DOCSLIB.ORG

Cognitive Dysfunction in Psychiatric Disorders: Characteristics, Causes and the Quest for Improved Therapy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cognitive Dysfunction in Psychiatric Disorders: Characteristics, Causes and the Quest for Improved Therapy REVIEWS Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy Mark J. Millan1, Yves Agid2, Martin Brüne3, Edward T. Bullmore4, Cameron S. Carter5, Nicola S. Clayton6, Richard Connor7, Sabrina Davis8, Bill Deakin9, Robert J. DeRubeis10, Bruno Dubois11, Mark A. Geyer12, Guy M. Goodwin13, Philip Gorwood14, Thérèse M. Jay14, Marian Joëls15, Isabelle M. Mansuy16, Andreas Meyer-Lindenberg17, Declan Murphy18, Edmund Rolls19, Bernd Saletu20, Michael Spedding21, John Sweeney22, Miles Whittington23 and Larry J. Young24 Abstract | Studies of psychiatric disorders have traditionally focused on emotional symptoms such as depression, anxiety and hallucinations. However, poorly controlled cognitive deficits are equally prominent and severely compromise quality of life, including social and professional integration. Consequently, intensive efforts are being made to characterize the cellular and cerebral circuits underpinning cognitive function, define the nature and causes of cognitive impairment in psychiatric disorders and identify more effective treatments. Successful development will depend on rigorous validation in animal models as well as in patients, including measures of real-world cognitive functioning. This article critically discusses these issues, highlighting the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders. Cognition Historically, philosophers have subdivided the study relevant dimension of psychiatric disorders that cuts A suite of interrelated of the human mind and behaviour into two broad across traditional diagnostic boundaries, and improved conscious (and unconscious) categories: the cognitive (how we know the world) and treatment should be a major goal in efforts to enhance mental activities, including: the affective (how we feel about it). This division is, how- quality of life for patients. pre-attentional sensory cognition gating; attention; learning and ever, arbitrary as — a highly complex construct memory; problem solving, (FIG. 1) — and emotion interact; cognitive status can Cognitive dysfunction in psychiatric disorders planning, reasoning and colour the processing of emotions, and changes in mood Challenges of defining and characterizing cognitive judgment; understanding, affect cognitive function1,2. deficits. Alzheimer’s disease is characterized by poor knowing and representing; learning memory creativity, intuition and It is therefore surprising that changes in emotion are and , Parkinson’s disease by motor insight; ‘spontaneous’ thought; universally recognized as being inherent to psychiatric impairment, depression by melancholy, and schizophre- introspection; as well as mental disorders and their classification, whereas cognitive nia by delusions; however, these and related diagnoses time travel, self-awareness and impairment — which has an equally disabling effect on are also accompanied by a range of symptoms involving meta-cognition (thinking and patients — has been comparatively neglected. Despite alterations in mood, motor behaviour, appetite, sleep, knowledge about cognition). this close interrelationship between cognition and diurnal rhythms and, most pertinently, cognitive func- mood, the cognitive deficits of psychiatric disorders are tion. For example, psychosis is common in Alzheimer’s not just a secondary consequence of perturbed affect, disease, depression can be just as debilitating as motor and their underlying neurobiological substrates differ. deficits in Parkinson’s disease, and perturbed cognition 1Institut de Recherche Servier, Although certain symptoms of psychiatric disorders — is a characteristic of both psychiatric and neurological 78290 Croissy/Seine, France. such as depression, delusions and anxiety — are allevi- disorders (TABLE 1). Correspondence to M.J.M. e-mail: ated by current drugs, cognitive deficits are not usually Defining the precise nature of changes in cognition 3,4 [email protected] improved, and may even be worsened . Cognitive is challenging. Specificity relative to generalized changes doi:10.1038/nrd3628 dysfunction is, therefore, a poorly controlled and highly in overall intelligence remains under discussion, in NATURE REVIEWS | DRUG DISCOVERY VOLUME 11 | FEBRUARY 2012 | 141 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS 12 Author addresses in obsessive compulsive disorder (OCD) and recurrent, unwanted recall (flashbacks) in post-traumatic stress dis- 2ICM, Pitié-Salpétrière University Hospital, 47 boulevard de l’Hôpital, 75013 Paris, France. order (PTSD)13,14. The latter state represents a form of 3 Research Department of Cognitive Neuropsychiatry and Psychiatric Preventive ‘hyper-memory’ resulting from defective processes of Medicine, LWL University Hospital, Ruhr-University Bochum, Alexandrinenstr. 1, fear extinction — an active process for suppressing nega- 44791 Bochum, Germany. 4University of Cambridge and GlaxoSmithKline, Cambridge Biomedical Campus, tive emotional memories — rather than just the decay of 14,15 Cambridge CB2 0SZ, UK. the mechanisms involved in storage and recall (FIG. 2). 5University of California, Davis, Sacramento, California 95817, USA. Phobias and social anxiety disorder are likewise typi- 6Department of Experimental Psychology, University of Cambridge, Cambridge fied by blunted fear extinction16,17. Comparatively little CB2 3EB, UK. cognitive disturbance has been documented for gen- 7Department of Biology, University of Massachusetts Dartmouth, 02747 North eralized anxiety disorder, despite some subtle changes Dartmouth, USA. and a negative cognitive bias to threatening stimuli16,17 8 Centre National de la Recherche Scientifique, University of Paris-Sud, 91400 Orsay, (TABLE 1). Cognitive dysfunction in panic disorders is France. mainly confined to excessive attention and hyperreactivity 9Neuroscience and Psychiatry Unit, University of Manchester, Manchester M13 9PT, UK. to threatening — but not emotionally neutral — stimuli. 10University of Pennsylvania, 19104 Philadelphia, USA. processing speed 11Institut du Cerveau et de la Moelle Epinière (ICM), Université Pierre et Marie Curie, Interestingly, may actually be acceler- 16,18 Paris 6, UMR-S975 Paris, France. ated in panic disorders . Schizophrenia is charac- 12University of California San Diego, La Jolla, California 92093‑0804, USA. terized by a broad pattern of cognitive deficits, from 13University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK. attention and working memory to social cognition and 14INSERM; Université Paris, Descartes, Centre de Psychiatrie et Neurosciences U894, language7,19–22 (BOX 1). Impairments in bipolar disorder, 75014 Paris, France. which shares certain genetic risk factors with schizo­ 15Department of Neuroscience and Pharmacology, Rudolf Magnus Institute, University phrenia (Supplementary information S1 (figure)), are Medical Center Utrecht, 3584 CG Utrecht, The Netherlands. similar but generally less severe19,23,24 (TABLE 1). 16 Brain Research Institute, University of Zürich and ETHZ, 8057 Zürich, Switzerland. Cognitive impairment is not traditionally associated 17Central Institute of Mental Health, Heidelberg University, Medical Faculty Mannheim, with depression but it is common, broad-based and D‑68159 Mannheim, Germany. 4,19,25,26 18Institute of Psychiatry, King’s College London, Denmark Hill, London SE5 8AF, UK. often debilitating . Poor performance in certain 19Oxford Centre for Computational Neuroscience and Department of Computer tasks reflects reduced reward, low motivation and/or Science, University of Warwick, Coventry CV4 7AL, UK. an incapacity for sustained effort — possibly owing to 20Department of Psychiatry and Psychotherapy, Medical University of Vienna, disruption of limbic dopaminergic signalling4,10. This Waehringer Gürtel 18‑20, A‑1090 Vienna, Austria. does not, however, provide a satisfactory explanation 21Les Laboratoires Servier, 50 Rue Carnot, 92284 Suresnes Cedex, France. for overall cognitive impairment. For example, the bias 22 University of Texas Southwestern, Dallas 75235, Texas, USA. of patients suffering from depression towards affectively 23Newcastle University, Newcastle NE2 4HH, UK. negative — and even ambiguous — stimuli (such as 24 Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd, facial expressions) involves diminished top-down fronto- Atlanta, Georgia 30329, USA. cortical cognitive control of emotional processing2,27. Deficits in attention deficit hyperactivity disorder (ADHD) are not restricted to attention; they affect Learning particular for schizophrenia and autism spectrum dis- several other cognitive domains, including an inter- The active, experience- and/or orders (ASDs), in which development is abnormal5–8. related impairment in working memory and process- training-driven acquisition of Furthermore, the precise interrelationship between ing speed28,29. Among the deficits characterizing OCD, information or behaviour. The alterations in cognition and changes in mood, reward, impairment of procedural learning is of particular note12,30. term ‘conditioning’ is usually used in an experimental context motor performance and effort can be difficult to estab- Finally, although disrupted social cognition is a cardi- 9,10 of associative learning. Learning lish . Finally, apart from treatment, various other factors nal symptom of ASD, several other domains are also necessitates complementary modify cognitive performance and its measurement in affected9,31,32
Load more

Recommended publications
  • Effects of Chronic Systemic Low-Impact Ampakine Treatment On
    Biomedicine & Pharmacotherapy 105 (2018) 540–544 Contents lists available at ScienceDirect Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha Effects of chronic systemic low-impact ampakine treatment on neurotrophin T expression in rat brain ⁎ Daniel P. Radin , Steven Johnson, Richard Purcell, Arnold S. Lippa RespireRx Pharmaceuticals, Inc., 126 Valley Road, Glen Rock, NJ, 07452, United States ARTICLE INFO ABSTRACT Keywords: Neurotrophin dysregulation has been implicated in a large number of neurodegenerative and neuropsychiatric Ampakine diseases. Unfortunately, neurotrophins cannot cross the blood brain barrier thus, novel means of up regulating BDNF their expression are greatly needed. It has been demonstrated previously that neurotrophins are up regulated in Cognitive enhancement response to increases in brain activity. Therefore, molecules that act as cognitive enhancers may provide a LTP clinical means of up regulating neurotrophin expression. Ampakines are a class of molecules that act as positive Neurotrophin allosteric modulators of AMPA-type glutamate receptors. Currently, they are being developed to prevent opioid- NGF induced respiratory depression without sacrificing the analgesic properties of the opioids. In addition, these molecules increase neuronal activity and have been shown to restore age-related deficits in LTP in aged rats. In the current study, we examined whether two different ampakines could increase levels of BDNF and NGF at doses that are active in behavioral measures of cognition. Results demonstrate that ampakines CX516 and CX691 induce differential increases in neurotrophins across several brain regions. Notable increases in NGF were ob- served in the dentate gyrus and piriform cortex while notable BDNF increases were observed in basolateral and lateral nuclei of the amygdala.
    [Show full text]
  • Neuroenhancement in Healthy Adults, Part I: Pharmaceutical
    l Rese ca arc ni h li & C f B o i o l e Journal of a t h n Fond et al., J Clinic Res Bioeth 2015, 6:2 r i c u s o J DOI: 10.4172/2155-9627.1000213 ISSN: 2155-9627 Clinical Research & Bioethics Review Article Open Access Neuroenhancement in Healthy Adults, Part I: Pharmaceutical Cognitive Enhancement: A Systematic Review Fond G1,2*, Micoulaud-Franchi JA3, Macgregor A2, Richieri R3,4, Miot S5,6, Lopez R2, Abbar M7, Lancon C3 and Repantis D8 1Université Paris Est-Créteil, Psychiatry and Addiction Pole University Hospitals Henri Mondor, Inserm U955, Eq 15 Psychiatric Genetics, DHU Pe-psy, FondaMental Foundation, Scientific Cooperation Foundation Mental Health, National Network of Schizophrenia Expert Centers, F-94000, France 2Inserm 1061, University Psychiatry Service, University of Montpellier 1, CHU Montpellier F-34000, France 3POLE Academic Psychiatry, CHU Sainte-Marguerite, F-13274 Marseille, Cedex 09, France 4 Public Health Laboratory, Faculty of Medicine, EA 3279, F-13385 Marseille, Cedex 05, France 5Inserm U1061, Idiopathic Hypersomnia Narcolepsy National Reference Centre, Unit of sleep disorders, University of Montpellier 1, CHU Montpellier F-34000, Paris, France 6Inserm U952, CNRS UMR 7224, Pierre and Marie Curie University, F-75000, Paris, France 7CHU Carémeau, University of Nîmes, Nîmes, F-31000, France 8Department of Psychiatry, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Eschenallee 3, 14050 Berlin, Germany *Corresponding author: Dr. Guillaume Fond, Pole de Psychiatrie, Hôpital A. Chenevier, 40 rue de Mesly, Créteil F-94010, France, Tel: (33)178682372; Fax: (33)178682381; E-mail: [email protected] Received date: January 06, 2015, Accepted date: February 23, 2015, Published date: February 28, 2015 Copyright: © 2015 Fond G, et al.
    [Show full text]
  • WO 2016/001643 Al 7 January 2016 (07.01.2016) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/001643 Al 7 January 2016 (07.01.2016) P O P C T (51) International Patent Classification: (74) Agents: GILL JENNINGS & EVERY LLP et al; The A61P 25/28 (2006.01) A61K 31/194 (2006.01) Broadgate Tower, 20 Primrose Street, London EC2A 2ES A61P 25/16 (2006.01) A61K 31/205 (2006.01) (GB). A23L 1/30 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/GB20 15/05 1898 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (22) International Filing Date: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 29 June 2015 (29.06.2015) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (26) Publication Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (30) Priority Data: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 141 1570.3 30 June 2014 (30.06.2014) GB TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 1412414.3 11 July 2014 ( 11.07.2014) GB (84) Designated States (unless otherwise indicated, for every (71) Applicant: MITOCHONDRIAL SUBSTRATE INVEN¬ kind of regional protection available): ARIPO (BW, GH, TION LIMITED [GB/GB]; 39 Glasslyn Road, London GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, N8 8RJ (GB).
    [Show full text]
  • Glutamatergic Regulation of Cognition and Functional Brain Connectivity: Insights from Pharmacological, Genetic and Translational Schizophrenia Research
    Title: Glutamatergic regulation of cognition and functional brain connectivity: insights from pharmacological, genetic and translational schizophrenia research Authors: Dr Maria R Dauvermann (1,2) , Dr Graham Lee (2) , Dr Neil Dawson (3) Affiliations: 1. School of Psychology, National University of Ireland, Galway, Galway, Ireland 2. McGovern Institute for Brain Research, Massachusetts Institute of Technology, 77 Massachusetts Ave, Cambridge, MA, 02139, USA 3. Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YQ, UK Abstract The pharmacological modulation of glutamatergic neurotransmission to improve cognitive function has been a focus of intensive research, particularly in relation to the cognitive deficits seen in schizophrenia. Despite this effort there has been little success in the clinical use of glutamatergic compounds as procognitive drugs. Here we review a selection of the drugs used to modulate glutamatergic signalling and how they impact on cognitive function in rodents and humans. We highlight how glutamatergic dysfunction, and NMDA receptor hypofunction in particular, is a key mechanism contributing to the cognitive deficits observed in schizophrenia, and outline some of the glutamatergic targets that have been tested as putative procognitive targets for the disorder. Using translational research in this area as a leading exemplar, namely models of NMDA receptor hypofunction, we discuss how the study of functional brain network connectivity can provide new insight
    [Show full text]
  • 33123126.Pdf
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Caltech Authors 10912 • The Journal of Neuroscience, October 3, 2007 • 27(40):10912–10917 Neurobiology of Disease Brain-Derived Neurotrophic Factor Expression and Respiratory Function Improve after Ampakine Treatment in a Mouse Model of Rett Syndrome Michael Ogier,1 Hong Wang,1 Elizabeth Hong,2 Qifang Wang,1 Michael E. Greenberg,2 and David M. Katz1 1Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, and 2Departments of Neurology and Neurobiology, Harvard Medical School, Boston, Massachusetts 02115 Rett syndrome (RTT) is caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). Although MeCP2 is thought to act as a transcriptional repressor of brain-derived neurotrophic factor (BDNF), Mecp2 null mice, which develop an RTT-like phenotype, exhibit progressive deficits in BDNF expression. These deficits are particularly significant in the brainstem and nodose cranial sensory ganglia (NGs), structures critical for cardiorespiratory homeostasis, and may be linked to the severe respiratory abnormalities characteristic of RTT. Therefore, the present study used Mecp2 null mice to further define the role of MeCP2 in regulation of BDNF expression and neural function, focusing on NG neurons and respiratory control. We find that mutant neurons express signif- icantly lower levels of BDNF than wild-type cells in vitro,asin vivo, under both depolarizing and nondepolarizing conditions. However, BDNF levels in mutant NG cells can be increased by chronic depolarization in vitro or by treatment of Mecp2 null mice with CX546, an ampakine drug that facilitates activation of glutamatergic AMPA receptors.
    [Show full text]
  • Drug Delivery System for Use in the Treatment Or Diagnosis of Neurological Disorders
    (19) TZZ __T (11) EP 2 774 991 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 10.09.2014 Bulletin 2014/37 C12N 15/86 (2006.01) A61K 48/00 (2006.01) (21) Application number: 13001491.3 (22) Date of filing: 22.03.2013 (84) Designated Contracting States: • Manninga, Heiko AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 37073 Göttingen (DE) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO •Götzke,Armin PL PT RO RS SE SI SK SM TR 97070 Würzburg (DE) Designated Extension States: • Glassmann, Alexander BA ME 50999 Köln (DE) (30) Priority: 06.03.2013 PCT/EP2013/000656 (74) Representative: von Renesse, Dorothea et al König-Szynka-Tilmann-von Renesse (71) Applicant: Life Science Inkubator Betriebs GmbH Patentanwälte Partnerschaft mbB & Co. KG Postfach 11 09 46 53175 Bonn (DE) 40509 Düsseldorf (DE) (72) Inventors: • Demina, Victoria 53175 Bonn (DE) (54) Drug delivery system for use in the treatment or diagnosis of neurological disorders (57) The invention relates to VLP derived from poly- ment or diagnosis of a neurological disease, in particular oma virus loaded with a drug (cargo) as a drug delivery multiple sclerosis, Parkinsons’s disease or Alzheimer’s system for transporting said drug into the CNS for treat- disease. EP 2 774 991 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 774 991 A1 Description FIELD OF THE INVENTION 5 [0001] The invention relates to the use of virus like particles (VLP) of the type of human polyoma virus for use as drug delivery system for the treatment or diagnosis of neurological disorders.
    [Show full text]
  • A Abacavir Abacavirum Abakaviiri Abagovomab Abagovomabum
    A abacavir abacavirum abakaviiri abagovomab abagovomabum abagovomabi abamectin abamectinum abamektiini abametapir abametapirum abametapiiri abanoquil abanoquilum abanokiili abaperidone abaperidonum abaperidoni abarelix abarelixum abareliksi abatacept abataceptum abatasepti abciximab abciximabum absiksimabi abecarnil abecarnilum abekarniili abediterol abediterolum abediteroli abetimus abetimusum abetimuusi abexinostat abexinostatum abeksinostaatti abicipar pegol abiciparum pegolum abisipaaripegoli abiraterone abirateronum abirateroni abitesartan abitesartanum abitesartaani ablukast ablukastum ablukasti abrilumab abrilumabum abrilumabi abrineurin abrineurinum abrineuriini abunidazol abunidazolum abunidatsoli acadesine acadesinum akadesiini acamprosate acamprosatum akamprosaatti acarbose acarbosum akarboosi acebrochol acebrocholum asebrokoli aceburic acid acidum aceburicum asebuurihappo acebutolol acebutololum asebutololi acecainide acecainidum asekainidi acecarbromal acecarbromalum asekarbromaali aceclidine aceclidinum aseklidiini aceclofenac aceclofenacum aseklofenaakki acedapsone acedapsonum asedapsoni acediasulfone sodium acediasulfonum natricum asediasulfoninatrium acefluranol acefluranolum asefluranoli acefurtiamine acefurtiaminum asefurtiamiini acefylline clofibrol acefyllinum clofibrolum asefylliiniklofibroli acefylline piperazine acefyllinum piperazinum asefylliinipiperatsiini aceglatone aceglatonum aseglatoni aceglutamide aceglutamidum aseglutamidi acemannan acemannanum asemannaani acemetacin acemetacinum asemetasiini aceneuramic
    [Show full text]
  • The Likelihood of Cognitive Enhancement
    Pharmacology, Biochemistry and Behavior 99 (2011) 116–129 Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh Review The likelihood of cognitive enhancement Gary Lynch a,b,⁎, Linda C. Palmer b, Christine M. Gall b a Department of Psychiatry and Human Behavior, University of California, Irvine CA 92697-4291, United States b Department of Anatomy and Neurobiology, University of California, Irvine CA 92697-4291, United States article info abstract Available online 6 January 2011 Whether drugs that enhance cognition in healthy individuals will appear in the near future has become a topic of considerable interest. We address this possibility using a three variable system (psychological effect, Keywords: neurobiological mechanism, and efficiency vs. capabilities) for classifying candidates. Ritalin and modafinil, Ampakine two currently available compounds, operate on primary psychological states that in turn affect cognitive Learning operations (attention and memory), but there is little evidence that these effects translate into improvements Arousal in complex cognitive processing. A second category of potential enhancers includes agents that improve Methylphenidate Modafinil memory encoding, generally without large changes in primary psychological states. Unfortunately, there is Social issues little information on how these compounds affect cognitive performance in standard psychological tests. Recent experiments have identified a number of sites at which memory drugs could, in principle, manipulate the cell biological systems underlying the learning-related long-term potentiation (LTP) effect; this may explain the remarkable diversity of memory promoting compounds. Indeed, many of these agents are known to have positive effects on LTP. A possible third category of enhancement drugs directed specifically at integrated cognitive operations is nearly empty.
    [Show full text]
  • Aniracetam Does Not Improve Working Memory in Neurologically Healthy Pigeons
    RESEARCH ARTICLE Aniracetam does not improve working memory in neurologically healthy pigeons Hannah Phillips1*, Arlene McDowell2, Birgitte S. Mielby2, Ian G. Tucker2, 1 Michael ColomboID * 1 Department of Psychology, University of Otago, Dunedin, Otago, New Zealand, 2 School of Pharmacy, University of Otago, Dunedin, Otago, New Zealand * [email protected] (HP); [email protected] (MC) Abstract a1111111111 Understanding the effects of cognitive enhancing drugs is an important area of research. a1111111111 a1111111111 Much of the research, however, has focused on restoring memory following some sort of a1111111111 disruption to the brain, such as damage or injections of scopolamine. Aniracetam is a posi- a1111111111 tive AMPA-receptor modulator that has shown promise for improving memory under condi- tions when the brain has been damaged, but its effectiveness in improving memory in neurologically healthy subjects is unclear. The aim of the present study was to examine the effects of aniracetam (100mg/kg and 200 mg/kg) on short-term memory in ªneurologically OPEN ACCESS healthyº pigeons. Pigeons were administered aniracetam via either intramuscular injection Citation: Phillips H, McDowell A, Mielby BS, Tucker or orally, either 30 or 60 minutes prior to testing on a delayed matching-to-sample task. Anir- IG, Colombo M (2019) Aniracetam does not acetam had no effect on the pigeons' memory performance, nor did it affect response improve working memory in neurologically healthy latency. These findings add to the growing evidence that, while effective at improving mem- pigeons. PLoS ONE 14(4): e0215612. https://doi. ory function in models of impaired memory, aniracetam has no effect in improving memory org/10.1371/journal.pone.0215612 in healthy organisms.
    [Show full text]
  • Positive Allosteric Modulators of the Α-Amino-3- Hydroxy-5-Methyl-4-Isoxazole-Propionic Acid (AMPA)⎮
    Positive Allosteric Modulators of the α-amino-3- hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)⎮ Receptor Simon J.A. Grove, Craig Jamieson*, John K.F. Maclean, John A. Morrow & Zoran Rankovic Merck Research Laboratories, MSD Ltd, Newhouse, Motherwell, Lanarkshire ML1 5SH, UK [email protected] * Corresponding author at current address: Dept of Pure & Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK. Phone: +44 141 548 4830. Fax: +44 141 548 5743 1.1 Introduction L-glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays a fundamental role in the control of motor function, cognition and mood. The physiological effects of glutamate are mediated through two functionally distinct receptor families. While activation of metabotropic (G-protein coupled) glutamate receptors results in modulation of neuronal excitability and transmission, the ionotropic glutamate receptors (ligand-gated ion channels) are responsible for mediating the fast synaptic response to extracellular glutamate. The ionotropic glutamate receptors are divided up into three subclasses on the basis of molecular and pharmacological differences and are ⎮ Non Standard Abbreviations: α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA); Attention Deficit Hyperactivity Disorder (ADHD); Central Nervous System (CNS); Cyclothiazide (CTZ); Fluorowillardine (FW); Glutamate Receptor (GluR); Ligand Binding Domain (LBD); Human Embryonic Kidney (HEK); K+ channel from Streptomyces lividans (KcsA); Leucine Isoleucine Valine binding protein (LIVbp); Long Term Potentiation (LTP); N-Methyl-D-Aspartate (NMDA); Transmembrane (TM). 1 named after the agonists that were originally identified to selectively activate them: AMPA (α-amino-3- hydroxy-5-methyl-4-isoxazole-propionic acid), NMDA (N-methyl-D-aspartate) and kainate (2-carboxy- 3-carboxymethyl-4-isopropenylpyrrolidine)1,2.
    [Show full text]
  • Berrchem Company Ltd API List
    Berrchem Company Ltd API List 136470-78-5 Aba cavir 154229-19-3 Abiraterone 226954-04-7 AC-5216 57960-19-7 Ace qui nocyl 6622-91-9 4-(A cetic A cid) Pyridine hydr ochloride 5 -Acetylamino-2-a min o-4-picoli ne 93273-63-3 4-Acetyl-2-bromobenz onitrile 49 669 -13-8 2-A cetyl-6-bromopyridine 561 72-71-5 1-Acetyl-cycl opropane carboxylic aci d 57 756 -36-2 4-Acetyl -2,3,4, 5-tetrahydr o-1H-1, 4-benz odiaz epine 550 79-83-9 Acitretin 55077-30-0 Aclatonium napadisilate 10523-68-9 2-A dama ntanami ne hydrochlori de 10 6941 -25-7 Adefovir 1991-10-1 aldrich 80863-62-3 A LITAME 315-30-0 Allopurinol 850649-62-6 Alogliptin benzoat e 25526-93-6 Alovudi ne 8 50-52-2 ALT RENOGEST 645-05-6 Altretami ne 177036-94-1 AMBRISENTAN 61618-27-7 Amfe nac sodi um 773 7-17-9 Ami noacetone hydr ochl oride 2498 -50-2 4-A minobenzami dine Dihydrochlori de 3 7141-01-8 1-A minobenzene -3,4, 5-tricarboxylic acid 23031-78-9 3-A mino -1, 2- benzisothiazole 7644-4-4 2-Ami no -4’-bromoa cetophenone HCl 20776-51-6 2-a mino -3-bromobenzoic aci d 135776-98-6 (2-A mino -4-bro mo -phenyl)-phenyl-metha none 2-Amin o-4’-chlor oacetophe none HCl salt 89604-91-1 7-Ami no -3-Chl oro Cephalos porani c Acid 5399 4-69-7 7-Amin o-3-Chlor o Cephal ospora nic Acid 112 885 -41-3 4-A mino -5-chloro-2-etho xy-N-((4 -(4-fluor obe nzyl)-2-morpholinyl)methyl)benza mide 100371 0-83-5 2-Amin o-5-chlor o-4-fluor o-3-hydr oxypyridi ne 14394-56-0 6-A mino -4-Chl oro -5-M ethylpyrimidi ne 51564 -92-2 2-A min o-6-chloro -4-pi coline 58483-95-7 5-AMI NO-2-CHLO RO PYRIDI NE-4-CA RBOXY LIC ACID 214353-17-0
    [Show full text]
  • Haploinsufficiency of Rai1 and Its Effect on Bdnf Expression
    Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2010 HAPLOINSUFFICIENCY OF RAI1 AND ITS EFFECT ON BDNF EXPRESSION Sun Kim Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Medical Genetics Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/165 This Thesis 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]. © Sun H. Kim, 2010 All Rights Reserved i HAPLOINSUFFICIENCY OF RAI1 AND ITS EFFECT ON BDNF EXPRESSION A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. by Sun H. Kim Bachelor of Science (B.S.) The George Washington University, 2008 Director: Sarah H. Elsea, Ph.D.,F.A.C.M.G. Associate Professor, Departments of Pediatrics and Human and Molecular Genetics Virginia Commonwealth University Richmond, Virginia December, 2010 ii Acknowledgements First, I would like to give a big thank you to Dr. Sarah Elsea for being a great mentor throughout my master’s career. She has guided me in the right directions, and showed an extraordinary willingness to help at any time. I thank her for supporting me and my research project and always being available to discuss ideas and suggestions. She has always listened carefully to me and showed an interest in my ideas. Above all, she has helped me in becoming not only a better scientist, but also a better person.
    [Show full text]