Table Of ContentBrain Messengers
and the Pituitary
Eugenio E. Muller
Department o f Pharmacolog y
University o f Mila n
Milan, Ital y
Giuseppe Nistico
Department o f Pharmacolog y
University o f Catanzar o
Catanzaro, Ital y
Academic Press , Inc .
Ηarcourt Brace Jovanovich, Publishers
San Dieg o Ne w Yor k Berkele y Bosto n
London Sydne y Toky o Toront o
COPYRIGHT © 1989, 1977 BY ACADEMIC PRESS, INC.
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Library of Congress Cataloging-in-Publication Data
Muller, Ε . E.
Brain messengersa n dt hep ituitary / Eugenio E .M uller,G iusepp e
Nistico.
p. cm .
Bibliography: p.
ISBN0 -12-510310- 7( alk .p aper)
1.A denohypophysis—Metabolism—Regulation. 2 .A denohypophysis—
Innervation. 3 .A denohypophysis—Pathophysiology.
.4.N eurotransmitters—Physiologica le ffect . 5 .N europeptides—
Physiologicale ffect . 6 .N euroendocrinology. I . Nistico,
Giuseppe. II . Title.
[DNLM:1 .B rain—physiology. 2 .N euroregulators—physiology .
3.P ituitar y Hormones ,A nterior—physiology.Q V1 26M 958b]
QP188.P58M851 98 8
DNLM/DLC
forL ibrar yo fC ongress8 7-3075 0
CIP
PRINTED IN THE UNITED STATES OF AMERICA
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To our wives
Preface
More tha n a decad e ha s elapse d sinc e w e publishe d ou r comprehensiv e mono
graph Neurotransmitters and Anterior Pituitary Function (Academi c Press ,
1977). Sinc e then , researc h o n thes e fascinatin g aspect s o f neuroendocrinolog y
has continue d a t a n almos t breathtakin g pace . I t i s no w clea r that , i n additio n t o
the classica l brai n neurotransmitters , a n increasin g numbe r o f neuropeptide s
affecting interneurona l communicatio n ar e presen t i n variou s centra l nervou s
system (CNS ) regions . Th e complexit y o f th e syste m stem s fro m th e abundanc e
of differen t neurotransmitte r an d neuropeptid e neuron s presen t i n th e mediobasa l
hypothalamus an d elsewher e an d th e variou s way s the y ma y interac t re
ciprocally. Anothe r reaso n fo r complexit y stem s fro m coexistence , e.g. , occur
rence an d the n releas e o f tw o transmitte r molecule s fro m th e sam e nerv e ending .
Although thes e event s undoubtedl y provid e greate r versatilit y an d sophisticatio n
to th e vocabular y o f synapti c transmission , the y confoun d prope r understandin g
of th e physiolog y an d pathophysiolog y o f neuroendocrin e control .
This boo k considers , initiall y an d comprehensively , th e mai n biochemica l
and electrophysiologica l mechanism s underlyin g synapti c communication , es
pecially i n vie w o f th e mos t recen t knowledg e o n cotransmissio n an d recepto r
plasticity, describe s th e topographica l localizatio n an d functio n o f classica l neu
rotransmitter an d neuropeptid e neurons , an d focuse s o n a serie s o f recentl y
developed drug s tha t affec t selectiv e aspect s o f neurotransmitte r an d henc e neu
roendocrine function . Th e experimenta l evidenc e tha t th e brai n control s pituitar y
function vi a specifi c hypophysiotropi c regulator y hormone s i s the n reviewe d i n
relation t o th e secretio n o f ACT H an d pro-opiomelanocortin-derive d peptides ,
GH, gonadotropins , Prl , an d TSH . Studie s o n th e chemica l isolation , identifica
tion an d synthesis , pituitar y effects , extraendocrin e actions , an d therapeuti c use s
of classica l hypophysiotropi c hormone s ar e reported , wit h specia l emphasi s
placed o n th e tw o newcomers , CR F an d GHRH . A separat e evaluatio n i s the n
presented o f th e neuroendocrine effect s o f a n increasin g numbe r o f neuropeptide s
whose physiologica l rol e i n th e contro l o f pituitar y functio n await s clarification ,
although som e o f the m no w appea r t o b e stron g candidate s a s regulator y hor
mones. Spac e i s als o allotte d t o th e pituitar y glan d viewe d a s th e targe t o f CNS -
derived an d periphera l hormona l influences , e.g. , purporte d mechanism s o f ac
tion o f regulator y an d othe r neurohormones , occurrenc e an d characteristic s o f
pituitary receptors , functiona l neurohormonal-neurotransmitte r an d periphera l
hormone interactions . Th e experimenta l evidenc e linkin g brai n neurotransmitter s
to th e secretio n o f hypothalami c hormone s an d henc e t o anterio r pituitar y hor -
xi
xii Prefac e
mones o r t o neuroendocrin e feedbac k regulatio n i s the n widel y reviewed . Final
ly, a separat e sectio n describe s new , excitin g evidenc e fo r neurotransmitter -
neuropeptide dysfunctio n a s a n etiolog y fo r specifi c neuroendocrin e disorder s
and th e potentia l o f th e neuropharmacologi c approac h t o th e diagnosi s an d
therapy.
We hav e relie d o n Neurotransmitters and Anterior Pituitary Function a s a
basis fo r thi s book . Ou r objectiv e ha s bee n t o provid e no t onl y a compilatio n o f
data bu t also , wheneve r possible , informatio n t o giv e reader s a n appreciatio n o f
the significanc e o f th e advance s i n th e field. Sometimes , however , th e flo w o f
new finding s ha s bee n s o massiv e a s t o hinde r thi s task , an d fo r thi s w e no w
apologize. W e hop e nevertheles s tha t thi s comprehensiv e work , whic h include s
more tha n 400 0 reference s an d ove r 7 0 tables , wil l b e a s wa s it s predecessor , a n
invaluable sourc e o f informatio n t o student s an d researcher s i n neuroen
docrinology an d neurobiology , neuropharmacology , neurophysiology , an d psy
chiatry. Clinica l neuroendocrinologist s wil l als o find i n this volum e th e rational e
for th e saf e an d prope r us e o f powerfu l CNS-actin g compounds .
We ar e particularl y gratefu l t o Dr . Giacint o Bagett a fo r hi s untirin g ai d i n
the preparatio n o f th e monograp h an d t o Mari a Lup o fo r providin g invaluabl e
help wit h th e literatur e survey . W e gratefull y acknowledg e Sando z Base l an d
Sandoz Ital y fo r permissio n t o us e th e fron t cove r ar t an d fo r assistanc e i n
printing it , respectively .
Eugenio E . Mulle r
Giuseppe Nistic o
List of Abbreviations
(Other abbreviations used are defined in the text.)
BDZ benzodiazepine
bid twice daily
A angiotensin BLA basolateral amygdala
A angstrom B maximal number of
max
AA arachidonic acid binding sites
Al angiotensin I BMI bicuculline methiodide
All angiotensin II
AC adenylate cyclase
n-AChR nicotinic receptors
ACh acetylcholine Ca2 + calcium
AChE acetylcholinesterase 2-CADO 2 -chloroadenosine
ACTH adrenocorticotropic cAMP cyclic adenosine
hormone monophosphate
ADP adenosine diphosphate 3',5'- 3',5 '-cyclic adenosine
AF64A ethylcholine mustard cAMP monophosphate
azaridinium ion CAs catecholamines
AHA anterior hypothalamic area CaM calmodulin
Ala alanine CAT choline acetyltransferase
AOAA aminooxyacetic acid β-CCE ethyl-p-carboline-3-
AP anterior pituitary carboxylate
APP avian pancreatic CCK cholecystokinin
polypeptide β-CCM methyl^-carboline-3-
APUD amine precursor uptake carboxylate
cells and decarboxylation CD carbidopa
cells CE cortical extracts
ARC n. arcuate nucleus of the CGD constitutional growth delay
hypothalamus CGRP calcitonin gene-related
Arg arginine peptide
AS antiserum CHA cyclohexyladenosine
Asn asparagine ChE cholinesterase
Asp aspartic acid CLIP corticotropin-like
ATP adenosine triphosphate intermediate lobe
ATPase adenosine triphosphatase peptide
AVP arginine vasopressin CLON clonidine
CMC carboxymethyl-cellulose
Β CNA central nucleus of the
amygdala
ΒΑ bioassay CNS central nervous system
BAL 2,3 -dimercaptopropanol COMT catechol-0-
BBB blood/brain barrier methyltransferase
BPP bovine pancreatic CPA M)-cyclopentyladenosine
polypeptide mCPP 1 -(3-chlorophenyl)-
BBS bombesin piperazine
XIV Lis to f Abbreviation s
CRFc orticotropin-releasin g DSTd examethason es uppressio n
factor test
CRHc orticotropin-releasin g DTPd orsa lt egmenta lp athwa y
hormone
CSDc ystein es ulfini c
Ε
decarboxylase
CSF cerebrospina lf lui d epinephrine
CTc alcitoni n estradiol
Cysc ystein e EB estradiol benzoat e
ECoG electrocorticographic
ECT electroconvulsivet herap y
ED mediane ffectiv ed os e
50
DAd opamin e EDTA ethylenediaminetetracetic
DAGd iacylglycero l acid
DAGO (D-Ala 2-MePhe4-Gly-ol5)- EEG electroencephalogram
enkephalin EGF epidermalg rowt hf acto r
4-DAMP4 -diphenylactoxy-N - EGTA ehtyleneglycolbis^-
methyl-piperidine aminoethyl ether)AW -
methiodide tetraacetica ci d
DAOd iamin eo xidas e EM electronm icroscop y
dbcAMPd ibutyry lc ycli ca denosin e β-END β-endorphin
monophosphate ENK enkephalin
D-β-Η dopamines-hydroxylas e EOPs endogenouso pioi d
DBI diazepa mb indin gi nhibito r peptides
DDCd iethyldithiocarbamat e EOS ethanolamine-O-sulfate
2-DG 2-deoxy-D-glucos e EV estradiolv alerat e
DHEd ihydroergocriptin e
DHP1 ,4-dihydropyridin e
DHTd ihydrotestosteron e
5,6-DHT 5,6-dihydrox yt ryp tamine
5,7-DHT 5,7-dihydroxytryptamin e FG7142 3-carboline-3-carboxylic
DKP diketopiperazin e acid methylamid e
DMCM 6,7-dimethoxy-4-ethyl^ - FRP FSH-releasingp eptid e
carboline-3-carboxylate FSH follicle-stimulating
DMI desmethylimipramine hormone
DMNd orsomedia ln ucleu s FSHRH follicle-stimulating
Ν,Ν-ΌΜΎ N,N-dimethyltryptamin e hormone-releasing
cDNAc omplementar y hormone
deoxyribonucleica ci d
DOB l-(2,5-dimethoxy-4-bromo -
phenyl)-2-aminopropane
DOI 1 -(2,5-dimethoxy-4-iodo- GABA 7-aminobutyrica ci d
phenyl)-2-aminopropane GABA-T 7-aminobutyrica ci d
DOM l-(2,5-dimethoxy-4 - transaminase
methyl-phenyl)-2- GABOB 7-aminoS-hydroxybutyric
aminopropane acid
dopad ihydroxyphenylalanin e GAD glutamica ci d
DOPAC3 ,4-dihydroxyphenylaceti c decarboxylase
acid GAD-I glutamica ci d
DOPS3 ,4-dihydroxyphenylserin e decarboxylase I
DPTAd iethylenetriaminepentaace - GAD-II glutamica ci d
tica ci d decarboxylaseI I
DPX l,3-diethyl-8 - GAG 7-acetylenicG AB A
phenylxanthine GAP GnRH-associated peptid e
Listo f Abbreviation s XV
GDEE L-glutamica cidd iethy l HPLCh igh-pressur el iqui d
ester chromatography
GH growthh ormon e 5-HTs erotoni n
cGH canineg rowt hh ormon e 5-HTP5 -hydroxytryptopha n
hGH humang rowt hh ormon e HVAh omovanilli ca ci d
rGH ratg rowt hh ormon e
GHB 7-hydroxybutyrate
GH-IF-GIF growthh ormone-inhibitin g I
orG H-RI F factor,g rowt hh ormon e
IADAsi ndirectl ya ctin g dopamin e
release-inhibitingf actor ,
agonists
ors omatostati n
IBMXi sobutylmethylxanthin e
GHRH growthh ormone-releasin g
ici ntracisterna l
hormone
IC i nhibitor yc oncentratio n
Gi guaninen ucleotid eb indin g 50
required t os uppres s
protein( inhibitory )
50%o fi nhibitabl e
GI gastrointestinal
hormone releas e
GIP gastrici nhibitor y
icvi ntracerebroventricula r
polypeptide
ICYPi odocyanopindolo l
Gin glutamine
IFNi nterfero n
Glu glutamica ci d
IGFi nsulin-lik eg rowt hf acto r
Gly glycine
IgGi mmunoglobuli n
GMP guanosinem onophosphat e
IGHDi solate dg rowt hh ormon e
cGMP cyclicg uanosin e
deficiency
monophosphate
IHi diopathi ch yper
GnRH gonadotropin-releasing
prolactinemia
hormone
IHHi diopathi c hypogonado
GRF growthh ormone-releasin g
tropich ypogonadis m
factor
ILi ntermediat e lob e
GRF-LA GRF-likea ctivit y
Hei soleucin e
GRP gastrin-releasingp eptid e
im intramuscula r
Gs guaninen ucleotid eb indin g
INIi soniazi d
protein( stimulatory )
IPi nterpeduncula rn ucleu s
GTP guanosinet riphosphat e
IP inositol-1,4,5-trisphosphat e
GTT glucoset oleranc et es t 3
ipi ntraperitoneall y
IPSPi nhibitor y postsynapti c
potential
Η IRi mmunoreactiv e
ISO isoproterenol
Η histamine
hCG humanc horioni c iv intravenous
gonadotropin
HD histidined ecarboxylas e κ
HE hypothalamice xtract s
HHAA hypothalamo-hypophyseal- K dissociationc onstan t
d
adrenala xi s
HHTA hypothalamo-hypophyseal-
thyroida xi s L
5-HIAA 5-hydroxyindoleacetica ci d
HIOMT hydroxyindole-O- L-AAAD L-aromatica minoa ci d
methyltransferase decarboxylase
His histidine L-dopa L-dihydroxyphenylalanine
HIT hypothalamoinfundibular Leu leucine
tract Leu-ENK leucine-enkephalin
HMW highm olecula rw eigh t LH luteinizingh ormon e
xvi Lis to f Abbreviation s
LHAl atera lh ypothalami ca re a MPZm edia lp alisad ez on e
LH-MFBl atera lh ypothalami c Mm olecula rm as s
r
medialf orebrai nb undl e MSHm elanocyte-stimulatin g
LHRHl uteinizin g hormone - hormone
releasing hormon e 3-MT3 -methoxytyramin e
L-5-HTP L-5-hydroxytryptophan
LI- lik ei mmunoreactivit y Ν
β-LPHβ -lipotropi n
LPZl atera lp alisad ez on e η.n ucleu s
LTl eukotrien e NADn icotinamid ea denin e
L-TH L-tyrosine hydroxylas e dinucleotide
L-Trp L-tryptophan NASA f-acetylserotoni n
L-Tyr L-tyrosine NATN -acetyltransferas e
LVPl ysin ev asopressi n NEn orepinephrin e
NEC A 5'-N-ethylcarboxyamido -
adenosine
Μ
NEFAn onesterifie df att ya cid s
MAsm onoamine s NILn eurointermediat el ob e
MAOm onoamin e oxidas e Nlen orleucin e
MAO-Am onoamin eo xidas e A NMDA Ar-methyl -D,L-aspartica ci d
MAO-Bm onoamin eo xidas e Β NMRn uclea r magneti c resonanc e
MAOIsm onoamin eo xidas e NMSΛ ^-methscopolamin e
inhibitors Nomn omifensin e
MBHm edia lb asa lh ypothalamu s NPn europhysi n
MCRm etaboli cc learanc er at e 1- NP 1 - naphthyl piperazine
α-MD a-methyldop a NPYn europeptid e Y
MEm edia ne minenc e NTn eurotensi n
MEDm edia ne ffectiv ed os e
5-MeODMT5 -methoxy-N,iV - Ο
dimethyltryptamine
5-MeOT5 -methoxytryptamin e ODNo ctadeca-neuropeptid e
Metm ethionin e 17-OHCS1 7-hydroxycorticosteroid s
Met-ENKm ethionine-enkephali n 5-OHDA5 -hydroxydopamin e
MFBm edia lf orebrai nb undl e 6-OHDA6 -hydroxydopamin e
MFMD DL-monofluoromethyldopa 6-OH-dopa6 -hydroxydop a
MHPGm ethoxyhydroxyphenylgly - 8-OH-8 4rydroxy-2-(di-w -
col DPATp ropylamino)tetrali n
MIFm elanocyte-inhibitin g 2-OHE2 -hydroxyestradio l
factor 4-OHT4 -hydroxytryptolin e
ΜΓΤm onoiodotyrosin e 6-OHT6 -hydroxytryptolin e
α-MmTa -methyl-m-tyrosin e 7-OHT7 -hydroxytryptolin e
MNAm edia ln ucleu so ft h e OVLTo rganu mv asculosu m
amygdala laminaet erminali s
ct-MNEα -methy ln orepinephrin e
MPDP l-methyl-4-phenyl-2,3 -
dihydropiridinium
intermediate Ρp rogesteron e
MPOAm edia lp reopti ca re a PACPX1 ,3-dipropyl-8-(2-amino-4 -
MPP + 1 - methy1 -4-phenyl pyridine chloro)-phenylxanthine
2-MPP 1 - (2-methoxyphenyl)- PADp rimar ya ffectiv e disorder s
piperazine PAS p-aminosalicyli c
α-ΜρΤ a-methyl-p-tyrosin e pCA p-chloroamphetamin e
MPTP l-methyl-4-phenyl- l ,2,3,6 - pCMA p-chloro-N -
tetrahydropyridine methylamphetamine
List of Abbreviations xvi i
pCPA p-chlorophenylalanin e sc subcutaneou s
PETp ositro ne missio n SCNs uprachiasmati cn ucleu s
tomography SDs tandar d deviatio n
PGp rostaglandi n SDSs odiu m dodecy ls ulfat e
PGDHp rostaglandi n SELs ubependyma l laye r
dehydrogenase SEMs tandar d erro ro ft h em ea n
PGIp rostacycli n Ser serin e
2
pGlup yroglutami ca ci d SIFs mal li ntensel y fluorescent
PGOp ontogeniculooccipita l cells
Phep henylalanin e SK substanc e Κ
PHIp eptid eh istidin ei soleucin e SS-LI somatostatin-lik e
amide immunoreactivity
PHMp eptid eh istidin e SM somatomedi n
methioninea mid e SM-Cs omatomedi n C
Pisp hosphoinositide s SMEs tal km edia n eminenc e
PIAp henylisopropyladenosin e SON supraopti c nucleu s
PIFp rolactin-inhibitin gf acto r SP substanc e Ρ
PIP PIP SPIRs piperon e o rs piroperido l
2 2
phosphatidy linisitol-4, 5- SPOA septum-preopti ca re a
bisphosphate SRS-As low-reactin gs ubstanc eo f
PLA-2p hospholipas e A anaphylaxis
2
PMSGp regnan t mar es eru m SS somatostati n
gonadotropin SSAs uccini c semialdehyd e
PNMTp henylethanolamine-N - SVs odiu m valproat e
methyltransferase SWSs lo w wav e slee p
PNSp eriphera ln ervou ss yste m
poo rall y
POp reopti c
POAp reopti ca re a
Τt estosteron e
POMCp roopiomelanocorti n
T h alf-lif e
PPPp olyphloreti n phosphat e l/2
Tt riiodothyronin e
3-PPP 3-(3-hydroxyphenyl)-#-n - 3
Tt hyroxin e
propylpiperidine 4
TBG thyroxine-binding-globuli n
PRFp rolactin-releasin gf acto r
TCAt ricarboxyli ca ci d cycl e
Prlp rolacti n
TFMPP l-(3 -
Prop rolin e
trifluoromethylphenyl)-
8-PSTp -sulfopheny lt heophyllin e
piperazine
PtdI n sp hosphatidylinosito l
TGFt ransformin g growt hf acto r
PVNp araventricula rn ucleu s
THt yrosin e hydroxylas e
THBC tetrahydro^-carboline s
Thrt hreonin e
QNBq uinuclidiny lb enzylat e TIt uberoinfundibula r
tid thre e time s a d a y
TIDAt uberoinfundibula r
dopamine
REM rapid ey em ovemen t slee p
TMB-88 -(N,N-diethylamino)octy l
RH regulatoryh ormon e
3,4,5-trimethoxy-
RIA radioimmunoassay
benzoateH C R
mRNA messenger ribonucleic a ci d
TPOt ryptopha n pyrrolas e
RNase ribonuclease
TRHt hyrotropin-releasin g
hormone
TRH-OHT R Hf re ea ci d
SAM S-adenosylmethionine Trpt ryptopha n
8
Sari-Ala- saralasin Trp-Ht ryptopha n hydroxylas e
