Table Of ContentT S S
HE EROTONIN YSTEM
T S S
HE EROTONIN YSTEM
History, Neuropharmacology, and
Pathology
Edited by
MARK D. TRICKLEBANK
Centre for Neuroimaging Sciences, Institute of Psychiatry
Psychology and Neuroscience, King’s College London,
London, United Kingdom
EILEEN DALY
Department of Forensic and Neurodevelopment Sciences,
Institute of Psychiatry, Psychology and Neuroscience,
King’s College, London, United Kingdom
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Dedication
I would like to dedicate this volume to Dr John Fozard and Professor
Gerald Curzon, both of whom had unexpected confidence in me at an
early stage without whose influence I would not have had the privilege of
having a scientific career. I am deeply grateful to both of them.
Mark D. Tricklebank
October 31, 2018
List of Contributors
JohanAlsiö
DepartmentofPsychology,UniversityofCambridge,Cambridge,UnitedKingdom;
MRCandWellcomeTrustBehaviouralandClinicalNeuroscienceInstitute,Universityof
Cambridge,Cambridge,UnitedKingdom
SebastianF.A.Axelsson
DepartmentofPsychology,UniversityofCambridge,Cambridge,UnitedKingdom;
MRCandWellcomeTrustBehaviouralandClinicalNeuroscienceInstitute,Universityof
Cambridge,Cambridge,UnitedKingdom
PhilipJ.Cowen
DepartmentofPsychiatry,UniversityofOxford,Oxford,UnitedKingdom
EileenDaly
DepartmentofForensicandNeurodevelopmentalSciences,InstituteofPsychiatry,
PsychologyandNeuroscience,King’sCollegeLondon,London,UnitedKingdom
DianaC.Esquivel-Franco
DepartmentofNeurobiology,BehaviouralNeuroscienceUnit,GroningenInstitutefor
EvolutionaryLifeSciences,UniversityofGroningen,TheNetherlands;Departmentof
CellBiologyandPhysiology,BiomedicalResearchInstitute,NationalAutonomous
UniversityofMexico,Mexico
CatherineJ.Harmer
DepartmentofPsychiatry,UniversityofOxford,Oxford,UnitedKingdom
DanielHoyer
DepartmentofPharmacologyandTherapeutics,SchoolofBiomedicalSciences,Facultyof
Medicine,DentistryandHealthSciences,TheUniversityofMelbourne,Parkville,VIC,
Australia;TheFloreyInstituteofNeuroscienceandMentalHealth,TheUniversityof
Melbourne,Parkville,VIC,Australia;DepartmentofMolecularMedicine,TheScripps
ResearchInstitute,LaJolla,CA,UnitedStates
MonicaR.Leslie
SectionofEatingDisorders/PsychologicalMedicine,InstituteofPsychiatry,Psychology
andNeuroscience,King’sCollegeLondon,London,UnitedKingdom
DanielMartins
DepartmentofNeuroimaging,InstituteofPsychiatry,PsychologyandNeuroscience,
King’sCollegeLondon,London,UnitedKingdom
MitulA.Mehta
DepartmentofNeuroimaging,InstituteofPsychiatry,Psychology&Neuroscience,King’s
CollegeLondon,London,UnitedKingdom
SimonR.O.Nilsson
NeuroscienceInstitute,NewYorkUniversityMedicalCenter,NewYork,NY,United
States;DepartmentofNeuroscienceandPhysiology,NewYorkUniversityMedical
Center,NewYork,NY,UnitedStates
xiii
xiv ListofContributors
BerendOlivier
DepartmentofNeurobiology,BehaviouralNeuroscienceUnit,GroningenInstitutefor
EvolutionaryLifeSciences,UniversityofGroningen,TheNetherlands;Departmentof
Psychopharmacology,UtrechtInstituteforPharmaceuticalSciences,UtrechtUniversity,
TheNetherlands;DepartmentofPsychiatry,YaleUniversitySchoolofMedicine,New
Haven,CT,UnitedStates
JocelienD.A.Olivier
DepartmentofNeurobiology,BehaviouralNeuroscienceUnit,GroningenInstitutefor
EvolutionaryLifeSciences,UniversityofGroningen,TheNetherlands
MarijaM.Petrinovic
DepartmentofForensicandNeurodevelopmentalSciences,InstituteofPsychiatry,
PsychologyandNeuroscience,King’sCollegeLondon,London,UnitedKingdom;The
SacklerInstituteforTranslationalNeurodevelopment,InstituteofPsychiatry,Psychology
andNeuroscience,King’sCollegeLondon,London,UnitedKingdom;MRCCentrefor
NeurodevelopmentalDisorders,King’sCollegeLondon,London,UnitedKingdom
BenjaminU.Phillips
DepartmentofPsychology,UniversityofCambridge,Cambridge,UnitedKingdom;
MRCandWellcomeTrustBehaviouralandClinicalNeuroscienceInstitute,Universityof
Cambridge,Cambridge,UnitedKingdom
IvanaRosenwieg
DepartmentofNeuroimaging,InstituteofPsychiatry,PsychologyandNeuroscience,
KingsCollegeLondon,London,UnitedKingdom
MarkD.Tricklebank
CentreforNeuroimagingSciences,InstituteofPsychiatryPsychologyandNeuroscience,
King’sCollegeLondon,London,UnitedKingdom
CarlosM.Villalón
DepartmentofPharmacobiology,Cinvestav-Coapa,MexicoCity,Mexico
MarcelD.Waldinger
DepartmentofPharmacologyandPhysiology,DrexelUniversityCollegeofMedicine,
Philadelphia,PA,UnitedStates
RobertWichers
DepartmentofForensicandNeurodevelopmentalSciences,InstituteofPsychiatry,
PsychologyandNeuroscience,King’sCollegeLondon,London,UnitedKingdom
TarekZghoul
DepartmentofPsychiatry,UniversityofOxford,Oxford,UnitedKingdom
Editors’ Biography
Dr Mark D. Tricklebank, BSc, MSc, PhD, DSc, FBphS, earned his PhD
from the University of Manchester, and after completing postdoctoral train-
ing at the Institute of Neurology, he joined the pharmaceutical company
Merrell Dow in Strasbourg, where he was instrumental in the identification
ofthefunctionalrelevanceofthenewlyidentified5-HT1Arecognitionsite.
He then moved to Merck at Terlings Park, where he worked with Susan
Iversen to identify the behavioral effects of the NMDA receptor antagonist
MK-801 and showed them to be identical to those of phencyclidine and
ketamine. Thereafter serving as head of the Mental Health Unit at Sandoz
Pharma in Basel, he was appointed director of In Vivo Pharmacology at the
Lilly Research Centre, Windlesham, where he conceived and founded the
LillyCentreforCognitiveNeuroscience,oneofthefirstindustrial-academic
partnerships in the United Kingdom. Aftera variedcareer of several decades
in the pharmaceutical industry, he now serves as a Wellcome Trust Fellow
in the Institute of Psychiatry, Psychology and Neuroscience at King’s
CollegeLondon,andhaspublishedmorethan160papers.
DrEileenDaly,PhD,isaSeniorLecturerintheDepartmentofForensic
and Neurodevelopmental Sciences at King’s College London. When at the
National Institute of Aging, National Institutes of Health, USA, she mea-
sured neurotransmitter metabolites in human CSF and rodent brain.
RelocatingtotheInstituteofPsychiatryinLondon,shecompletedherPhD
in Developmental Neuroscience with a project using Acute Tryptophan
Depletion to modulate serotonin in Autism Spectrum Disorder, and
then looking at the brain with fMRI. She continues to study the role of
neurotransmitters in developmental disorders and is the author of more than
100papers.
xv
Preface
Serotonin first became my mistress whilst studying for a masters in neuro-
chemistry at the Institute of Psychiatry when I visited the lab of Gerald
Curzon at the Institute of Neurology looking for a student project with
him. As a graduate in psychology and biochemistry I was somewhat disap-
pointed that the emphasis on understanding the biochemistry of mental
disorder that I had hoped for was missing from the course. There seemed
to be much more interest in the control of respiration cycles, that is, the
brain was treated as an extension of the liver. But Gerald introduced me
to the metabolism of serotonin. When he opened a store cupboard to
reveal trays of little brown bottles which on careful examination I found
to contain lysergic acid diethylamide, my heart leapt with excitement.
The project was exactly what I was looking for: this was 1971 after all. It
felt somewhat uncanny that serotonin had been discovered in the year of
my birth. And even more uncanny that I would one day work for the
Company Sandoz where Hoffman had first extracted LSD from rye mold
in a city where each year on April 19th they celebrate Hoffman’s 1943
finding with Bicycle day. My Mentor at Sandoz was the cardiovascular
pharmacologist John Fozard with whom I had worked a few years earlier
at Merrell-Dow in Strasbourgand in whose group I met my second mis-
tress, 8-OHDPAT and enjoyed a menage a trois with the 5-Ht1A recep-
tor and serotonin in a relationship remarkable for its longevity and
scientific relevance. I thank the Wellcome Trust and Professor Steven
Williams for supporting my return to the Institute of Psychiatry, where I
am focused on understanding the role of 5-HT1A receptors in the control
of the release of oxytocin in the hope that they might be repurposed for
the treatment of disorders associated with impaired social cognition such
as Autism Spectrum disorders.
Mark D. Tricklebank,
August 2018
xvii
CHAPTERONE
The metabolism of indoleamines
Mark D. Tricklebank and Daniel Martins
DepartmentofNeuroimaging,InstituteofPsychiatry,PsychologyandNeuroscience,King’sCollege
London,London,UnitedKingdom
Introduction
The history of the discovery of serotonin is described in a detailed
and quite excellent way by Patricia Whitaker Azmitia [1(cid:1)4] in an article
published in Neuropsychopharmacology in 1999. Recognizing that cardiovas-
cular disease was the overriding cause of premature death in the 1930s
and 1940s, biological and pharmaceutical research was heavily concen-
trated on the discovery of the causes of hypertension and heart disease.
The serotonin story begins with the Italian Vittorio Erspamer who
focused his life’s work on the isolation of drugs from natural sources. He
particularly concentrated on nitrogenous substances causing the contrac-
tion of smooth muscle that can be found in the skin and intestines of a
variety of small animals. In the process, he found one substance in the
enterochromaffin cells of mammalian gut which he called enteramine [5].
Its potential functional importance was amplified to him when he discov-
ered the same compound in the salivary glands of the octopus. In 1952,
enteramine was established as the same muscle contractant that Twarog and
Page [6] had identified in clotted blood and that they called serotonin
(tonic substance in serum, hence serotonin). Serotonin was later identified
chemically as 5-hydroxytryptamine by Rapport, Green, and Page [6].
Serotonin was then found by Betty Twarog to be present in both rodent
and human brains. However, the detailed architecture of its cell bodies
and projection fields had to wait for Falk and Hillarp to develop their fluo-
rescence histochemical technique in order to probe and demonstrate its
extensive distribution in brain tissue [7]. It was immediately seen to be
concentrated very selectively within the large multipolar neurons of the
midline raphe cells first noticed by Ramon and Cajal [8]. Once its chemi-
cal structure was determined as 5-hydroxytryptamine (Fig. 1.1), a major
TheSerotoninSystem. ©2019ElsevierInc.
DOI:https://doi.org/10.1016/B978-0-12-813323-1.00001-3 Allrightsreserved. 1
