AN ORAL HISTORY OF NEUROPSYCHOPHARMACOLOGY THE FIRST FIFTY YEARS Peer Interviews Volume Three: Neuropharmacology Copyright © 2011 ACNP Thomas A. Ban (series editor) AN ORAL HISTORY OF NEUROPSYCHOPHARMACOLOGY Fridolin Sulser (volume editor) VOLUME 3: NEUROPHARMACOLOGY All rights reserved. No part of this book may be used or reproduced in any manner without written permission from the American College of Neuropsychopharmacology (ACNP). Library of Congress Cataloging-in-Publication Data Thomas A. Ban, Fridoln Sulser (eds): An Oral History of Neuropsychopharmacology: The First Fifty Years, Peer Interviews Includes bibliographical references and index ISBN: 1461161614 ISBN-13: 9781461161615 1. Neuropharmacology 2. Neurotransmitterr era 3. Mode of action of psychotropic drugs 4. Psychotropic drug development Publisher: ACNP ACNP Executive Office 5034A Thoroughbred Lane Brentwood, Tennessee 37027 U.S.A. Email: [email protected] Website: www.acnp.org Cover design by Jessie Blackwell; JBlackwell Design www.jblackwelldesign.com AMERICAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY AN ORAL HISTORY OF NEUROPSYCHOPHARMACOLOGY THE FIRST FIFTY YEARS Peer Interviews Edited by Thomas A. Ban Co-editors Volume 1: Starting Up - Edward Shorter Volume 2: Neurophysiology - Max Fink Volume 3: Neuropharmacology - Fridolin Sulser Volume 4: Psychoharmacology - Jerome Levine Volume 5: Neuropsychopharmacology - Samuel Gershon Volume 6: Addiction - Herbert D. Kleber Volume 7: Special Areas - Barry Blackwell Volume 8: Diverse Topics - Carl Salzman Volume 9: Update - Barry Blackwell Volume 10: History of the ACNP - Martin M. Katz VOLUME 3 NEUROPHARMACOLOGY ACNP 2011 VOLUME 3 Fridolin Sulser NEUROPHARMACOLOGY The Neurotransmitter Era in Neuropsychopharmacology Preface Thomas A. Ban Dedicated to the Memory of Bernard B. Brodie, President ACNP, 1965 PREFACE Thomas A. Ban In 1957 Ralph Gerard coined the term “psychotropic drugs” for chemicals which can control or induce mental pathology.1 Neuropharmacology studies the molecular substrate involved in the mode of action of these drugs. Interviewees, in the first two volumes of this series, reflected on their contributions to the delineation of the effects of psychotropic drugs on be- havioral measures (Volume 1) and neurophysiologic parameters (Volume 2). In Volume 3 the emphasis shifts and interviewees reflect on their contributions to the development of neuropharmacological research. Since neurophrama- cological research may provide information on the biochemical underpinning of mental pathology, neuropharmacology has been the moving force of psy- chotropic drug development during the fifty years covered in Volume 3. Development of neuropharmacology was triggered in the 1950s by the serendipitous discovery of the first set of effective psychotropic drugs; chlor- promazine, reserpine, meprobamate, iproniazid and imipramine in the treat- ment of mental pathology.2 The commercial success of these drugs, and es- pecially of chlorpromazine and meprobamate, stimulated the pharmaceutical industry to develop substances with similar effects. By the end of the 1950s there were twelve effective drugs for the treatment of psychoses, seven for the treatment of depression, and two for the treatment of anxiety.* In 1967 an “expert committee” of the World Health Organization (WHO) classified psychotropic drugs into five categories: neuroleptics (major tranquilizers, antipsychotics), anxiolytic sedatives (minor tranquilizers), antidepressants, psychostimulants, and psychodysleptics (psychomimetics).3 By the end of the 20th century two further categories were added: mood stabilizers and cognitive enhancers. Each of these categories was broad, and within each category there were substances with different pharmacological actions. The WHO classification has had a major impact on neuropharmacology and on psychotropic drug development. * Drugs for the treatment of psychoses at the end of the 1950’s: chlorpromazine, chlorprothixene, haloper- idol, methotrimeprazine (levomepromazine,) perphenazine, prochlorperazine, reserpine, thiopropazate, thioproperazine, thioridazine, trifluoperazine, and triflupromazine. Drugs for the treatment of depression by the end of the 1950’s: amitriptyline, imipramine iproniazid, isocarboxazid, nialamide, phenelzine, and tranylcypromine. Drugs for the treatment of anxiety by the end of the 1950s: hydroxyzine and meprobamate x AN Oral History of Neuropsychopharmacology – Neuropharmacology Neurotransmitters The initial targets of neuropharmacological research were neurotrans- mitters. By the end of the 1950s there were six neurotransmitters identi- fied: acetylcholine, norepinephrine (noradrenalin), serotonin, dopamine, γ-aminobutyric acid, and substance P. Acetylcholine (ACh) was first detected at parasympathetic nerve endings in 1914 by Henry Dale.4 The effect of the substance on adjacent cells to the nerve endings was first noted by Otto Loewi in 1921.5 In 1937 ACh was isolated from brain homogenates by Juda Quastel and his associates,6 and Stedman and Stedman.7 The effect of ACh on neuronal transmission in the spinal cord was demonstrated by Eccles and his associates in 1954.8 Sympathin was first detected at sympathetic nerve endings in 1904 by R.T. Elliott. 9, 10 The substance was identified as noradrenaline (NA)/norepineph- rine (NE)11 and separated from adrenaline/epinephrine by Ulf Von Euler in 1946.12 In 1954, Marthe Vogt reported on the concentration of NE in different parts of the brain in normal conditions and after the administration of drugs.13 In 1884 Stevens and Lee described a vasoconstrictor substance in the blood.14 The substance was crystallized from ox serum by Rapport, Green and Page, and identified as 5-hydroxytryptamine (5HT), referred to as sero- tonin, in 1948.15 In 1937 Vittorio Erspamer extracted a substance from the enterochromaffin cells of the intestinal mucosa of rabbits, he referred to as enteramine.16 In 1952 he recognized that enteramine was a structurally iden- tical indoleamine with serotonin.17 In 1953 Twarog and Page demonstrated the presence,18 and in 1954 Amin, Crawford and Gaddum described the dis- tribution of 5HT in the brain.19 Dopamine (DA) an intermediary in the synthesis of NE from tyrosine was detected in the brain in 1957 by Kathleen Montagu.20 The same sub- stance was identified in 1958 by Arvid Carlsson and his associates.21 In 1959 Carlsson described the distribution of dopamine in the central nervous system. He also demonstrated that DA was not just an inactive intermediary, a precursor of NE, but an active neurotransmitter in the brain.22 The distribu- tion of dopamine was further elaborated by Bertler and Rosengren,23 and Sano and his associates24 in the same year (1959). The presence of γ-aminobutyric acid (GABA) in plants and bacteria has been known since the late 19th century. In 1950 Awapara and his associ- ates,25 and Roberts and Frankel26 detected the presence of GABA in the brain. Seven years later, in 1957, Purpura and his associates,27 and Curtis and his associates28 demonstrated its marked depressant action on nerve terminals and identified GABA as an inhibitory neurotransmitter. Preface xi Substance P (SP) was detected in the intestine and in the brain in 1931 by Von Euler and Gaddum.29 In 1952 Zetler had shown the presence of the sub- stance in high concentration in the human cerebral cortex,30 and in 1959 he demonstrated that SP is a centrally acting transmitter of inhibitory neurons.31 The Aminco Bowman spectrophotofluorimeter (SPEC) was introduced in 195532 and employed in the same year by Bernard Brodie and his associates for measuring the concentration of neurotransmitter monoamines, such as NE, 5-HT and DA and their metabolites in the brain. (See, Overview, Volume1.) SPEC complemented paper, gas and high-speed liquid chromatography and was instrumental in opening up research in neuropharmacology. The enzyme monoamineoxidase (MAO), involved in the oxidative deami- nation of monoamines,33 was first detected in the liver by Blaschko and his associates in 1937.34 The same year MAO was also detected in the brain by Pugh and Quastel.35 In 1938, MAO oxidase was separated from diamine oxi- dase by Zeller.36 Psychotropic Drugs Psychotropic drug development has been closely linked to neurophar- macological research and for about thirty years it was dominated by studies on the effect of drugs on neurotransmitter mediated signal transduction in the brain. Developments in the neuropharmacology of neuroleptics (antipsychot- ics) began in the mid 1950s with the demonstration of a linear relationship between the sedative and the anti-5HT effect of chlorpromazine (CPZ) and its congeners.37 In the late 1950s, neuroleptics were divided into “sedative” or CPZ-type, and “incisive” or prochlorperazine-type drugs.38 There was no difference in therapeutic efficacy between the two groups, but “incisive” neu- roleptics were more potent on a mg per kg basis and produced more fre- quent and severe extrapyramidal symptoms/signs (EPS).39 In the early 1960s DA receptor blockade was implicated in the mode of action of neuroleptics,40 and amphetamine antagonism was introduced as a pharmacological screen for the detection of potential antipsychotic drugs.41 By the mid-1960s, “incisive” neuroleptics dominated the treatment of schizophrenia. During the 1970s their dominance was perpetuated by the demonstration that they block do- 42,43 pamine-D2 receptors ; by the finding of an inverse relationship between DA receptor blocking potency and dose requirements44; and by the formulation