DOCSLIB.ORG

Tesis Doctoral Aránzazu Ferrer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tesis Doctoral Aránzazu Ferrer DEPARTAMENT PSICOBIOLOGIA ESTUDIO DE LA MEDIACIÓN DEL SISTEMA HISTAMINÉRGICO EN EL EFECTO PRODUCIDO POR LA AMITRIPTILINA SOBRE LA EVITACIÓN INHIBITORIA EN RATONES ARÁNZAZU FERRER AÑÓ UNIVERSITAT DE VALENCIA Servei de Publicacions 2009 Aquesta Tesi Doctoral va ser presentada a València el dia 19 de desembre de 2008 davant un tribunal format per: - Dª. Alicia Salvador Fernández-Montejo - D. Jorge L. Arias Pérez - Dª. Azucena Valencia Jiménez - D. José María Calés de Juan - D. Santiago Monleón Verdú Va ser dirigida per: D. Andrés Parra Guerrero Dª. Concepción Vinader Caerols ©Copyright: Servei de Publicacions Aránzazu Ferrer Añó Depòsit legal: I.S.B.N.:978-84-370-7427-6 D.L.:V-1286-2009 Edita: Universitat de València Servei de Publicacions C/ Artes Gráficas, 13 bajo 46010 València Spain Telèfon: 963864115 UNIVERSITAT DE VALÈNCIA Facultad de Psicología Departamento de Psicobiología ESTUDIO DE LA MEDIACIÓN DEL SISTEMA HISTAMINÉRGICO EN EL EFECTO PRODUCIDO POR LA AMITRIPTILINA SOBRE LA EVITACIÓN INHIBITORIA EN RATONES TESIS DOCTORAL Presentada por: Aránzazu Ferrer Añó Dirigida por: Dr. Andrés Parra Guerrero Dra. Concepción Vinader Caerols Valencia, 2008 I UNIVERSITAT DE VALÈNCIA Facultad de Psicología Departamento de Psicobiología ESTUDIO DE LA MEDIACIÓN DEL SISTEMA HISTAMINÉRGICO EN EL EFECTO PRODUCIDO POR LA AMITRIPTILINA SOBRE LA EVITACIÓN INHIBITORIA EN RATONES TESIS DOCTORAL Presentada por: Aránzazu Ferrer Añó Directores: Dr. Andrés Parra Guerrero Dra. Concepción Vinader Caerols Valencia, 2008 II III a todas aquellas mujeres que no renuncian a disfrutar de una vida profesional y de una vida familiar a todos aquellos que aportan su granito de arena para que su lucha sea victoria IV V Agradecimientos: Mi más sincero agradecimiento a todas las personas que han contribuido a la elaboración de esta tesis. En especial, a mis tutores por permitir y dirigir mi camino como investigadora. A Andrés por compartir conmigo sus conocimientos, por su apoyo en ciertos momentos delicados, por su sinceridad, elegancia y por ese espíritu investigador tan magnético como contagioso. A Concha por el valioso tiempo empleado en corregir y dirigir esta tesis, por su espíritu de lucha y fortaleza. a Vicente, mi marido, por la participación activa en la elaboración de la tesis, por enseñarme conocimientos de informática, por su inestimable paciencia y apoyo . a mis hijas, Eva y Andrea, por hacer que intente sacar lo mejor que hay en mí; que luchen por sus sueños aunque los objetivos cambien por el camino. Ir a por lo que se desea por encima de los contratiempos, como un tiro de flecha, directo a su objetivo. a mis padres, por inculcarme el amor al estudio y al trabajo bien hecho, y por hacer que estos años de austeridad hayan sido mejor de lo que podrían haber sido. a quienes me hicieron sentir miembro de un grupo en el principio de mi vida como investigadora: Andrés, Concha, MCarmen Arenas, Santiago, Ana Martos, Estrella, Eva Mª Ortega y Dori. a Estrella, por iniciar la línea de investigación que he continuado y cuya tesis ha sido referencia continua en la presente, por su sinceridad, naturalidad, honestidad, sencillez, amistad, por contribuir a mi formación como investigadora y por estar siempre ahí a pesar de la distancia. al Fotoclub Alboraier. A Ana Rodri, por su amistad y por estar en mi ordenador con sus esperados mensajes. A Vicente, Esperanza, Esther Paredes, MCarmen Benitez, y Ester por su colaboración empujando el tren. A Loli, porque desde el anonimato he sentido su apoyo a mi trabajo. al Dr. Salvador Lluch y a Alexis Aceituno por sus consejos de farmacología. VI a Ferrán, Sonia, y Carmen Carrasco por ser algún día la única y sincera sonrisa que yo viera. A Ferrán por velar por la buena marcha de los experimentos, por sus silbidos ahuyentadores de problemas. A Carmen Carrasco, Rosa Redolat, Inés y Paloma Vicens por sus consejos en la realización de los experimentos para mi Tesina. a Marisa, José Carlos, Eva Martín, Luisa, Paco y Blanca por su profesionalidad. a Javi, Bruno, Manuel, Conchín, Inés, Paloma Vicens, Maribel, Paloma Botella, Gabriel, Juan, Cristina y al resto de mis compañeros por ayudarme cuando lo he necesitado y por hacer más agradables las horas pasadas en la Facultad. A Victoria, Chiara y Eva Mª Ortega por ayudarme en la realización de los experimentos. a quien pueda ayudarme a encontrar un lugar en la investigación o en la clínica del trastorno bipolar y su tratamiento, ganando mi sustento haciendo lo que tanto me atrae y desconozco. Litio. De alguna manera esconde el misterio de la unión cuerpo-alma, esconde la brújula del alma humana, capaz de mostrarnos el camino entre el paraíso y el infierno emocional. La cara oculta de la luna. al Dr. Santiago Grisolía por concederme una beca para asistir a los cursos de su Cátedra. A él y a quienes trabajan con él, como Pili, por ser enamorados de la ciencia e intentar que los nuevos descubrimientos estén al alcance de todos. a la Generalitat Valenciana por la concesión del proyecto GV97-SH-22-89 y al Ministerio de Ciencia y Tecnología por la concesión del proyecto de investigación BSO2003-07163, que han permitido la realización de esta tesis. A José Luis Gomis, Director General de Farmacia y Productos Sanitarios de la Conselleria de Sanitat por proporcionarme los datos de consumo de amitriptilina y antidepresivos en la Comunidad Valenciana. GRACIAS VII ÍNDICE CAPÍTULO 1- INTRODUCCIÓN........................................................................ 9 CAPÍTULO 2- FÁRMACOS ANTIDEPRESIVOS............................................. 13 2.1- Introducción................................................................................................... 13 2.1.1- Clasificación, curso y etiología de la depresión...................................... 13 2.1.2- Bases biológicas de la depresión............................................................. 22 2.2- Clasificación y efectos secundarios............................................................... 35 2.2.1- Clasificación de los antidepresivos......................................................... 35 2.2.2- Efectos secundarios................................................................................. 41 2.3- Amitriptilina................................................................................................... 45 2.3.1- Introducción............................................................................................ 45 2.3.2- Farmacocinética...................................................................................... 47 2.3.3- Mecanismo de acción de la amitriptilina................................................ 50 CAPÍTULO 3- MEMORIA.................................................................................... 55 3.1- Introducción................................................................................................... 55 3.2- Memoria......................................................................................................... 57 3.2.1- Tipos de memoria................................................................................... 62 3.2.2- Anatomía de la memoria......................................................................... 65 3.2.3- Sistemas de neurotransmisión que intervienen en la memoria............... 79 3.2.4- Biología molecular de la memoria.......................................................... 98 3.3- Condicionamiento de evitación inhibitoria.................................................... 102 3.3.1- Introducción............................................................................................ 102 1 3.3.2- Neurobiología de la evitación inhibitoria................................................ 105 CAPÍTULO 4- ANTIDEPRESIVOS Y MEMORIA........................................... 123 4.1- Introducción................................................................................................... 123 4.2- Depresión y memoria..................................................................................... 124 4.3- Antidepresivos y memoria............................................................................. 129 4.3.1- Efectos cognitivos de los antidepresivos en humanos............................ 129 4.3.2- Efectos de los antidepresivos en animales.............................................. 136 CAPÍTULO 5- OBJETIVOS E HIPÓTESIS....................................................... 143 CAPÍTULO 6- EXPERIMENTOS........................................................................ 145 6.1- EXPERIMENTO 1: “Efecto de la administración postadquisición de amitriptilina sobre el aprendizaje de evitación inhibitoria con dos intensidades de shock (0,2 y 0,4 mA) y extinción forzada.”.............................................................. 147 6.1.1- Introducción............................................................................................ 147 6.1.2- Material y método................................................................................... 148 6.1.3- Resultados............................................................................................... 153 6.1.4- Discusión................................................................................................. 155 6.2- EXPERIMENTO 2: “Efecto de la administración pre y postadquisición de amitriptilina sobre el aprendizaje de evitación inhibitoria y la ejecución en el laberinto en cruz elevado”......................................................................................... 157 6.2.1- Introducción...........................................................................................
Load more

Recommended publications
  • 111 Physiology, Biochemistry and Pharmacology
    Reviews of 111 Physiology, Biochemistry and Pharmacology Editors M. P. Blaustein, Baltimore • H. Grunicke, Innsbruck E. Habermann, Giel3en • H. Neurath, Seattle S. Numa, Kyoto • D. Pette, Konstanz B. Sakmann, G6ttingen • U. Trendelenburg, Wiirzburg K.J. Ullrich, Frankfurt/M With 32 Figures and 10 Tables Springer-Verlag Berlin Heidelberg New York London Paris Tokyo ISBN 3-540-19156-9 Springer-Verlag Berlin Heidelberg NewYork 1SBN 0-387-19156-9 Springer-Verlag NewYork Berlin Heidelberg Library of Congress-Catalog-Card Number 74-3674 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. Duplication of this publication or parts thereof is only permitted under the provisions of the German Copyright Law of September 9, 1965, in its version of June 24, 1985, and a copyright fee must always be paid. Violations fall under the prosecution act of the German Copyright Law. © Springer-Verlag Berlin Heidelberg 1988 Printed in Germany The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant pro- tective laws and regulations and therefore free for general use. Product Liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Typesetting:K+ V Fotosatz, Beerfelden Offsetprinting and Binding: Konrad Triltsch, D-8700 W~rzburg 2127/3130-543210- Printed on acid-free paper Contents Regulation of Blood Pressure by Central Neuro- transmitters and Neuropeptides By A.
    [Show full text]
  • Effects of the Nicotinic Agonist Varenicline, Nicotinic Antagonist R-Bpidi, and DAT Inhibitor R-Modafinil on Co-Use of Ethanol and Nicotine in Female P Rats
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Psychopharmacology Manuscript Author (Berl) Manuscript Author . Author manuscript; available in PMC 2019 May 01. Published in final edited form as: Psychopharmacology (Berl). 2018 May ; 235(5): 1439–1453. doi:10.1007/s00213-018-4853-4. Effects of the nicotinic agonist varenicline, nicotinic antagonist r-bPiDI, and DAT inhibitor R-modafinil on co-use of ethanol and nicotine in female P rats. Sarah E. Maggio1, Meredith A. Saunders1, Thomas A. Baxter1, Kimberly Nixon2, Mark A. Prendergast1, Guangrong Zheng3, Peter Crooks3, Linda P. Dwoskin2, Rachel D. Slack4, Amy H. Newman4, Richard L. Bell5, and Michael T. Bardo1 1Department of Psychology, University of Kentucky, Lexington, KY 40536, USA. 2Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA. 3Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas, Little Rock, AR 72205, USA. 4Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse- Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA. 5Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Abstract Rationale: Co-users of alcohol and nicotine are the largest group of polysubstance users worldwide. Commonalities in mechanisms of action for ethanol (EtOH) and nicotine proposes the possibility of developing a single pharmacotherapeutic to treat co-use. Objectives: Toward developing a preclinical model of co-use, female alcohol-preferring (P) rats were trained for voluntary EtOH drinking and i.v. nicotine self-administration in three phases: (1) EtOH alone (0 vs. 15%, 2-bottle choice); (2) nicotine alone (0.03 mg/kg/infusion, active vs.
    [Show full text]
  • (19) United States (12) Patent Application Publication (10) Pub
    US 20130289061A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0289061 A1 Bhide et al. (43) Pub. Date: Oct. 31, 2013 (54) METHODS AND COMPOSITIONS TO Publication Classi?cation PREVENT ADDICTION (51) Int. Cl. (71) Applicant: The General Hospital Corporation, A61K 31/485 (2006-01) Boston’ MA (Us) A61K 31/4458 (2006.01) (52) U.S. Cl. (72) Inventors: Pradeep G. Bhide; Peabody, MA (US); CPC """"" " A61K31/485 (201301); ‘4161223011? Jmm‘“ Zhu’ Ansm’ MA. (Us); USPC ......... .. 514/282; 514/317; 514/654; 514/618; Thomas J. Spencer; Carhsle; MA (US); 514/279 Joseph Biederman; Brookline; MA (Us) (57) ABSTRACT Disclosed herein is a method of reducing or preventing the development of aversion to a CNS stimulant in a subject (21) App1_ NO_; 13/924,815 comprising; administering a therapeutic amount of the neu rological stimulant and administering an antagonist of the kappa opioid receptor; to thereby reduce or prevent the devel - . opment of aversion to the CNS stimulant in the subject. Also (22) Flled' Jun‘ 24’ 2013 disclosed is a method of reducing or preventing the develop ment of addiction to a CNS stimulant in a subj ect; comprising; _ _ administering the CNS stimulant and administering a mu Related U‘s‘ Apphcatlon Data opioid receptor antagonist to thereby reduce or prevent the (63) Continuation of application NO 13/389,959, ?led on development of addiction to the CNS stimulant in the subject. Apt 27’ 2012’ ?led as application NO_ PCT/US2010/ Also disclosed are pharmaceutical compositions comprising 045486 on Aug' 13 2010' a central nervous system stimulant and an opioid receptor ’ antagonist.
    [Show full text]
  • 7 Nicotinic Receptor Agonists
    CORE Metadata, citation and similar papers at core.ac.uk Provided by PubMed Central The Open Medicinal Chemistry Journal, 2010, 4, 37-56 37 Open Access 7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease Jun Toyohara, and Kenji Hashimoto* Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan Abstract: Accumulating evidence suggests that 7 nicotinic receptors (7 nAChRs), a subtype of nAChRs, play a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer’s disease (AD). A number of psychopharmacological and genetic studies shown that 7 nAChRs play an important role in the deficits of P50 auditory evoked potential in patients with schizophrenia, and that 7 nAChR agonists would be potential therapeutic drugs for cognitive impairments associated with P50 deficits in schizophrenia. Furthermore, some studies have demonstrated that 7 nAChRs might play a key role in the amyloid- (A)-mediated pathology of AD, and that 7 nAChR agonists would be potential therapeutic drugs for A deposition in the brains of patients with AD. Interestingly, the altered expression of 7 nAChRs in the postmortem brain tissues from patients with schizophrenia and AD has been reported. Based on all these findings, selective 7 nAChR agonists can be considered potential therapeutic drugs for cognitive impairments in both schizophrenia and AD. In this article, we review the recent research into the role of 7 nAChRs in the pathophysiology of these diseases and into the potential use of novel 7 nAChR agonists as therapeutic drugs. Keywords: 7 Nicotinic receptors, Cognition, Schizophrenia, Alzheimer’s disease.
    [Show full text]
  • Nicotinic Acetylcholine Receptor Signaling in Neuroprotection
    Akinori Akaike · Shun Shimohama Yoshimi Misu Editors Nicotinic Acetylcholine Receptor Signaling in Neuroprotection Nicotinic Acetylcholine Receptor Signaling in Neuroprotection Akinori Akaike • Shun Shimohama Yoshimi Misu Editors Nicotinic Acetylcholine Receptor Signaling in Neuroprotection Editors Akinori Akaike Shun Shimohama Department of Pharmacology, Graduate Department of Neurology, School of School of Pharmaceutical Sciences Medicine Kyoto University Sapporo Medical University Kyoto, Japan Sapporo, Hokkaido, Japan Wakayama Medical University Wakayama, Japan Yoshimi Misu Graduate School of Medicine Yokohama City University Yokohama, Kanagawa, Japan ISBN 978-981-10-8487-4 ISBN 978-981-10-8488-1 (eBook) https://doi.org/10.1007/978-981-10-8488-1 Library of Congress Control Number: 2018936753 © The Editor(s) (if applicable) and The Author(s) 2018. This book is an open access publication. Open Access This book is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this book are included in the book’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the book’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. The use of general descriptive names, registered names, trademarks, service marks, etc.
    [Show full text]
  • Neuronal Nicotinic Receptors
    NEURONAL NICOTINIC RECEPTORS Dr Christopher G V Sharples and preparations lend themselves to physiological and pharmacological investigations, and there followed a Professor Susan Wonnacott period of intense study of the properties of nAChR- mediating transmission at these sites. nAChRs at the Department of Biology and Biochemistry, muscle endplate and in sympathetic ganglia could be University of Bath, Bath BA2 7AY, UK distinguished by their respective preferences for C10 and C6 polymethylene bistrimethylammonium Susan Wonnacott is Professor of compounds, notably decamethonium and Neuroscience and Christopher Sharples is a hexamethonium,5 providing the first hint of diversity post-doctoral research officer within the among nAChRs. Department of Biology and Biochemistry at Biochemical approaches to elucidate the structure the University of Bath. Their research and function of the nAChR protein in the 1970’s were focuses on understanding the molecular and facilitated by the abundance of nicotinic synapses cellular events underlying the effects of akin to the muscle endplate, in electric organs of the acute and chronic nicotinic receptor electric ray,Torpedo , and eel, Electrophorus . High stimulation. This is with the goal of affinity snakea -toxins, principallyaa -bungarotoxin ( - Bgt), enabled the nAChR protein to be purified, and elucidating the structure, function and subsequently resolved into 4 different subunits regulation of neuronal nicotinic receptors. designateda ,bg , and d .6 An additional subunit, e , was subsequently identified in adult muscle. In the early 1980’s, these subunits were cloned and sequenced, The nicotinic acetylcholine receptor (nAChR) arguably and the era of the molecular analysis of the nAChR has the longest history of experimental study of any commenced.
    [Show full text]
  • The Effect of Sazetidine-A and Other Nicotinic Ligands on Nicotine Controlled Goal-Tracking in Female and Male Rats
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of Kentucky University of Kentucky UKnowledge Pharmaceutical Sciences Faculty Publications Pharmaceutical Sciences 2-2017 The Effect of Sazetidine-A and Other Nicotinic Ligands on Nicotine Controlled Goal-Tracking in Female and Male Rats S. Charntikov University of New Hampshire A. M. Falco University of Nebraska - Lincoln K. Fink University of Nebraska - Lincoln Linda P. Dwoskin University of Kentucky, [email protected] See next page for additional authors Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Follow this and additional works at: https://uknowledge.uky.edu/ps_facpub Part of the Chemicals and Drugs Commons, Neuroscience and Neurobiology Commons, and the Pharmacy and Pharmaceutical Sciences Commons Authors S. Charntikov, A. M. Falco, K. Fink, Linda P. Dwoskin, and R. A. Bevins The Effect of Sazetidine-A and Other Nicotinic Ligands on Nicotine Controlled Goal- Tracking in Female and Male Rats Notes/Citation Information Published in Neuropharmacology, v. 113, part A, p. 354-366. © 2016 Elsevier Ltd. All rights reserved. This manuscript version is made available under the CC‐BY‐NC‐ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/. The document available for download is the author's post-peer-review final draft of the article. Digital Object Identifier (DOI) https://doi.org/10.1016/j.neuropharm.2016.10.014 This article is available at UKnowledge: https://uknowledge.uky.edu/ps_facpub/128 HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Neuropharmacology Manuscript Author .
    [Show full text]
  • [3H]Acetylcholine to Muscarinic Cholinergic Receptors’
    0270.6474/85/0506-1577$02.00/O The Journal of Neuroscience CopyrIght 0 Smety for Neurosmnce Vol. 5, No. 6, pp. 1577-1582 Prrnted rn U S.A. June 1985 High-affinity Binding of [3H]Acetylcholine to Muscarinic Cholinergic Receptors’ KENNETH J. KELLAR,2 ANDREA M. MARTINO, DONALD P. HALL, Jr., ROCHELLE D. SCHWARTZ,3 AND RICHARD L. TAYLOR Department of Pharmacology, Georgetown University, Schools of Medicine and Dentistry, Washington, DC 20007 Abstract affinities (Birdsall et al., 1978). Evidence for this was obtained using the agonist ligand [3H]oxotremorine-M (Birdsall et al., 1978). High-affinity binding of [3H]acetylcholine to muscarinic Studies of the actions of muscarinic agonists and detailed analy- cholinergic sites in rat CNS and peripheral tissues was meas- ses of binding competition curves between muscarinic agonists and ured in the presence of cytisin, which occupies nicotinic [3H]antagonists have led to the concept of muscarinic receptor cholinergic receptors. The muscarinic sites were character- subtypes (Rattan and Goyal, 1974; Goyal and Rattan, 1978; Birdsall ized with regard to binding kinetics, pharmacology, anatom- et al., 1978). This concept was reinforced by the discovery of the ical distribution, and regulation by guanyl nucleotides. These selective actions and binding properties of the antagonist pirenze- binding sites have characteristics of high-affinity muscarinic pine (Hammer et al., 1980; Hammer and Giachetti, 1982; Watson et cholinergic receptors with a Kd of approximately 30 nM. Most al., 1983; Luthin and Wolfe, 1984). An evolving classification scheme of the muscarinic agonist and antagonist drugs tested have for these muscarinic receptors divides them into M-l and M-2 high affinity for the [3H]acetylcholine binding site, but piren- subtypes (Goyal and Rattan, 1978; for reviews, see Hirschowitz et zepine, an antagonist which is selective for M-l receptors, al., 1984).
    [Show full text]
  • Nicotinic Ach Receptors
    Nicotinic ACh Receptors Susan Wonnacott and Jacques Barik Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK Susan Wonnacott is Professor of Neuroscience in the Department of Biology and Biochemistry at the University of Bath. Her research focuses on understanding the roles of nicotinic acetylcholine receptors in the mammalian brain and the molecular and cellular events initiated by acute and chronic nicotinic receptor stimulation. Jacques Barik was a PhD student in the Bath group and is continuing in addiction research at the Collège de France in Paris. Introduction and there followed detailed studies of the properties The nicotinic acetylcholine receptor (nAChR) is the of nAChRs mediating synaptic transmission at prototype of the cys-loop family of ligand-gated ion these sites. nAChRs at the muscle endplate and in sympathetic ganglia could be distinguished channels (LGIC) that also includes GABAA, GABAC, by their respective preferences for C10 and C6 glycine, 5-HT3 receptors, and invertebrate glutamate-, histamine-, and 5-HT-gated chloride channels.1,2 polymethylene bistrimethylammonium compounds, 7 nAChRs in skeletal muscle have been characterised notably decamethonium and hexamethonium. This DRIVING RESEARCH FURTHER in detail whereas mammalian neuronal nAChRs provided the first evidence that muscle and neuronal DRIVING RESEARCH FURTHER in the central nervous system have more recently nAChRs are structurally different. become the focus of intense research efforts. This In the 1970s, elucidation of the structure and function was fuelled by the realisation that nAChRs in the brain of the muscle nAChR, using biochemical approaches, and spinal cord are potential therapeutic targets for was facilitated by the abundance of nicotinic synapses a range of neurological and psychiatric conditions.
    [Show full text]
  • Involvement of Nicotinic Receptor Subtypes in the Behavioral Effects of Nicotinic Drugs in Squirrel Monkeys
    1521-0103/366/2/397–409$35.00 https://doi.org/10.1124/jpet.118.248070 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 366:397–409, August 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Involvement of Nicotinic Receptor Subtypes in the Behavioral Effects of Nicotinic Drugs in Squirrel Monkeys Sarah L. Withey,1 Michelle R. Doyle,1,2 Jack Bergman, and Rajeev I. Desai Preclinical Pharmacology Laboratory, McLean Hospital/Harvard Medical School, Belmont, Massachusetts Received January 27, 2018; accepted May 17, 2018 ABSTRACT Evidence suggests that the a4b2, but not the a7, subtype of the except for lobeline, the nicotinic agonists produced either full nicotinic acetylcholine receptor (nAChR) plays a key role in [(1)-epibatidine, (2)-epibatidine, and nicotine] or partial (vare- Downloaded from mediating the behavioral effects of nicotine and related drugs. nicline, cytisine, anabaseine, and isoarecolone) substitution for However, the importance of other nAChR subtypes remains (1)-epibatidine. In interaction studies with antagonists differing unclear. The present studies were conducted to examine the in selectivity, (1)-epibatidine discrimination was substan- involvement of nAChR subtypes by determining the effects of tively antagonized by mecamylamine, slightly attenuated selected nicotinic agonists and antagonists in squirrel monkeys by hexamethonium (peripherally restricted) or dihydro- b a either 1) responding for food reinforcement or 2) discriminating the -erythroidine, and not altered by methyllycaconitine ( 7 jpet.aspetjournals.org nicotinic agonist (1)-epibatidine (0.001 mg/kg) from vehicle. In selective). Varenicline and cytisine enhanced (1)-epibati- food-reinforcement studies, nicotine, (1)-epibatidine, varenicline dine’s discriminative-stimulus effects.
    [Show full text]
  • United States Patent 19 11 Patent Number: 5,446,070 Mantelle (45) Date of Patent: "Aug
    USOO544607OA United States Patent 19 11 Patent Number: 5,446,070 Mantelle (45) Date of Patent: "Aug. 29, 1995 54 COMPOST ONS AND METHODS FOR 4,659,714 4/1987 Watt-Smith ......................... 514/260 TOPCAL ADMNSTRATION OF 4,675,009 6/1987 Hymes .......... ... 604/304 PHARMACEUTICALLY ACTIVE AGENTS 4,695,465 9/1987 Kigasawa .............................. 424/19 4,748,022 5/1988 Busciglio. ... 424/195 75 Inventor: Juan A. Mantelle, Miami, Fla. 4,765,983 8/1988 Takayanagi. ... 424/434 4,789,667 12/1988 Makino ............ ... 514/16 73) Assignee: Nover Pharmaceuticals, Inc., Miami, 4,867,970 9/1989 Newsham et al. ... 424/435 Fla. 4,888,354 12/1989 Chang .............. ... 514/424 4,894,232 1/1990 Reul ............. ... 424/439 * Notice: The portion of the term of this patent 4,900,552 2/1990 Sanvordeker .... ... 424/422 subsequent to Aug. 10, 2010 has been 4,900,554 2/1990 Yanagibashi. ... 424/448 disclaimed. 4,937,078 6/1990 Mezei........... ... 424/450 Appl. No.: 112,330 4,940,587 7/1990 Jenkins ..... ... 424/480 21 4,981,875 l/1991 Leusner ... ... 514/774 22 Filed: Aug. 27, 1993 5,023,082 6/1991 Friedman . ... 424/426 5,234,957 8/1993 Mantelle ........................... 514/772.6 Related U.S. Application Data FOREIGN PATENT DOCUMENTS 63 Continuation-in-part of PCT/US92/01730, Feb. 27, 0002425 6/1979 European Pat. Off. 1992, which is a continuation-in-part of Ser. No. 0139127 5/1985 European Pat. Off. 813,196, Dec. 23, 1991, Pat. No. 5,234,957, which is a 0159168 10/1985 European Pat.
    [Show full text]
  • Biological Processes Underlying Co-Use of Alcohol and Nicotine
    BIOLOGICAL MECHANISMS BIOLOGICAL PROCESSES UNDERLYING The fact that alcohol and tobacco are readily and legally CO-USE OF ALCOHOL AND NICOTINE: available likely contributes to their co-use. Over the past two NEURONAL MECHANISMS, CROSS­ decades, however, it has become increasingly clear that bio­ TOLERANCE, AND GENETIC FACTORS logical factors also contribute to the concurrent use of alco­ hol and nicotine—that is, certain common physiological mechanisms may account for people’s liability to use both Douglas Funk, Ph.D.; Peter W. Marinelli, Ph.D.; alcohol and nicotine. Several such mechanisms have been and Anh D. Lê, Ph.D. suggested. For example, both alcohol and nicotine may enhance a person’s motivation to also consume the other drug by act­ Alcohol and nicotine are two of the oldest and most ing on a common target in the brain that is responsible for commonly used recreational drugs, and many people use the reinforcing effects of both drugs. Alternatively, cross-toler­ both of them together. Although their ready availability ance between the two drugs may reduce the drugs’ aversive likely contributes to the strong correlation between alcohol effects and motivate people to use more of the drugs in order and nicotine use, several lines of evidence suggest that to achieve the same rewarding effects. (The concept of cross- biological factors play a role as well. For example, both tolerance will be explained in more detail in the section “Toler­ alcohol and nicotine act on a brain system called the ance and Cross-Tolerance.”) The study of this possible mech­ mesolimbic dopamine system, which mediates the rewarding and reinforcing properties of both drugs.
    [Show full text]