DOCSLIB.ORG

Interaction of the Dopaminergic and Serotonergic Systems in Rat Brain

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Interaction of the Dopaminergic and Serotonergic Systems in Rat Brain KUOPION YLIOPISTON JULKAISUJA A. FARMASEUTTISET TIETEET 113 KUOPIO UNIVERSITY PUBLICATIONS A. PHARMACEUTICAL SCIENCES 113 TIINA KÄÄRIÄINEN Interaction of the Dopaminergic and Serotonergic Systems in Rat Brain Studies in Parkinsonian Models and Brain Microdialysis Doctoral dissertation To be presented by permission of the Faculty of Pharmacy of the University of Kuopio for public examination in Mediteknia Auditorium, Mediteknia building, University of Kuopio, on Saturday 13th December 2008, at 1 p.m. Department of Pharmacology and Toxicology Faculty of Pharmacy University of Kuopio JOKA KUOPIO 2008 Distributor: Kuopio University Library P.O. Box 1627 FI-70211 KUOPIO FINLAND Tel. +358 40 355 3430 Fax +358 17 163 410 http://www.uku.fi/kirjasto/julkaisutoiminta/julkmyyn.html Series Editor: Docent Pekka Jarho, Ph.D. Department of Pharmaceutical Chemistry Author’s address: Department of Pharmacology and Toxicology University of Kuopio P.O. Box 1627 FI-70211 KUOPIO Tel. +358 40 355 3776 Fax +358 17 162 424 E-mail: [email protected] Supervisors: Professor Pekka T. Männistö, M.D., Ph.D. Division of Pharmacology and Toxicology Faculty of Pharmacy University of Helsinki Senior assistant Anne Lecklin, Ph.D. Department of Pharmacology and Toxicology University of Kuopio Reviewers: Docent Pekka Rauhala, M.D., Ph.D. Institute of Biomedicine University of Helsinki Docent Seppo Kaakkola, M.D., Ph.D. Department of Neurology Helsinki University Central Hospital Opponent: Professor Raimo K. Tuominen, M.D., Ph.D. Division of Pharmacology and Toxicology Faculty of Pharmacy University of Helsinki ISBN 978-951-27-0851-2 ISBN 978-951-27-1144-4 (PDF) ISSN 1235-0478 Kopijyvä Kuopio 2008 Finland 3 Kääriäinen, Tiina. Interaction of the dopaminergic and serotonergic systems in rat brain: Studies in parkinsonian models and brain microdialysis. Kuopio University Publications A. Pharmaceutical Sciences 113. 2008. 125 p. ISBN 978-951-27-0851-2 ISBN 978-951-27-1144-4 (PDF) ISSN 1235-0478 ABSTRACT Dopamine and serotonin (5-hydroxytryptamine; 5-HT) are involved in several essential brain functions as well as in various neurological and mental disorders. Anatomical, electrophysiological and biochemical data point to an important interplay of the serotonergic and dopaminergic pathways. In particular, the serotonergic system has a modulatory role of on dopaminergic neurotransmission in the central nervous system (CNS). Various 5-HT receptor subtypes modulate dopamine release both directly by 5-HT receptors located on dopaminergic neurons, and indirectly via 5-HT heteroreceptors present on GABAergic neurons. Brain 5-HT/dopamine interactions are also putative targets for drug therapies in disorders related to alterations in dopaminergic or serotonergic neurotransmission, such as Parkinson’s disease (PD), schizophrenia and depression. However, the mechanisms to explain the interactions between 5-HT and dopamine in these brain dysfunctions are not well defined. The objectives of this study were 1) to explore the role of striatal 5-HT in the unilateral rat model of PD, and 2) to assess the ability of 5-HT2A/2C and 5-HT1A receptor ligands to modulate accumbal and striatal dopamine release and metabolism in normal rats. Also 3) the advantages and disadvantages of two types of 6-hydroxydopamine (6-OHDA)-lesion models were evaluated in neuroprotection studies with a flavonoid, quercetin. It was shown that acute intrastriatal L-dopa infusion decreased contralateral rotation of unilaterally 6-OHDA-lesioned rats, evidently by desensitization of ipsilateral dopamine D2 receptors. In an acute study, the decrease in the amount of rotations and imbalance of striatal 5-HT levels between intact and lesion side were abolished by inhibition of 5-HT synthesis. In a long-term study, continuous 2- week intrastriatal L-dopa infusion in 6-OHDA-rats also decreased the number of contralateral rotations induced by peripheral L-dopa and induced marked alterations in the ipsilateral serotonergic system (such as a long-term increase in 5-HT synthesizing enzyme tryptophan hydroxylase) as assessed on day 70 post- infusion. In normal rats, the anxiolytic 5-HT2A/2C antagonist, deramciclane, had an antidopaminergic effect similar to that of neuroleptics or the anxiolytic 5-HT1A agonist buspirone at a high dose. At least a 5-fold margin was found between the anxiolytic and neuroleptic doses of deramciclane in the rat. Striatal 5-HT content was differently affected by the two types of unilateral 6-OHDA-lesion models. Since it is known that striatal 5-HT is reduced in PD patients, it seems that the 6-OHDA medial forebrain bundle- lesioned rat models this situation unilaterally rather well. In these models, quercetin had no effect indicative of neuroprotection against nigrostriatal dopaminergic or serotonergic 6-OHDA-induced neuron damage in vivo. In conclusion, these results highlight the role of 5-HT neurons in the striatal dopaminergic imbalance that is responsible for the rotational behavior seen in the unilateral 6-OHDA rat. This study provides new information about the serotonergic effects after local exogenous L-dopa in acute and long-term administrations into the striatum of dopamine depleted rat. The results may help to further clarify the role of the serotonergic system in the action of L-dopa under dopamine deficiency. Additionally, the clear unilateral 5-HT damage in this widely used rat model should be taken into account in further studies. This study also confirms earlier reports of dopamine modulating properties of 5-HT1A and 5-HT2A/2C ligands, particularly in the mesolimbic system, and provides further evidence that combined affinity of 5-HT/ dopamine D2 receptors may be beneficial in drug actions modulating dopaminergic tone in the CNS. The lack of effect of quercetin in 6-OHDA-rats casts serious doubt on the neuroprotective effects of this bioflavonoid in experimental PD in vivo. National Library of Medicine Classification: WL 359, WL 307, QY 58, QV 126, WK 725 Medical Subject Headings: Parkinson Disease; Disease Models, Animal; Brain; Corpus Striatum; Neurotransmitter Agents; Serotonin; Receptors, Serotonin; Dopamine; Receptors, Dopamine; Ligands; Levodopa; Behavior, Animal; Rotation; Tryptophan Hydroxylase; Flavonoids; Quercetin; Oxidopamine; Microdialysis; Rats 4 5 “If the human brain were so simple that we could understand it, we would be so simple that we couldn’t.” Emerson Pugh, English philosopher, 1997 6 ACKNOWLEDGEMENTS The present study was carried out in the Department of Pharmacology and Toxicology, University of Kuopio, during the years 2003 – 2008. I want to express my deepest gratitude to my principal supervisor Professor Pekka T. Männistö, who made this thesis possible. His encouragement, support and vast expertise have guided me throughout this project. Furthermore, even though he left to work in the University of Helsinki in 2004, he has always been able to find time for me. It has been a great privilege to work with Pekka. I wish also to thank my second supervisor, Anne Lecklin, Ph.D. for being my local adviser here in Kuopio. I express my gratitude to the official reviewers Docent Pekka Rauhala and Docent Seppo Kaakkola for their valuable comments and constructive criticism for improving the manuscript of this thesis. Furthermore, I am very grateful to Ewen MacDonald, Ph.D. for revising the language. I am honored to have Professor Raimo K. Tuominen as my opponent. I am indebted to my all co-authors for their significant contributions to this work. Especially, I wish to thank my collaborators in PTM’s team in Viikki, University of Helsinki; J. Arturo García-Horsman, Ph.D., Mikko Käenmäki, M.Sc., Bernardino Ossola, M.Sc. and Marjo Piltonen, M.Sc. I want to express my special thanks to Marjo Piltonen for her help and friendship during these studies and for her kind hospitality during my several visits to Helsinki. I also wish to thank Marko Huotari, Ph.D., for introducing me the world of the stereotaxis during my early days in the Department. I sincerely thank all of the present and former personnel of Department of Pharmacology and Toxicology. I wish to thank my colleagues, particularly Markus Forsberg, Ph.D., Aaro Jalkanen, M.Sc., Pasi Lampela, Ph.D., Šárka Lehtonen, Ph.D., Timo Myöhänen, Ph.D., Katja Puttonen, M.Sc., Minna Rahnasto, M.Sc., Kaisa Salminen, M.Sc., Timo Sarajärvi, M.Sc., Marjo Tampio, M.Sc., and Jarkko Venäläinen, Ph.D., for their support and friendship. I wish to express my special and sincere thanks to Markus Forsberg for being a mentor particularly during the time when I was completing this thesis, and for many discussions regarding scientific and not-so- scientific matters. I am grateful for Pirjo Hänninen and Jaana Leskinen for their excellent technical assistance and advice, and I wish to thank Leena Oksanen for all the help during these years. I owe special thanks to the personnel of National Laboratory Animal Center for their seamless collaboration. I also wish to thank all of those who may not find their names here, but who contributed in some way during these years. I warmly thank all my dear friends outside the university, especially Merja Rytkönen, Kristiina “Krisu” Saarelainen, Leena Tähtivaara and Anu von Delvig with their families, for sharing the joys and sorrows for many years. In addition, you all have supported me through this long process – I am so fortunate to have friends like you! I express my warmest gratitude to my family; my parents, Irma and Seppo, and my little brothers, Mikko, Antti and Olli for their endless encouragement, care, support and understanding – you have always had confidence in me. Special thanks to Antti for many joyful moments and for your curiosity about scientific issues – there really is a bit of art in everything, even in science! Per aspera ad astra. Finally, I am ready for the new and fascinating challenges which lay ahead of me in the brighter future. This work was supported in part by grants from the Finnish Cultural Foundation of Northern Savo, the Finnish Parkinson Foundation, University of Kuopio and the Foundation of Aleksanteri Mikkonen, which are greatly appreciated.
Load more

Recommended publications
  • (Danio Rerio Hamilton 1822) Adulto: Diferenças Entre Modelos Comportamentais, Linhagens E Efeitos Do Estresse Predatório Agudo
    I CAIO MAXIMINO DE OLIVEIRA Papel da serotonina no comportamento defensivo do paulistinha (Danio rerio Hamilton 1822) adulto: Diferenças entre modelos comportamentais, linhagens e efeitos do estresse predatório agudo Tese apresentada ao Programa de Pós- Graduação em Neurociências e Biologia Celular do Instituto de Ciências Biológicas da Universidade Federal do Pará, como requisito parcial para obtenção do título de Doutor em Neurociências e Biologia Celular Área de concentração: Neurociências Orientador: Prof. Dr. Anderson Manoel Herculano Belém/PA 2014 CIP – Catalogação na Publicação OL48p Oliveira, Caio Maximino de, 1983- Papel da serotonina no comportamento defensivo do paulistinha (Danio rerio Hamilton 1822) adulto: Diferenças entre modelos comportamentais, linhagens, e efeitos do estresse predatório agudo / Caio Maximino de Oliveira ± 2014 Orientador: Anderson Manoel Herculano Tese (Doutorado) ± Universidade Federal do Pará, Programa de Pós- Graduação em Neurociências e Biologia Celular, Belém/PA, 2014 1. Neuropsicofarmacologia. 2. Neurociências. 3. Psicopatologia. I. Herculano, Anderson Manoel, orient. II. Título CDD: 610 CDU: 615 III CAIO MAXIMINO DE OLIVEIRA Papel da serotonina no comportamento defensivo do paulistinha (Danio rerio Hamilton 1822) adulto: Diferenças entre modelos comportamentais, linhagens e efeitos do estresse predatório agudo Tese apresentada ao Programa de Pós-Graduação em Neurociências e Biologia Celular do Instituto de Ciências Biológicas da Universidade Federal do Pará, como requisito parcial para obtenção do título de Doutor em Neurociências e Biologia Celular (Ênfase em Neurociências) pela Comissão Julgadora composta pelos membros: COMISSÃO JULGADORA ___________________________________ Prof. Dr. Anderson Manoel Herculano Universidade Federal do Pará (Presidente) ___________________________________ Prof. Dr. Amauri Gouveia Jr. Universidade Federal do Pará ___________________________________ Prof. Dr. Fernando Allan Rocha Universidade Federal do Pará ___________________________________ Prof.
    [Show full text]
  • Use of Compounds Binding to the Sigma Receptor Ligands for the Treatment of Neuropathic Pain Developing As a Consequence of Chemotherapy
    (19) & (11) EP 2 090 311 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 19.08.2009 Bulletin 2009/34 A61K 31/495 (2006.01) A61P 25/02 (2006.01) A61P 29/02 (2006.01) (21) Application number: 08384001.7 (22) Date of filing: 18.02.2008 (84) Designated Contracting States: • Vela Hernàndez, José Miguel AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 08028 Barcelona (ES) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT • Zamanillo-Castanedo, Daniel RO SE SI SK TR 08041 Barcelona (ES) Designated Extension States: • Nieto-López, Francisco Rafael AL BA MK RS Dpt. Farmacia, Facultad de Medicina 18012 Granada (ES) (71) Applicant: Laboratorios Del. Dr. Esteve, S.A. 08041 Barcelona (ES) (74) Representative: Peters, Hajo et al Graf von Stosch (72) Inventors: Patentanwaltsgesellschaft mbH • Baeyens-Cabrera, José Manuel Prinzregentenstrasse 22 Dpt. Farmacia, F. Medicina 80538 München (DE) 18012 Granada (ES) • Buschmann, Helmut H. Remarks: 08960 Sant Just Desvern (ES) The references to the drawing(s) no. 6 are deemed to be deleted (Rule 56(4) EPC). (54) Use of compounds binding to the sigma receptor ligands for the treatment of neuropathic pain developing as a consequence of chemotherapy (57) The present invention refers to the use of compounds binding to the sigma receptor for the treatment or prevention of neuropathic pain resulting from chemotherapy. EP 2 090 311 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 090 311 A1 Description Field of the invention 5 [0001] The present invention refers to the use of compounds binding to the sigma receptor for the treatment or prevention of neuropathic pain resulting from chemotherapy.
    [Show full text]
  • Supplementary Tables, Figures and Other Documents
    Clinical Relevance of a 16-Gene Pharmacogenetic Panel Test for Medication Management in a Cohort of 135 Patients David Niedrig1,2, Ali Rahmany1,3, Kai Heib4, Karl-Dietrich Hatz4, Katja Ludin5, Andrea M. Burden3, Markus Béchir6, Andreas Serra7, Stefan Russmann1,3,7,* 1 drugsafety.ch; Zurich, Switzerland 2 Hospital Pharmacy, Clinic Hirslanden Zurich; Zurich Switzerland 3 Swiss Federal Institute of Technology Zurich (ETHZ); Zurich, Switzerland 4 INTLAB AG; Uetikon am See, Switzerland 5 Labor Risch, Molecular Genetics; Berne, Switzerland 6 Center for Internal Medicine, Clinic Hirslanden Aarau; Aarau, Switzerland 7 Institute of Internal Medicine and Nephrology, Clinic Hirslanden Zurich; Zurich, Switzerland * Correspondence: [email protected]; Tel.: +41 (0)44 221 1003 Supplementary Tables, Figures and Other Documents Figure S1: Example of credit-card sized pharmacogenomic profile issued to patients 1 Table S2: SNPs analyzed by the 16-gene panel test Gene Allele rs number ABCB1 Haplotypes 1236-2677- rs1045642 ABCB1 3435 rs1128503 ABCB1 rs2032582 COMT Haplotypes 6269-4633- rs4633 COMT 4818-4680 rs4680 COMT rs4818 COMT rs6269 CYP1A2 *1C rs2069514 CYP1A2 *1F rs762551 CYP1A2 *1K rs12720461 CYP1A2 *7 rs56107638 CYP1A2 *11 rs72547513 CYP2B6 *6 rs3745274 CYP2B6 *18 rs28399499 CYP2C19 *2 rs4244285 CYP2C19 *3 rs4986893 CYP2C19 *4 rs28399504 CYP2C19 *5 rs56337013 CYP2C19 *6 rs72552267 CYP2C19 *7 rs72558186 CYP2C19 *8 rs41291556 CYP2C19 *17 rs12248560 CYP2C9 *2 rs1799853 CYP2C9 *3 rs1057910 CYP2C9 *4 rs56165452 CYP2C9 *5 rs28371686 CYP2C9 *6 rs9332131 CYP2C9
    [Show full text]
  • 付表 ⅠA 指定を受けた医薬の有効成分 Annex ⅠA Designated
    付表ⅠA 指定を受けた医薬の有効成分 Annex ⅠA Designated Pharmaceutical Active Ingredients 号(Sub-heading) 品名 Description 2818.30 アルゲルドラート algeldrate 2833.22 アルスルフ alusulf 2842.10 アルマシラート almasilate 2842.10 シマルドラート simaldrate 2842.90 硫酸アルマドラ ート almadrate sulfate 2842.90 アルマガート almagate 2842.90 カルバルドラード carbaldrate 2842.90 ヒドロタルシト hydrotalcite 2842.90 マガルドラート magaldrate 2843.30 オーラノフィン auranofin 2843.30 金チオグリカニド aurothioglycanide 2843.30 金チオりんご酸ナトリウム sodium aurothiomalate 2843.30 金チオ硫酸ナトリウム sodium aurotiosulfate 2843.90 カルボプラチン carboplatin 2843.90 シスプラチン cisplatin 2843.90 デキソルマプラチン dexormaplatin 2843.90 エンロプラチン enloplatin 2843.90 イプロプラチン iproplatin 2843.90 ロバプラチン lobaplatin 2843.90 ミボプラチン miboplatin 2843.90 ネダプラチン nedaplatin 2843.90 オルマプラチン ormaplatin 2843.90 オキサリプラチン oxaliplatin 2843.90 セブリプラチン sebriplatin 2843.90 スピロプラチン spiroplatin 2843.90 ゼニプラチン zeniplatin 2844.40 アルツモマブ altumomab 2844.40 塩化セシウム(131Cs) cesium (131 Cs) chloride 2844.40 クロルメロドリン(197Hg) chlormerodrin (197 Hg) 2844.40 シアノコバラミン(57Co) cyanocobalamin (57 Co) 2844.40 シアノコバラミン(58Co) cyanocobalamin (58 Co) 2844.40 シアノコバラミン(60Co) cyanocobalamin (60 Co) 2844.40 エチオダイズド油(131I) ethiodized oil (131 I) 2844.40 くえん酸第二鉄(59Fe)注射液 ferric (59 Fe) citrate in 2844.40 フィブリノゲン(125I) fibrinogen (125 I) 2844.40 フルデオキシグルコー ス(18F) fludeoxyglucose ( 18 F) 2844.40 フルオロドパ(18F) fluorodopa (18 F) 2844.40 くえん酸ガリウム(67Ga) gallium (67 Ga) citrate 2844.40 金コロイド(198Au) gold (198 Au), colloidal 2844.40 イオベングアン(131I) iobenguane (131 I) 2844.40 よう化人血清アルブミン(125I) iodinated (125 I) human serum albumin 2844.40 よう化人血清アルブミン(131I) iodinated
    [Show full text]
  • Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration
    International Journal of Molecular Sciences Review Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration Cristina Angeloni 1 , Martina Gatti 2, Cecilia Prata 3,* , Silvana Hrelia 4 and Tullia Maraldi 2 1 School of Pharmacy, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy; [email protected] 2 Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124 Modena, Italy; [email protected] (M.G.); [email protected] (T.M.) 3 Department of Pharmacy and Biotechnology, Alma Mater Studiorum—University of Bologna, Via Irnerio 48, 40126 Bologna, Italy 4 Department for Life Quality Studies, Alma Mater Studiorum—University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy; [email protected] * Correspondence: [email protected] Received: 7 April 2020; Accepted: 4 May 2020; Published: 7 May 2020 Abstract: Neurodegenerative diseases include a variety of pathologies such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and so forth, which share many common characteristics such as oxidative stress, glycation, abnormal protein deposition, inflammation, and progressive neuronal loss. The last century has witnessed significant research to identify mechanisms and risk factors contributing to the complex etiopathogenesis of neurodegenerative diseases, such as genetic, vascular/metabolic, and lifestyle-related factors, which often co-occur and interact with each other. Apart from several environmental or genetic factors, in recent years, much evidence hints that impairment in redox homeostasis is a common mechanism in different neurological diseases. However, from a pharmacological perspective, oxidative stress is a difficult target, and antioxidants, the only strategy used so far, have been ineffective or even provoked side effects.
    [Show full text]
  • 5994392 Tion of Application No. 67375.734 Eb3-1685, PEN. T
    USOO5994392A United States Patent (19) 11 Patent Number: 5,994,392 Shashoua (45) Date of Patent: Nov.30, 1999 54 ANTIPSYCHOTIC PRODRUGS COMPRISING 5,120,760 6/1992 Horrobin ................................. 514/458 AN ANTIPSYCHOTICAGENT COUPLED TO 5,141,958 8/1992 Crozier-Willi et al. ................ 514/558 AN UNSATURATED FATTY ACID 5,216,023 6/1993 Literati et al. .......................... 514/538 5,246,726 9/1993 Horrobin et al. ....................... 424/646 5,516,800 5/1996 Horrobin et al. ....................... 514/560 75 Inventor: Victor E. Shashoua, Brookline, Mass. 5,580,556 12/1996 Horrobin ................................ 424/85.4 73 Assignee: Neuromedica, Inc., Conshohocken, Pa. FOREIGN PATENT DOCUMENTS 30009 6/1981 European Pat. Off.. 21 Appl. No.: 08/462,820 009 1694 10/1983 European Pat. Off.. 22 Filed: Jun. 5, 1995 09 1694 10/1983 European Pat. Off.. 91694 10/1983 European Pat. Off.. Related U.S. Application Data 59-025327 2/1984 Japan. 1153629 6/1989 Japan. 63 Continuation of application No. 08/080,675, Jun. 21, 1993, 1203331 8/1989 Japan. abandoned, which is a continuation of application No. 07/952,191, Sep. 28, 1992, abandoned, which is a continu- (List continued on next page.) ation of application No. 07/577,329, Sep. 4, 1990, aban doned, which is a continuation-in-part of application No. OTHER PUBLICATIONS 07/535,812,tion of application Jun. 11, No. 1990, 67,375.734 abandoned, Eb3-1685, which is a continu-PEN. T. Higuchi et al. 66 Prodrugs as Noye Drug Delivery Sys 4,933,324, which is a continuation-in-part of application No.
    [Show full text]
  • Predicting Drug Interactions from Dissolution Studies
    PREDICTING DRUG INTERACTIONS FROM DISSOLUTION STUDIES Imre Klebovich Semmelweis University Department of Pharmaceutics Disso India – Goa 2015 International Annual Symposium on Dissolution Science 31 st August– 1st September, 2015, Goa, India THE BASIC LOGIC OF NOVEL DRUG RESEARCH CONCEPT in-celebro in-silico in-vitro in-vivo MAIN TYPES OF DRUG INTERACTIONS - Drug - Food - Alcohol Pleasure-giving - Smoking materials - Caffeine Drug - Transporters Interactions - Pharmacogenomics - Psychoactive drugs - Antacid and inhibitor of gastric juice secretion DRUG-FOOD INTERACTION COMPARISON ON IN VITRO DISSOLUTION AND IN VIVO HUMAN ABSORPTION PARAMETERS ON FIVE DIFFERENT ORAL FLUMECINOL PREPARATIONS CHEMICAL STRUCTURE OF FLUMECINOL (ZIXORYNR) hepatic enzyme inducer (CYP-450 2B1) METHOD OF FORMULATION OF DIFFERENT ORAL FLUMECINOL PREPARATIONS Symbol Formulation Methodfortechnology adsorbate in hard absorption of flumecinol on O—O Adsorbate gelatine capsule the surface of silicium dioxide microcapsules in hard microencapsulation by Δ—Δ Microcapsules gelaine capsule coacervation technique ß-cyclodextrine inclusion complexation by x—x tablet inclusion complex ß-cyclodextrine micropellets in hard forming of micropellets by a □—□ Micropellets I. gelaine capsule I. centrifugal granulator micropellets in hard forming of micropellets by a ●—● Micropellets II. gelaine capsule II. centrifugal granulator MEAN CUMULATIVE PERCENT OF FLUMECINOL IN VITRO DISSOLVED AT PH 1.2 OF FIVE FORMULATIONS PHARMACOKINETIC CURVES OF FLUMECINOL IN HUMAN AFTER 100 MG SINGLE ORAL
    [Show full text]
  • GPCR/G Protein
    Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com GPCR/G Protein G Protein Coupled Receptors (GPCRs) perceive many extracellular signals and transduce them to heterotrimeric G proteins, which further transduce these signals intracellular to appropriate downstream effectors and thereby play an important role in various signaling pathways. G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). In unstimulated cells, the state of G alpha is defined by its interaction with GDP, G beta-gamma, and a GPCR. Upon receptor stimulation by a ligand, G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. These effects include activating the MAPK and PI3K pathways, as well as inhibition of the Na+/H+ exchanger in the plasma membrane, and the lowering of intracellular Ca2+ levels. Most human GPCRs can be grouped into five main families named; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin, forming the GRAFS classification system. A series of studies showed that aberrant GPCR Signaling including those for GPCR-PCa, PSGR2, CaSR, GPR30, and GPR39 are associated with tumorigenesis or metastasis, thus interfering with these receptors and their downstream targets might provide an opportunity for the development of new strategies for cancer diagnosis, prevention and treatment. At present, modulators of GPCRs form a key area for the pharmaceutical industry, representing approximately 27% of all FDA-approved drugs. References: [1] Moreira IS. Biochim Biophys Acta. 2014 Jan;1840(1):16-33.
    [Show full text]
  • Diamandis Thesis
    !"!#$ CHEMICAL GENETIC INTERROGATION OF NEURAL STEM CELLS: PHENOTYPE AND FUNCTION OF NEUROTRANSMITTER PATHWAYS IN NORMAL AND BRAIN TUMOUR INITIATING NEURAL PRECUSOR CELLS by Phedias Diamandis A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy. Department of Molecular Genetics University of Toronto © Copyright by Phedias Diamandis 2010 Phenotype and Function of Neurotransmitter Pathways in Normal and Brain Tumor Initiating Neural Precursor Cells Phedias Diamandis Doctor of Philosophy Department of Molecular Genetics University of Toronto 2010 &'(!)&*!% The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain brings promise for the treatment of neurological diseases and has yielded new insight into brain cancer. The complete repertoire of signaling pathways that governs these cells however remains largely uncharacterized. This thesis describes how chemical genetic approaches can be used to probe and better define the operational circuitry of the NSC. I describe the development of a small molecule chemical genetic screen of NSCs that uncovered an unappreciated precursor role of a number of neurotransmitter pathways commonly thought to operate primarily in the mature central nervous system (CNS). Given the similarities between stem cells and cancer, I then translated this knowledge to demonstrate that these neurotransmitter regulatory effects are also conserved within cultures of cancer stem cells. I then provide experimental and epidemiologically support for this hypothesis and suggest that neurotransmitter signals may also regulate the expansion of precursor cells that drive tumor growth in the brain. Specifically, I first evaluate the effects of neurochemicals in mouse models of brain tumors. I then outline a retrospective meta-analysis of brain tumor incidence rates in psychiatric patients presumed to be chronically taking neuromodulators similar to those identified in the initial screen.
    [Show full text]
  • Rat Animal Models for Screening Medications to Treat Alcohol Use Disorders
    ACCEPTED MANUSCRIPT Selectively Bred Rats Page 1 of 75 Rat Animal Models for Screening Medications to Treat Alcohol Use Disorders Richard L. Bell*1, Sheketha R. Hauser1, Tiebing Liang2, Youssef Sari3, Antoinette Maldonado-Devincci4, and Zachary A. Rodd1 1Indiana University School of Medicine, Department of Psychiatry, Indianapolis, IN 46202, USA 2Indiana University School of Medicine, Department of Gastroenterology, Indianapolis, IN 46202, USA 3University of Toledo, Department of Pharmacology, Toledo, OH 43614, USA 4North Carolina A&T University, Department of Psychology, Greensboro, NC 27411, USA *Send correspondence to: Richard L. Bell, Ph.D.; Associate Professor; Department of Psychiatry; Indiana University School of Medicine; Neuroscience Research Building, NB300C; 320 West 15th Street; Indianapolis, IN 46202; e-mail: [email protected] MANUSCRIPT Key Words: alcohol use disorder; alcoholism; genetically predisposed; selectively bred; pharmacotherapy; family history positive; AA; HAD; P; msP; sP; UChB; WHP Chemical compounds studied in this article Ethanol (PubChem CID: 702); Acamprosate (PubChem CID: 71158); Baclofen (PubChem CID: 2284); Ceftriaxone (PubChem CID: 5479530); Fluoxetine (PubChem CID: 3386); Naltrexone (PubChem CID: 5360515); Prazosin (PubChem CID: 4893); Rolipram (PubChem CID: 5092); Topiramate (PubChem CID: 5284627); Varenicline (PubChem CID: 5310966) ACCEPTED _________________________________________________________________________________ This is the author's manuscript of the article published in final edited form as: Bell, R. L., Hauser, S. R., Liang, T., Sari, Y., Maldonado-Devincci, A., & Rodd, Z. A. (2017). Rat animal models for screening medications to treat alcohol use disorders. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2017.02.004 ACCEPTED MANUSCRIPT Selectively Bred Rats Page 2 of 75 The purpose of this review is to present animal research models that can be used to screen and/or repurpose medications for the treatment of alcohol abuse and dependence.
    [Show full text]
  • Pharmaceutical Appendix to the Tariff Schedule 2
    Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. ABACAVIR 136470-78-5 ACIDUM LIDADRONICUM 63132-38-7 ABAFUNGIN 129639-79-8 ACIDUM SALCAPROZICUM 183990-46-7 ABAMECTIN 65195-55-3 ACIDUM SALCLOBUZICUM 387825-03-8 ABANOQUIL 90402-40-7 ACIFRAN 72420-38-3 ABAPERIDONUM 183849-43-6 ACIPIMOX 51037-30-0 ABARELIX 183552-38-7 ACITAZANOLAST 114607-46-4 ABATACEPTUM 332348-12-6 ACITEMATE 101197-99-3 ABCIXIMAB 143653-53-6 ACITRETIN 55079-83-9 ABECARNIL 111841-85-1 ACIVICIN 42228-92-2 ABETIMUSUM 167362-48-3 ACLANTATE 39633-62-0 ABIRATERONE 154229-19-3 ACLARUBICIN 57576-44-0 ABITESARTAN 137882-98-5 ACLATONIUM NAPADISILATE 55077-30-0 ABLUKAST 96566-25-5 ACODAZOLE 79152-85-5 ABRINEURINUM 178535-93-8 ACOLBIFENUM 182167-02-8 ABUNIDAZOLE 91017-58-2 ACONIAZIDE 13410-86-1 ACADESINE 2627-69-2 ACOTIAMIDUM 185106-16-5 ACAMPROSATE 77337-76-9
    [Show full text]
  • Serotonergic Modulation of Zebrafish Behavior
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Progress in Neuro-Psychopharmacology & Biological Psychiatry 55 (2014) 50–66 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp Serotonergic modulation of zebrafish behavior: Towards a paradox Anderson Manoel Herculano a,b, Caio Maximino b,c,⁎ a Neuroendocrinology Laboratory, Biological Sciences Institute, Federal University of Pará, Belém, PA, Brazil b “Frederico Graeff” Neurosciences and Behavior Laboratory, Department of Morphology and Physiological Sciences, Biological and Health Sciences Center, State University of Pará, Marabá, PA, Brazil c International Zebrafish Neuroscience Research Consortium, United States article info abstract Available online 28 March 2014 Due to the fish-specific genome duplication event (~320–350 mya), some genes which code for serotonin pro- teins were duplicated in teleosts; this duplication event was preceded by a reorganization of the serotonergic sys- Keywords: tem, with the appearance of the raphe nuclei (dependent on the isthmus organizer) and prosencephalic nuclei, Defensive behavior including the paraventricular and pretectal complexes. With the appearance of amniotes, duplicated genes were Offensive behavior lost, and the serotonergic system was reduced to a more complex raphe system. From a comparative point of Psychedelic drugs view, then, the serotonergic system of zebrafish and that of mammals shows many important differences. How- Serotonin ever, many different behavioral functions of serotonin, as well as the effects of drugs which affect the serotonergic Zebrafish system, seem to be conserved among species. For example, in both zebrafish and rodents acute serotonin reup- take inhibitors (SSRIs) seem to increase anxiety-like behavior, while chronic SSRIs decrease it; drugs which act at the 5-HT1A receptor seem to decrease anxiety-like behavior in both zebrafish and rodents.
    [Show full text]