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CONTRIBUTORS
D.T.Balu
HarvardMedicalSchool,Boston;McLeanHospital,Belmont,MA,UnitedStates
R.Bergeron
UniversityofOttawa;OttawaHospitalResearchInstitute,Ottawa,ON,Canada
R.D.Blakely
VanderbiltUniversitySchoolofMedicine,Nashville,TN,UnitedStates
I.Burd
IntegratedResearchCenterforFetalMedicine,JohnsHopkinsUniversitySchoolof
Medicine,Baltimore,MD,UnitedStates
M.G.Castro
TheMedicalSchool,TheUniversityofMichigan,AnnArbor,MI,UnitedStates
J.T.Coyle
McLeanHospitalandHarvardMedicalSchool,Belmont,MA,UnitedStates
E.A.Ennis
VanderbiltUniversitySchoolofMedicine,Nashville,TN,UnitedStates
M.H.Farah
JohnsHopkinsSchoolofMedicine,Baltimore,MD,UnitedStates
D.Goff
NYUSchoolofMedicine,NewYork,UnitedStates
A.M.Guillem
Children’sHospitalofPhiladelphiaResearchInstitute,UniversityofPennsylvania,
Philadelphia,PA,UnitedStates
K.R.Hollinger
JohnsHopkinsSchoolofMedicine,Baltimore,MD,UnitedStates
P.F.Jackson
JanssenPharmaceuticals,SanDiego,CA,UnitedStates
M.V.Johnston
KennedyKriegerInstituteforDisabilities,Baltimore,MD,UnitedStates
G.Kannan
IntegratedResearchCenterforFetalMedicine,JohnsHopkinsUniversitySchoolof
Medicine,Baltimore,MD,UnitedStates
P.Khacho
UniversityofOttawa,Ottawa,ON,Canada
xi
xii Contributors
E.D.London
BrainResearchInstitute,DavidGeffenSchoolofMedicineattheUniversityofCalifornia
LosAngeles,LosAngeles,CA,UnitedStates
P.R.Lowenstein
TheMedicalSchool,TheUniversityofMichigan,AnnArbor,MI,UnitedStates
P.Majer
InstituteofOrganicChemistryandBiochemistry,AcademyofSciencesoftheCzech
Republic,Prague,CzechRepublic
Z.Martinez-Lozada
Children’sHospitalofPhiladelphiaResearchInstitute,UniversityofPennsylvania,
Philadelphia,PA,UnitedStates
R.Rais
JohnsHopkinsSchoolofMedicine,Baltimore,MD,UnitedStates
M.B.Robinson
Children’sHospitalofPhiladelphiaResearchInstitute,UniversityofPennsylvania,
Philadelphia,PA,UnitedStates
R.Schwarcz
MarylandPsychiatricResearchCenter,UniversityofMarylandSchoolofMedicine,
Baltimore,MD,UnitedStates
B.S.Slusher
JohnsHopkinsSchoolofMedicine,Baltimore,MD,UnitedStates
G.E.Tsai
Harbor-UCLAMedicalCenter,LosAngelesBiomedicalResearchInstitute,Torrance,CA,
UnitedStates
J.J.Vornov
JohnsHopkinsSchoolofMedicine,Baltimore,MD;Medpace,Cincinnati,OH,
UnitedStates
B.Wang
UniversityofOttawa,Ottawa,ON,Canada
J.Welling
IntegratedResearchCenterforFetalMedicine,JohnsHopkinsUniversitySchoolof
Medicine,Baltimore,MD,UnitedStates
K.M.Wozniak
JohnsHopkinsSchoolofMedicine,Baltimore,MD,UnitedStates
FOREWORD
On July 1, 1966 I joined the Pharmacology Department’s faculty at Johns
Hopkins, while serving as a second-year resident in psychiatry. Though
I had only two days a week to devote to the Pharmacology Department,
I cobbled together a tiny laboratory with a single technician. My teaching
responsibilitiescompriseddeliveringacoupleoflecturesonpsychopharma-
cology.Attheircloseashort,exuberantmedicalstudent,wholookedtobe
16yearsold,approachedmewithabarrageofquestionsabouthowdrugsact
in thebrain.Afteraseriesof discussions,thisfellow,JoeCoyle, askedifhe
might spend a summer in my lab. I confessed that the lab was decidedly
nascent, but he persisted.
Thus began my most enduring and rewarding professional interaction.
There was no MD/PhD program in those days. Medical students like
Joe, who were interested in research, somehow assembled a collage of
summersandelectiveperiodstoobtainmeaningfulresearchtraining.Thus,
whilepursuingafull-timemedicalschoolcareerandgraduatinginthestan-
dard four years, Joe managed to carry out a remarkable opus of research.
Julie Axelrod had established reuptake of norepinephrine as a major
mechanism of its activation. In an exhaustive opus Leslie Iversen in
Cambridge, England had elucidated the transport kinetics of the process
intheisolatedperfusedratheart,consumingthousandsofratsintheprocess.
Itseemedtomethatthereoughttobeasimplerapproach,especiallyutiliz-
ingbraintissue.AlanGreen,amedicalschoolclassmateofJoe,hadexplored
norepinephrinetransportinsmallslicesofbraintissue,buttheirprocesswas
cumbersomeandvariable,asthesurfaceareaofthebraintissuechunksvar-
ied considerably. Joe approached the problem utilizing pinched-off nerve
endings,called“synaptosomes,”whichcouldbeobtainedbyhomogenizing
thebraingentlywithaTeflonpestleandpartiallypurifyingthenerveendings
onasucrosegradient,acumbersomeprocess.Moreover,thesalt-containing
solution necessary for the neurotransmitter transport process ruptured the
synaptosomes. Joe devised a simple, ingenious procedure, maintaining a
protective sucrose layer over the labile nerve endings.
Joe’s elegant approach enabled him to characterize norepinephrine and
dopamine uptake into nerve terminals in different regions of the brain
and work out kinetics of the process (Snyder & Coyle, 1969). He eluci-
dated the stereospecificity of the transport which was pronounced for
xiii
xiv Foreword
norepinephrine-containing areas of the brain but was more modest in the
corpus striatum, which utilized dopamine, a molecule that lacks stereoiso-
mers(Coyle&Snyder,1969a).Thissimple,sensitive,andspecificapproach
tomonitoringcatecholaminetransportfacilitatedassayingdozensofsamples
insimpleexperimentsthatconsumedonlyacoupleofhours.Intheprocess
he discovered that some antiparkinsonian drugs, thought to act solely as
anticholinergic agents, were also relatively potent inhibitors of dopamine
uptake and so may have a twofold mode of action in Parkinson’s disease.
This observation led to an influential publication in Science (Coyle &
Snyder, 1969b). Working only in summers and elective periods for about
two years of medical school, Joe produced three influential publications,
two of which were first-authored by him.
IrelatetheaboveepisodesinsomedetailtoconveyJoe’sabilitytoaddress
themostfundamentalquestionswithclarityandsimplicity.Aftergraduating
medicalschoolJoespenttwoyearsattheNIH—hismilitaryservice—with
Julie Axelrod, continuing his notable productivity. Because of his evident
talent and promise, Paul Talalay, Chair of the Hopkins Department of
Pharmacology, and Joel Elkes, Chair of Psychiatry, recruited Joe back to
Hopkins in a position wherein he could pursue psychiatry residency while
serving as a full-time Assistant Professor of Pharmacology. Joe fulfilled his
ample promise and, within a brief period of time, had been promoted to
AssociateProfessorandthenfullProfessorofPharmacologyandPsychiatry.
Though not trained as a pediatrician, Joe assumed the directorship of
PediatricPsychiatryatHopkinsandperformedinsuchanexemplaryfashion
thathewassoonrecruitedtoHarvardwherehehasremainedforthebalance
of his career.
Astheabovesummaryindicates,Joewasasuperstarprodigyfromtheday
hesetfootinthelaboratory.Muchoftheworkhedidinmylabasamedical
student took place while I was in London on sabbatical so that he largely
mentored himself. We corresponded regularly by hard-copy letters—no
email—that were often hand written and appended to data sheets. Joe’s
fecunditywassonotablethatItook painstogivehimfreerein, mentoring
only with the lightest of touches.
Making original discoveries is exhilarating. Equally important for me
is nurturing young talents. Joe was one of the very first of my mentees.
Witnessing his abundant creativity and emergence as a premier figure in
molecular psychiatry has been among the most rewarding experiences of
myprofessionallife.Besideshisowndiscoveries,Joehasspawnednumerous
researchers,someproceedingtopositionsofeminence.Joeistrulyagiantof
Foreword xv
psychopharmacology, psychiatry, and the neurosciences. The chapters in
thisvolumeattesttohisprofoundandlastingimpact.Itisajoytooffertrib-
ute to this most important figure in American medical science.
S.H. SNYDER
REFERENCES
Coyle,J.T.,&Snyder,S.H.(1969a).Catecholamineuptakebysynaptosomesinhomog-
enates of rat brain: Stereospecificity in different areas. The Journal of Pharmacology and
ExperimentalTherapeutics,170(2),221–231.
Coyle, J. T., & Snyder, S. H. (1969b). Antiparkinsonian drugs: Inhibition of dopamine
uptake in the corpus striatum as a possible mechanism of action. Science, 166(3907),
899–901.
Snyder, S. H., & Coyle, J. T. (1969). Regional differences in H3-norepinephrine
and H3-dopamine uptake into rat brain homogenates. The Journal of Pharmacology and
ExperimentalTherapeutics,165(1),78–86.
PREFACE
Curiosity, insight, and enthusiasm are hallmarks of the successful scientist
and educator. It is no surprise therefore that they are also prominent char-
acteristics of Joseph T. Coyle, MD, to whom this volume of Advances in
Pharmacology is dedicated. Over the past five decades, Dr. Coyle has made
significant and lasting contributions to the field of psychopharmacology
whiledefiningfundamentalpropertiesofneurotransmissionandtheneuro-
biologicalabnormalitiesassociatedwithahostofneurologicalandpsychiatric
disorders.Hisdiscoverieshaveforyearsinfluencedthedirectionofresearch
in both basic and clinical neurosciences. Dr. Coyle was a pioneer in trans-
lationalneurobiology,testingdirectlythepharmacotherapeuticrelevanceof
hislaboratorydiscoveries.Ithasbeenapleasureandprivilegetopreparethis
offeringinhishonorgiventhebreadthofhisresearchinterests,hissuccessas
mentor, and the impact of his work on the discipline of pharmacology.
A native of Chicago, Dr. Coyle received his Bachelor’s degree from
HolyCrossandhisMDdegreefromJohnsHopkinsMedicalSchool,where
healsocompletedanInternshipinPediatricsandaResidencyinPsychiatry.
Soon after graduating from Johns Hopkins he spent three years working at
theNationalInstituteofMentalHealthwithJuliusAxelrod,PhD,aNobel
laureate. While still in medical school, Dr. Coyle’s interest in biomedical
research drew him to the laboratory of Solomon Snyder, MD, one of the
world’s leading neuroscientists and psychopharmacologists. Together,
Drs. Coyle and Snyder, and subsequently Drs. Coyle and Axelrod,
performed some of the seminal studies on the transport and synthesis of
catecholaminesinbrainandondefiningtheroleoftheseneurotransmitters,
inparticulardopamine,inthemechanismofactionofpsychotropicagents.
In the Foreword to this volume Dr. Snyder details Dr. Coyle’s intellectual
and technical contributions to this work and the enthusiasm of this young
medical student for laboratory experimentation.
WhileaResidentinPsychiatry,Dr.Coylewasappointedtothefacultyat
Johns Hopkins Medical School where within a decade he was named the
Distinguished Service Professor of Child Psychiatry. During his tenure at
Johns Hopkins, Dr. Coyle was among the first to identify and characterize
glutamic acid-induced neurotoxicity and in the early 1980s demonstrated
that the peptide N-acetylaspartylglutamate (NAAG) is a neurotransmitter
in brain. In 1991, Dr. Coyle was appointed Chair of the Consolidated
xvii
xviii Preface
DepartmentofPsychiatryatHarvardMedicalSchool,whereheisatpresent
theEbenS.DraperProfessorofPsychiatryandNeuroscienceandDirector
oftheLaboratoryforPsychiatricandMolecularNeuroscience.Currentlyhis
research is focused primarily on determining the involvement of gluta-
matergic transmission in symptoms associated with psychiatric disorders,
in particular schizophrenia. Among his many honors and awards are
membership in the National Academy of Medicine (formerly Institute of
Medicine),andappointmentsasaFellowoftheAmericanAcademyofArts
and Science and as a Distinguished Fellow of the American Psychiatric
Association. Dr. Coyle is a past-president of the American College of
Neuropsychopharmacology and of the Society for Neuroscience, and a
past-editor of JAMA Psychiatry. He has authored hundreds of research and
review articles and authored or edited several books on neurobiology and
on the diagnosis and treatment of neuropsychiatric disorders.
Contained in this volume are review articles written by some of
Dr. Coyle’s former students and fellows. Besides providing background
information on the topic being covered, all include a discussion of recent
findings of contemporary importance and interest. Not only are these
reports of value in providing a sense of the breadth of research initiated
byDr.Coyle,theyalsoserveasaguidetocurrentandfuturestudiesinthese
areas. For example, included is a chapter by Dr. Edythe London on the
potential role of dopaminergic transmission in impulsivity and how this
may relate to the design of new therapies for amphetamine use disorder.
The origins of this work can be traced directly to Dr. Coyle’s studies on
dopamine transport in the 1960s and 1970s. Drs. Michael Robinson and
Michael Johnston have each written chapters on the glutamate system
and neurotoxicity, continuing the line of investigation initiated by
Dr. Coyle in the 1970s. Dr. Robinson describes the identification and
molecularcharacterizationofthefiveglutamatetransportersthatareknown
tobeinvolvedinregulatingthesynapticlevelsofthisneurotransmitter.He
highlightsdataindicatinghowalterationsinthesetransportersmaycontrib-
utetothedevelopmentofneurologicaldisorders.Dr.Johnstonreviewsthe
literatureontheroleofglutamatereceptorsinperinatalbraininjuryassoci-
ated with hypoxia-ischemia and intrauterine inflammation. He discusses
howthesestudiescouldleadtothedevelopmentofnoveltherapiestomin-
imize or prevent the brain damage associated with these developmental
insults.TheN-methyl-D-aspartate(NMDA)receptorasatargetforantipsy-
chotics is the subject of two articles, by Drs. Guochuan Tsai and Darrick
Preface xix
Balu.BothauthorssupporttheconceptthatNMDAreceptor,ie,glutamate
hypofunction,isresponsibleforsomesymptomsofschizophrenia,andhigh-
light the promise of targeting the glycine/D-serine co-agonist site of the
receptor, channel ionophores, the glycine transporter-1, and D-amino acid
oxidase. One of these treatments is D-cycloserine, an approach pioneered
someyearsagobyDr.CoyleandDr.DonaldGoff.Inhischapter,Dr.Goff
reports on recent studies indicating that intermittent administration of this
amino acid analog in conjunction with cognitive remediation diminishes
the negative symptoms of schizophrenia.
Also contained in this volume are articles on NAAG by Drs. Barbara
Slusher and Richard Bergeron. Dr. Slusher describes the development
and testing of inhibitors of glutamate carboxypeptidase II, a glial enzyme
responsibleforthemetabolismofNAAG.Shereviewstheliteraturedescrib-
inghowsuchagentsreduceglutamatergictransmissioninbrainbyincreasing
the levels of NAAG, and presents evidence that these effects may yield
therapeutic benefit in the treatment of a number of central nervous system
disorders. Dr. Bergeron describes recent work indicating that the effect
of NAAG on NMDA receptor activity is a function of the localization,
biochemical milieu, and molecular composition of the NMDA site.
Dr.RandyBlakelycommentsonthelatestliteratureconcerningthereg-
ulationofhigh-affinitycholineuptake,therate-limitingstepinthesynthesis
ofacetylcholine.Theoriginsofthisworkcanbetracedtoaseriesofstudies
performed by Dr. Coyle and his colleagues in the 1980s. At that time,
Dr. Coyle labeled the choline transporter with 3H-hemicholinium-3 and
demonstrated that this site was modulated under various physiological
and pathophysiological conditions. In his article, Dr. Blakely describes
recent workon novelapproaches for thechemical modulation of the cho-
linetransporteranddiscusseshowthiscouldyieldnewtherapeuticstrategies
for treating central nervous system disorders associated with dysfunctional
cholinergic transmission. Dr. Pedro Lowenstein, too, began his career in
Dr. Coyle’s laboratory working on the characterization and regulation of
high-affinity choline uptake in the mammalian brain but then veered out
topursueresearchintheareaofgenetherapyofbraintumors.Inhischapter,
Dr.LowensteingenerouslycreditsDr.Coyleforsettinghimonapaththat
has recently led to clinical trials using unprecedented immunotherapeutic
approaches for the treatment of gliomas.
Thetopicscoveredinthesechapters,aswellasthestatureoftheauthors,
illustrate Dr. Coyle’s influence on research in the neurosciences in general
xx Preface
and psychopharmacology in particular. Given the ongoing work in these
areas, there is no question that his ideas and discoveries will be exploited
byothersfordecadestocome.WhilethisvolumeofAdvancesinPharmacology
wasassembledtorecognizehiscontributionstothefield,nosinglebookor
article pays greater homage to him than the lasting importance of his work
andtherespecthehasearnedfromhisstudentsandpeers,bothasascientist
and as a generous and supportive friend. His curiosity, insight, and enthu-
siasm have not only influenced an entire generation of neuroscientists but
havealsobeenaboonforthethousandsofpatientsbenefitingfromhiswork.
ROBERT SCHWARCZ
Maryland Psychiatric Research Center,
Department of Psychiatry,
University of Maryland School of Medicine,
Baltimore, Maryland, USA
S.J. ENNA
Department of Molecular and Integrative Physiology,
Department of Pharmacology, Toxicology and Therapeutics,
University of Kansas Medical Center, Kansas City,
Kansas, USA
