An Oral History of Neuropsychopharmacology

AN ORAL HISTORY OF NEUROPSYCHOPHARMACOLOGY

THE FIRST FIFTY YEARS

Peer Interviews

Volume Three: Neuropharmacology

Thomas A. Ban (series editor)

AN ORAL HISTORY OF NEUROPSYCHOPHARMACOLOGY

Fridolin Sulser (volume editor)

VOLUME 4: PSYCHOPHARMACOLOGY

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-

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:

Website: www.acnp.org

Cover design by Jessie Blackwell; JBlackwell Design www.jblackwelldesign.com

AMERICAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY

AN ORAL HISTORY OF NEUROPSYCHOPHARMACOLOGY

PEER INTERVIEWS

The First Fifty Years

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

American College of Neuropsychopharmacology

Amazon

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.[i] 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 behavioral 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 neurophramacological research may provide information on the biochemical underpinning of mental pathology, neuropharmacology has been the moving force of psychotropic 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; chlorpromazine, reserpine, meprobamate, iproniazid and imipramine in the treatment of mental pathology.[ii] The commercial success of these drugs, and especially 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).[iii] 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.

Neurotransmitters

The initial targets of neuropharmacological research were neurotransmitters. By the end of the 1950s there were six neurotransmitters identified: 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.[iv] The effect of the substance on adjacent cells to the nerve endings was first noted by Otto Loewi in 1921.[v] In 1937 ACh was isolated from brain homogenates by Juda Quastel and his associates,[vi] and Stedman and Stedman.[vii] The effect of ACh on neuronal transmission in the spinal cord was demonstrated by Eccles and his associates in 1954.[viii]

Sympathin was first detected at sympathetic nerve endings in 1904 by R.T. Elliott. [ix], [x] The substance was identified as noradrenaline (NA)/norepinephrine (NE)[xi] and separated from adrenaline/epinephrine by Ulf Von Euler in 1946.[xii] 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.[xiii]

In 1884 Stevens and Lee described a vasoconstrictor substance in the blood.[xiv] The substance was crystallized from ox serum by Rapport, Green and Page, and identified as 5-hydroxytryptamine (5HT), referred to as serotonin, in 1948.[xv] In 1937 Vittorio Erspamer extracted a substance from the enterochromaffin cells of the intestinal mucosa of rabbits, he referred to as enteramine.[xvi] In 1952 he recognized that enteramine was a structurally identical indoleamine with serotonin.[xvii] In 1953 Twarog and Page demonstrated the presence,[xviii] and in 1954 Amin, Crawford and Gaddum described the distribution of 5HT in the brain.[xix]

Dopamine (DA) an intermediary in the synthesis of NE from tyrosine was detected in the brain in 1957 by Kathleen Montagu.[xx] The same substance was identified in 1958 by Arvid Carlsson and his associates.[xxi] In 1959 Carlsson described the distribution of dopamine in the central nervous sssytem. He also demonstrated that DA was not just an inactive intermediary, a precursor of NE, but an active neurotransmitter in the brain.[xxii] The distribution of dopamine was further elaborated by Bertler and Rosengren,[xxiii] and Sano and his associates[xxiv] 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 associates,[xxv] and Roberts and Frankel[xxvi] detected the presence of GABA in the brain. Seven years later, in 1957, Purpura and his associates,[xxvii] and Curtis and his associates[xxviii] demonstrated its marked depressant action on nerve terminals and identified GABA as an inhibitory neurotransmitter.

Substance P (SP) was detected in the intestine and in the brain in 1931 by Von Euler and Gaddum.[xxix] In 1952 Zetler had shown the presence of the substance in high concentration in the human cerebral cortex,[xxx] and in 1959 he demonstrated that SP is a centrally acting transmitter of inhibitory neurons.[xxxi]

The Aminco Bowman spectrophotofluorimeter (SPEC) was introduced in 1955[xxxii] 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 deamination of monoamines,[xxxiii] was first detected in the liver by Blaschko and his associates in 1937.[xxxiv] The same year MAO was also detected in the brain by Pugh and Quastel.[xxxv] In 1938, MAO oxidase was separated from diamine oxidase by Zeller.[xxxvi]

Psychotropic Drugs

Psychotropic drug development has been closely linked to neuropharmacological 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 (antipsychotics) 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.[xxxvii] In the late 1950s, neuroleptics were divided into “sedative” or CPZ-type, and “incisive” or prochlorperazine-type drugs.[xxxviii] There was no difference in therapeutic efficacy between the two groups, but “incisive” neuroleptics were more potent on a mg per kg basis and produced more frequent and severe extrapyramidal symptoms/signs (EPS).[xxxix] In the early 1960s DA receptor blockade was implicated in the mode of action of neuroleptics,[xl] and amphetamine antagonism was introduced as a pharmacological screen for the detection of potential antipsychotic drugs.[xli] By the mid-1960s, “incisive” neuroleptics dominated the treatment of schizophrenia. During the 1970s their dominance was perpetuated by the demonstration that they block dopamine-D2 receptors[xlii],[xliii]; by the finding of an inverse relationship between DA receptor blocking potency and dose requirements[xliv]; and by the formulation of the DA-hypothesis of schizophrenia.[xlv] In the late 1970s, the steadily growing number of patients with tardive dyskinesia turned interest to thioridazine, a piperidyl side chain containing sedative neuroleptic. Treatment with thioridazine induced considerably less frequent and severe EPS than treatment with incisive neuroleptics, but thioridazine produced cardiac conductance changes.[xlvi],[xlvii] (See, Gottschalk, Volumes 1 & 9; Ban, Volumes 4 & 9; Gallant, Volume 4.) In the early 1970s, clozapine, a substance with an even lesser propensity to induce EPS than thioridazine, was introduced in Europe.[xlviii] (See, Hippius, Volume 1; Ackenheil, Volume 8.) In the mid-1970s, clozapine was withdrawn from clinical use (in most countries) because of eighteen cases of agranulocytosis, including eight fatal cases, encountered in Finland.[xlix] In the mid-1980s, clozapine was re-introduced, and became the prototype of a series of so-called “atypical neuroleptics.” (See, Kane, Volume 4.) Atypical neuroleptics differ from “typical neuroleptics,” like haloperidol, by their lesser propensity to induce EPS and higher affinity to serotonin 5HT2A receptors than to dopamine-D2 receptors. (See, Meltzer, Volumes 5 &9.) They also have a broader receptor profile than “typical neuroleptics.” Thus, “atypical neuroleptics” are similar to CPZ-type of “sedative neuroleptics,” drugs with a broad receptor profile and higher affinity to serotonin-5HT2 receptors than to dopamine-D2 receptors.[l]

Developments in the neuropharmacology of iproniazid-like antidepressants began in the mid-1950s with the findings that iproniazid, a MAO inhibitor (MAOI), increased 5HT and NE in the brain and produced euphoria in some patients treated for tuberculosis.[li] In the late 1950s several MAOIs were introduced in the treatment of depression. By the early 1960s hepatotoxicity[lii] and hypertensive crises[liii] were encountered with some of these drugs. Deprenyl (selegiline) the first selective inhibitor of the Type B iso-enzyme of MAO was developed in the mid-1960s,[liv] and moclobemide, a selective inhibitor of the Type A iso-enzyme, in the mid-1970s.[lv], [lvi]

Developments in the neuropharmacology of imipramine-like antidepressants began in the late 1950’s with the demonstration that imipramine, a tricyclic substance, has antihistaminic, anticholinergic, noradrenergic, and serotonergic properties.[lvii] It reversed reserpine-induced sedation, hypothermia, ptosis and diarrhea.[lviii], [lix] In the early 1960s reserpine reversal was introduced as a pharmacological screen for the identification of imipramine-like antidepressants. About the same time, both imipramine and amitriptylime, the two available tricyclic antiepressnats, were found to block NE reuptake into neurons.[lx] Since reserpine-reversal with desipramine (DMI), the demethylated metabolite of imipramine, a selective NE re-uptake blocker, was more potent than with imipramine, and imipramine’s reserpine reversal was suspended by the administration of α-methyl-metatyrosine, a substance that blocked the formation of NE, the possibility was raised that NE and not 5HT is the neurrotrabsmitter involved in the antidepressant effect of these drugs.[lxi] In the mid-1960’s, the catecholamine hypothesis of affective disorders was formulated,[lxii] and several NE re-uptake inhibitor antidepressants (NARIs), including DMI[lxiii] and maprotiline,[lxiv] were introduced. (See, Bunney, Volume 5; John Davis, Volume 5; Schildkraut, Volume 5.) Then, in the 1970’s it was recognized that NE re-uptake inhibitors convert into 5HT reuptake inhibitors by halogenation.58,[lxv] It was also shown that an intact 5HT system was a prerequisite for ß-adrenergic receptor down regulation, a common characteristic of DMI-type of antidepressants.[lxvi] Simultaneously with this development the pharmacological concept of depression was extended by the introduction of the “behavioral despair - learned helplessness, swimming survival - test” in the screening for antidepressants. (See, Ackenheil, Volume 8.) The new test was based on a “stress model”, instead of the reserpine-model of depression. In 1980, a correspondence was shown between imipramine binding sites and 5HT binding sites in the human platelet[lxvii] and in the hypothalamus of the rat.[lxviii] Introduction of a series of selective 5HT re-uptake inhibitors (SSRIs) followed, and by the 1990s SSRIs became the main stream in the treatment of depression.[lxix][(] By the end of the 20th century with the introduction of venlafaxine, a non-selective, but prevailingly 5HT re-uptake inhibitor, a full complement of monoamine re-uptake inhibitors was completed.[lxx] With the introduction of reboxetine,[lxxi] a selective NE reuptake inhibitor, the circle opened in the early 1960s with the introduction of DMI was reopened.

The development of anxiolytic sedatives began in 1950 with the synthesis of meprobamate,[lxxii] a propanediol preparation that depressed multineuronal reflexes by accelerating acetylcholine breakdown at the synaptic cleft.[lxxiii] The substance was introduced in 1955, and became the first “blockbuster drug.”[lxxiv] In the 1960’s chlordiazepoxide, diazepam and several other benzodiazepine preparations were introduced and within a few years virtually replaced meprobamate in the treatment of anxiety.[lxxv] In the late 1970’s benzodiazepine receptors were identified[lxxvi] and it was shown that benzodiazepines acted on the GABA neurotransmitter system.[lxxvii] During the 1990s, SSRIs replaced benzodiazepines as the primary treatment of anxiety disorders.

The development of mood stabilizers began in the late 1940’s with the re-introduction of lithium into psychiatry by John Cade,[lxxviii] and the demonstration in the mid-1960s that lithium has mood stabilizing effects.[lxxix] In the mid 1970s, based on clinical observations, it was suggested that the anticonvulsants, carbamazepine[lxxx] and sodium valproate,[lxxxi] could also stabilize mood. In the late 1970s it was discovered that carbamazepine controlled amygdala kindled seizures (see, Post, Volume 5), and in 1980 it was demonstrated that in the action of sodium valproate the GABA system was involved.[lxxxii] In the 1990s several more drugs were introduced as mood stabilizers, including the anticonvulsant lamotrigine,[lxxxiii] as well as some atypical neuroleptics,[lxxxiv] like quetiapine[lxxxv] and risperidone.[lxxxvi]

The development of cognitive enhancers began in the mid 1950’s with the discovery that tetrahydroaminoacridane (THA), a cholinesterase inhibitor, controlled aberrant-behavior induced by atropine, an anticholinergic drug. (See, Gershon, Volume 1.) Interest in THA was revived in the 1970’s with William Summers report on the effect of THA in Alzheimer’s disease (AD),[lxxxvii] and with the demonstration that physostigmine, a short acting cholinesterase inhibitor, enhanced cognition in Stanford students. (See, Kenneth Davis, Volume 8.) In the 1990s several cholinesterase inhibitors, including galantamine,[lxxxviii] rivastigmine,[lxxxix] and donepezil were introduced in the treatment of AD.[xc]