao Paulo, Brazil, and 6 University Hospital Ch. Nicolle, Faculty of Medicine, INSERM, Rouen, France Abstract These updated guidelines are based on a fi rst edition of the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia published in 2006. For this 2012 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence- based update. These guidelines provide evidence-based practice recommendations that are clinically and scientifi cally meaningful. They are intended to be used by all physicians diagnosing and treating people suffering from schizophrenia. Based on the fi rst version of these guidelines, a systematic review of the MEDLINE/PUBMED database and the Cochrane Library, in addition to data extraction from national treatment guidelines, has been performed for this update.
    [Show full text]
  • Serotonergic System Modulation Holds Promise for L‐Dopa‐Induced Dyskinesias in Hemiparkinsonian Rats: a Systematic Review
    EXCLI Journal 2020;19:268-295 – ISSN 1611-2156 Received: January 03, 2020, accepted: February 24, 2020, published: March 02, 2020 Review article: SEROTONERGIC SYSTEM MODULATION HOLDS PROMISE FOR L‐DOPA‐INDUCED DYSKINESIAS IN HEMIPARKINSONIAN RATS: A SYSTEMATIC REVIEW Fereshteh Farajdokht1, 2, Saeed Sadigh-Eteghad2, Alireza Majdi2, Fariba Pashazadeh1,3, Seyyed Mehdi Vatandoust2, Mojtaba Ziaee4,5, Fatemeh Safari6, Pouran Karimi2, Javad Mahmoudi2* 1 Research Center for Evidence-Based Medicine (EBM), Health Management and Safety Promotion Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran 2 Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran 3 Iranian Evidence-Based Medicine (EBM) Center, a Joanna Briggs Institute Affiliated Group 4 Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran 5 Phytopharmacology Research Center, Maragheh University of Medical Sciences, Maragheh, Iran 6 Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran * Corresponding author: Dr. Javad Mahmoudi, Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran, Postal code: 5166614756, Iran, Tel: +984133351284, E-mails: [email protected], [email protected] http://dx.doi.org/10.17179/excli2020-1024 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/). ABSTRACT The alleged effects of serotonergic agents in alleviating levodopa-induced dyskinesias (LIDs) in parkinsonian patients are debatable. To this end, we systematically reviewed the serotonergic agents used for the treatment of LIDs in a 6-hydroxydopamine model of Parkinson’s disease in rats. We searched MEDLINE via PubMed, Embase, Google Scholar, and Proquest for entries no later than March 2018, and restricted the search to publications on serotonergic agents used for the treatment of LIDs in hemiparkinsonian rats.
    [Show full text]
  • A 1A9, A431 and A549 Cell Lines, 3478 12Α,13Α-Aziridinyl Epothilone
    Index A Acanthoscelides obtectus, 4091 1A9, A431 and A549 cell lines, 3478 Acanthostrongylophora, 1293 12a,13a-Aziridinyl epothilone derivatives, 990 Acari, 4070, 4083 Aaptos ciliata, 1292 Acaricides, 4070, 4076, 4083 AATs. See Anthocyanin acyltransferases Accelerated solvent extraction (ASE), 1017, (AATs) 2017, 2021–2023, 2032, 2037, 2111 Ab (1-42), 2287 p-Acceptors, 692 ABA biosynthesis, 1736 Accretion, 2405 Ab aggregation, 2286 Accumulation, 2321 Abdominal troubles, 3477 Acetaldehyde (ATL), 2902 Aberrant behavior, 1375 Acetaldehyde acid, 1783 Aberrant estrous cycles, 2421 Acetate, 50, 59 Abies alba, 2980 Acetate-mevalonate (Ac-MEV), 2943 Abietadiene synthase, 2725 Acetate pathway, 2314 Abiotic and biotic elicitors, 2783 Acetic acid (ACE), 851, 1608, 2884 Abiotic factor, 1697 Acetogenic bacteria, 2443 Abiotic stresses, 2930 Acetone, 3371 Ab neuropathology, 2285 Acetonitrile, 691, 1170, 1175 Ab oligomerization, 2285 3-Acetylaconitine, 1508 Ab oligomers, 2283 Acetyl-ACP, 963 Ab peptides, 1308, 2285 Acetyl-and butyrylcholinesterase inhibitors, Ab polymerization, 2287 3488 Abrin, 296 Acetylcholine (ACh), 1241, 1306, 1333, 1526, Abscisic acid (ABA), 2860, 3591 1527, 1529, 1530, 3710 Absolute configuration, 930, 3320 Acetylcholine esterase, 51, 52 Absolute configuration of monosaccharides, Acetylcholine esterase inhibitor activity, 2906 3319 Acetylcholinesterase (AChE), 41, 1246, 1308, Absorbance (A), 3334, 3380 1334, 1527, 1529–1533, 1535, 4097 Absorbance spectrum, 3929, 3933, 3934 Acetyl-CoA, 61, 584 Absorption, 1230, 2321, 2470–2476, Acetyl-CoA carboxylase (ACC), 1658, 1825 2478–2481, 3134, 3377, 3616, 4024 3-Acetyldeoxynivalenol, 3127, 3145 coefficient, 3380 15-Acetyl deoxynivalenol (15ADON), and metabolism, 1428 3127, 3145 wavelength, 4028 Acetylerucifoline, 1061 Abusive correlations, 2410 Acetylgaertneroside, 3054 Acacetin, 1830 60-O-Acetylgeniposide, 3058 Acacia, 865 8-O-Acetylharpagide, 3055 a2C adrenergic, 4124 Acetylintermedine, 1061 Acanthaceae, 801 Acetyllycopsamine, 1061 K.G.
    [Show full text]
  • Download Date 02/10/2021 14:22:57
    Exploration of cognitive and neurochemical deficits in an animal model of schizophrenia. Investigation into sub-chronic PCP-induced cognitive deficits using behavioural, neurochemical and electrophysiological techniques; and use of receptor-selective agents to study the pharmacology of antipsychotics in female rats. Item Type Thesis Authors McLean, Samantha L. Rights <a rel="license" href="http://creativecommons.org/licenses/ by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by- nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http:// creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. Download date 02/10/2021 14:22:57 Link to Item http://hdl.handle.net/10454/4451 University of Bradford eThesis This thesis is hosted in Bradford Scholars – The University of Bradford Open Access repository. Visit the repository for full metadata or to contact the repository team © University of Bradford. This work is licenced for reuse under a Creative Commons Licence. EXPLORATION OF COGNITIVE AND NEUROCHEMICAL DEFICITS IN AN ANIMAL MODEL OF SCHIZOPHRENIA Investigation into sub-chronic PCP-induced cognitive deficits using behavioural, neurochemical and electrophysiological techniques; and use of receptor-selective agents to study the pharmacology of antipsychotics in female rats Samantha Louise MCLEAN submitted for the degree of Doctor of Philosophy School of Pharmacy University of Bradford 2010 i ABSTRACT Keywords: Rat; Phencyclidine; Antipsychotics; Cognition; Dopamine; 5-HT; GABA Cognitive dysfunction is a core characteristic of schizophrenia, which can often persist when other symptoms, particularly positive symptoms, may be improved with drug treatment.
    [Show full text]
  • New Information of Dopaminergic Agents Based on Quantum Chemistry Calculations Guillermo Goode‑Romero1*, Ulrika Winnberg2, Laura Domínguez1, Ilich A
    www.nature.com/scientificreports OPEN New information of dopaminergic agents based on quantum chemistry calculations Guillermo Goode‑Romero1*, Ulrika Winnberg2, Laura Domínguez1, Ilich A. Ibarra3, Rubicelia Vargas4, Elisabeth Winnberg5 & Ana Martínez6* Dopamine is an important neurotransmitter that plays a key role in a wide range of both locomotive and cognitive functions in humans. Disturbances on the dopaminergic system cause, among others, psychosis, Parkinson’s disease and Huntington’s disease. Antipsychotics are drugs that interact primarily with the dopamine receptors and are thus important for the control of psychosis and related disorders. These drugs function as agonists or antagonists and are classifed as such in the literature. However, there is still much to learn about the underlying mechanism of action of these drugs. The goal of this investigation is to analyze the intrinsic chemical reactivity, more specifcally, the electron donor–acceptor capacity of 217 molecules used as dopaminergic substances, particularly focusing on drugs used to treat psychosis. We analyzed 86 molecules categorized as agonists and 131 molecules classifed as antagonists, applying Density Functional Theory calculations. Results show that most of the agonists are electron donors, as is dopamine, whereas most of the antagonists are electron acceptors. Therefore, a new characterization based on the electron transfer capacity is proposed in this study. This new classifcation can guide the clinical decision‑making process based on the physiopathological knowledge of the dopaminergic diseases. During the second half of the last century, a movement referred to as the third revolution in psychiatry emerged, directly related to the development of new antipsychotic drugs for the treatment of psychosis.
    [Show full text]
  • 1 5/17/2018 Nct02118610
    5/17/2018 NCT02118610 Treatment of Schizophrenia with l-tetrahydropalmatine (l-THP): a Novel Dopamine Antagonist with Anti-inflammatory and Antiprotozoal Activity 1 Abstract Schizophrenia is a devastating and complex illness, with multiple symptom and behavioral manifestations. Antipsychotic medications are the mainstay of treatment; however, many patients only partially respond to treatment. Development of new treatment has not progressed rapidly, in part, because the underlying etiopathophysiology of the illness is not well understood. To date, all pharmacological treatments approved for use in schizophrenia involve primary modulation of the dopamine system. Many agents without dopamine action have failed to demonstrate efficacy. There is growing evidence that schizophrenia may be, in part, due to an inflammatory process and pharmacological treatment approaches that decrease inflammation have shown promise. Thus, treatments that may have anti-inflammatory properties (e.g., TNF-alpha inhibition), but also possess dopamine modulation may prove to be beneficial. This novel medication, l-tetrahydropalmatine (l-THP), has robust anti-inflammatory properties, particularly TNF-alpha and ICAM inhibition; has antiprotozoal activity; and possesses an antipsychotic-like pharmacological profile of D1, D2 and D3 receptor antagonism. The high affinity of l-THP for D1 versus D2 receptors distinguishes it from first generation antipsychotics and its D1 to D2 ratio resembles that of the superior antipsychotic, clozapine. Also, an almost identical compound, l-stepholindine (l-SPD), demonstrates robust antipsychotic activity in humans (both positive and negative symptoms) and is currently used clinically in China. l-THP has been used for over 40 years clinically in China, has a good safety profile to date, and represents a novel and exciting mechanism for schizophrenia treatment.
    [Show full text]
  • ( 12 ) United States Patent
    US010493080B2 (12 ) United States Patent (10 ) Patent No.: US 10,493,080 B2 Schultz et al. (45 ) Date of Patent : Dec. 3 , 2019 ( 54 ) DIRECTED DIFFERENTIATION OF (56 ) References Cited OLIGODENDROCYTE PRECURSOR CELLS TO A MYELINATING CELL FATE U.S. PATENT DOCUMENTS 7,301,071 B2 11/2007 Zheng (71 ) Applicants : The Scripps Research Institute , La 7,304,071 B2 12/2007 Cochran et al. Jolla , CA (US ) ; Novartis AG , Basel 9,592,288 B2 3/2017 Schultz et al. 2003/0225072 A1 12/2003 Welsh et al. ( CH ) 2006/0258735 Al 11/2006 Meng et al. 2009/0155207 Al 6/2009 Hariri et al . (72 ) Inventors : Peter Schultz , La Jolla , CA (US ) ; Luke 2010/0189698 A1 7/2010 Willis Lairson , San Diego , CA (US ) ; Vishal 2012/0264719 Al 10/2012 Boulton Deshmukh , La Jolla , CA (US ) ; Costas 2016/0166687 Al 6/2016 Schultz et al. Lyssiotis , Boston , MA (US ) FOREIGN PATENT DOCUMENTS (73 ) Assignees : The Scripps Research Institute , La JP 10-218867 8/1998 Jolla , CA (US ) ; Novartis AG , Basel JP 2008-518896 5/2008 (CH ) JP 2010-533656 A 10/2010 WO 2008/143913 A1 11/2008 WO 2009/068668 Al 6/2009 ( * ) Notice : Subject to any disclaimer , the term of this WO 2009/153291 A1 12/2009 patent is extended or adjusted under 35 WO 2010/075239 Al 7/2010 U.S.C. 154 ( b ) by 0 days . (21 ) Appl. No .: 15 /418,572 OTHER PUBLICATIONS Molin - Holgado et al . “ Regulation of muscarinic receptor function in ( 22 ) Filed : Jan. 27 , 2017 developing oligodendrocytes by agonist exposure ” British Journal of Pharmacology, 2003 , 138 , pp .
    [Show full text]