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BOOKCHAPTER

Neurotransmitters
SimonJ.R.Heales
MedicalBiochemistry,Chapter41.1,551563

chServlet?publisherName=ELS&orderBeanReset=true&orderSource=ClinicalKey&contentID=B9781455745807000415)

LEARNINGOBJECTIVES

Afterreadingthischapteryoushouldbeableto:
Outlinethecriteriathatneedtobemetbeforeamoleculecanbeclassifiedasa
neurotransmitter.
Identifythemajorneurotransmittertypesandbeawarethatsomemoleculeshave
neurotransmitterpropertiesbutcannotinthestrictestsensebeclassifiedas
neurotransmitters.
Explainthegenerationofactionpotentials,appreciatehowneurotransmitterscanbe
excitatoryorinhibitory,andsummarizetheprocesswherebyaneurotransmitteris
releasedfromthepresynapticcell.
Describethedifferentneurotransmitterreceptorsandtheirgeneralmodeofaction.
Describethemajorbiochemicalpathwaysforneurotransmittersynthesisand
degradation.
Identifysomeclinicaldisordersthatcanariseasaresultofdisruptionof
neurotransmittermetabolism.

Introduction
Neurotransmittersaremoleculesthatactaschemicalsignalsbetweennervecells
Nervecellscommunicatewitheachotherandwithtargettissuesbysecretingchemical
messengers,calledneurotransmitters.Thischapterdescribesthevariousclassesof
neurotransmittersandhowtheyinteractwiththeirtargetcells.Itwilldiscusstheireffectsonthe
body,howalterationsintheirsignalingmaycausedisease,andhowpharmacologicmanipulation
oftheirconcentrationsmaybeusedtherapeutically.

Definitionofaneurotransmitter
Traditionally,foramoleculetobelabeledasaneurotransmitter,anumberofcriteriahavetobe

met:
Synthesisofthemoleculeoccurswithintheneuron,i.e.allbiosyntheticenzymes,
substrates,cofactors,etc.,mustbepresentfordenovosynthesis.
Storageofthemoleculeoccurswithinthenerveendingpriortorelease,e.g.insynaptic
vesicles.
Releaseofthemoleculefromthepresynapticendingoccursinresponsetoanappropriate
stimulussuchasanactionpotential.
Thereisbindingandrecognitionoftheputativeneurotransmittermoleculeonthe
postsynaptictargetcell.
Mechanismsexistfortheinactivationandterminationofthebiologicalactivityofthe
neurotransmitter.
Rigorousadherencetotheabovecriteriameansthatsomemoleculesthatareinvolvedinthe
crosstalkbetweenneuronsarenotinthestrictsenseclassifiedasneurotransmitters.Thus,nitric
oxide(NO),adenosine,neurosteroids,polyamines,etc.,areoftentermedneuromodulators
ratherthanneurotransmitters.

Classificationofneurotransmitters
AclassificationofneurotransmittersbasedonchemicalcompositionisshowninTable41.1.1
(t0010).Manyarederivedfromsimplecompounds,suchasaminoacids(Table41.1.2(t0015)),but
peptidesarealsonowknowntobeextremelyimportant.Theprincipaltransmittersinthe
peripheralnervoussystemarenorepinephrineandacetylcholine(ACh)(Fig.41.1.1(f0010)).
Table41.1.1
Classificationofneurotransmitters

Group

Examples

Amines

Acetylcholine(ACh),norepinephrine,epinephrine,dopamine,5HT

Aminoacids Glutamate,GABA
Purines

ATP,adenosine

Gases

Nitricoxide

Peptides

Endorphins,tachykinins,manyothers

5HT,5hydroxytryptamineGABA,aminobutyricacid.
Neurotransmitterscanbeclassifiedinseveralways.Theschemeshownreliesonchemicalsimilarities.All
exceptthepeptidesaresynthesizedatthenerveendingandpackagedintovesiclestherepeptidesare
synthesizedinthecellbodyandtransporteddowntheaxon.
Table41.1.2

Neurotransmittersoflowmolecularweight

Compound

Precursor

Siteofproduction

Aminoacids
Glutamate

Centralnervoussystem(CNS)

Aspartate

CNS

Glycine

Spinalcord

Aminoacidderivatives
GABA

Glutamate

CNS

Histamine

Histidine

Hypothalamus

Norepinephrine Tyrosine

Sympatheticnerves,CNS

Epinephrine

Tyrosine

Adrenalmedulla,afewCNSnerves

Dopamine

Tyrosine

CNS

5HT

Tryptophan CNS,enterochromaffingutcells,entericnerves

Purinederivatives
ATP
Adenosine

Sensory,enteric,sympatheticnerves
ATP

CNS,peripheralnerves

Arginine

Genitourinarytract,CNS

Choline

Parasympatheticnerves,CNS

Gas
Nitricoxide
Miscellaneous
Acetylcholine

Manyneurotransmittersaresimplecompounds,oftenderivedfromcommonaminoacids.

Fig.41.1.1
Transmittersintheautonomicnervoussystem.
Cate
cholaminesandacetylcholine(ACh)aretransmittersinthesympatheticandparasympathetic
nervoussystems.PreganglionicnervesallreleaseACh,whichbindstonicotinic(N)receptors.Mostpost

ganglionicsympatheticnervesreleasenorepinephrine(NE),whereaspostganglionicparasympatheticnerves
releaseACh,whichactsatmuscarinic(M)receptors.Adrenalglandsreleaseepinephrine.Motorneurons
releaseACh,whichactsatdistinctnicotinicreceptors.E,epinephrine(seealsoFig.41.1.3(f0020)).

Severaltransmittersmaybefoundinonenerve
Anearlydogmaofnervefunctionheldthatonenervecontainedonetransmitter.However,thisis
nowknowntobeanoversimplification,andcombinationsoftransmittersaretherule.Thepattern
ofcellulartransmittersmaycharacterizeaparticularfunctionalrole,butdetailsofthisalso
remainunclear.Amajorlowmolecularweighttransmittersuchasanamineisoftenpresent,
alongwithseveralpeptides,anaminoacid,andapurine.Sometimes,theremayevenbemore
thanonepossibletransmitterinaparticularvesicle,asisbelievedtobethecaseforadenosine
triphosphate(ATP)andnorepinephrineinsympatheticnerves.Insomecases,theintensityof
stimulationmaycontrolwhichtransmitterisreleased,peptidesoftenrequiringgreaterlevelsof
stimulus.Furthermore,differenttransmittersmayhaveadifferenttimescaleofaction.
Sympatheticnervesaregoodexamplesofnervesforwhichthisisthecase:itisbelievedthatATP
causestheirrapidexcitation,whereasnorepinephrineandtheneuromodulatorneuropeptideY
(NPY)causeaslowerphaseofaction.Insometissues,NPYonitsownmaybeabletoproducea
veryslowexcitation.

Neurotransmission
Actionpotentialsarecausedbychangesinionflowsacrosscellmembranes
Thesignalcarriedbyanervecellreflectsanabruptchangeinthevoltagepotentialdifference
acrossthecellmembrane.Thenormalrestingpotentialdifferenceisafewmillivolts,withthe
insideofthecellbeingnegative,andiscausedbyanimbalanceofionsacrosstheplasma
membrane:theconcentrationofK+ionismuchgreaterinsidecellsthanoutside,whereasthe
oppositeistrueforNa+ion.ThisdifferenceismaintainedbytheactionoftheNa+/K+ATPase
(Chapter24).Onlythoseionstowhichthemembraneispermeablecanaffectthepotential,as
theycancometoanelectrochemicalsteadystateunderthecombinedinfluenceofconcentration
andvoltagedifferences.BecausethemembraneinallrestingcellsiscomparativelypermeabletoK
+

asaresultofthepresenceofvoltageindependent(leakage)K+channels,thisionlargely
controlstherestingpotential.

Achangeinvoltagewhichtendstodrivetherestingpotentialtowardszerofromthe

Achangeinvoltagewhichtendstodrivetherestingpotentialtowardszerofromthe
normalnegativevoltageisknownasadepolarization,whereasaprocessthatincreases
thenegativepotentialiscalledhyperpolarization
Sofar,thispictureiscommontoallcells.However,nervecellscontainvoltagedependentsodium
channelsthatopenveryrapidlywhenadepolarizingchangeinvoltageisapplied.Whentheyopen,
theyallowtheinwardpassageofhugenumbersofNa+ionsfromtheextracellularfluid(Fig.
41.1.2(f0015)),whichswampstherestingvoltageanddrivesthemembranepotentialtopositive
values.Thisreversalofvoltageistheactionpotential.Almostimmediatelyafterwards,the
sodiumchannelscloseandsocalleddelayedpotassiumchannelsopen.Theserestorethenormal
restingbalanceofionsacrossthemembraneand,afterashortrefractoryperiod,thecellcan
conductanotheractionpotential.Meanwhile,theactionpotentialhasspreadbyelectrical
conductancetothenextsegmentofnervemembrane,andtheentirecyclestartsagain.

Fig.41.1.2
Generationofactionpotential.
Actionpotentialisformedasfollows.Atthestartofanactionpotential,themembraneisatitsrestingpotential
ofabout70mV.ThisismaintainedbyvoltageindependentK+channels.Whenanimpulseisinitiatedbya
signalfromaneurotransmitter,voltagedependentNa+channelsopen.TheseallowinflowofNa+ions,which
alterthemembranepotentialtopositivevalues.TheNa+channelsthencloseandK+channels,called
delayedrectifierchannels,opentorestoretheinitialbalanceofionsandthenegativemembranepotential.

Neurotransmittersaltertheactivityofvariousionchannelstocausechangesinthe
membranepotential
Excitatoryneurotransmitterscauseadepolarizingchangeinvoltage,inwhichcaseanaction
potentialismorelikelytooccur.Incontrast,inhibitorytransmittershyperpolarizethe
membraneandanactionpotentialisthenlesslikelytooccur.

Neurotransmittersactatsynapses
Neurotransmittersarereleasedintothespacebetweencellsataspecializedareaknownasa
synapse(Fig.41.1.3(f0020)).Inthesimplestcase,theydiffusefromthepresynapticmembrane
acrossthesynapticspaceorcleft,andbindtoreceptorsatthepostsynapticmembrane.However,
manyneurons,particularlythosecontainingamines,haveseveralvaricositiesalongtheaxon,

containingtransmitter.Thesevaricositiesmaynotbeclosetoanyneighboringcell,sotransmitter
releasedfromthemhasthepossibilityofaffectingmanyneurons.Nervesinnervatingsmooth
musclearecommonlyofthiskind.

Fig.41.1.3
Releaseofneurotransmitters.
Neurotransmittersarereleasedfromvesiclesatthesynapticmembrane.(A)Intherestingstate,vesiclesare
attachedtomicrotubules.(B)Whenanactionpotentialisreceived,calciumchannelsopen.(C)Vesiclesmove
totheplasmamembrane,and(D)bindtoacomplexofdockingproteins.(E)Neurotransmitterisreleased,
and(F)vesiclesarerecycled.

Whentheactionpotentialarrivesattheendoftheaxon,thechangeinvoltageopenscalcium
channels.Calciumentryisessentialformobilizationofvesiclescontainingtransmitter,andfor
theireventualfusionwiththesynapticmembraneandreleasethroughit.
Becausetransmittersarereleasedfromvesicles,impulsesarriveatthepostsynapticcellin
individualpackets,orquanta.Attheneuromuscularjunctionbetweennervesandskeletalmuscle
cells,alargenumberofvesiclesaredischargedatatime,andasingleimpulsemaythereforebe
enoughtostimulatecontractionofthemusclecell.Thenumberofvesiclesreleasedatsynapses
betweenneurons,however,ismuchsmallerconsequently,therecipientcellwillbestimulated
onlyifthetotalalgebraicsumofthevariouspositiveandnegativestimuliexceedsitsthreshold.As
eachcellinthebrainreceivesinputfromahugenumberofneurons,thisimpliesthatthereisafar
greatercapabilityforthefinecontrolofresponsesinthecentralnervoussystem(CNS)thanthere
isattheneuromuscularjunction.

Receptors
Neurotransmittersactbybindingtospecificreceptors,andopeningorclosingion
channels
Thereareseveralmechanismsbywhichreceptorsforexcitatoryneurotransmitterscancausethe
propagationofanactionpotentialinapostsynapticneuron.Directlyorindirectly,theycause
changesinionflowacrossthemembrane,untilthepotentialreachesthecriticalpoint,or

threshold,forinitiationofanactionpotential.Receptorsthatdirectlycontroltheopeningofan
ionchannelarecalledionotropic,whereasmetabotropicreceptorscausechangesinsecond
messengersystems,whichinturnalterthefunctionofchannelsthatareseparatefromthe
receptor.

Ionotropicreceptors(ionchannels)
Ionotropicreceptorscontainanionchannelwithintheirstructure(Fig.41.1.4(f0025)seealso
Chapter8).ExamplesincludethenicotinicAChreceptorandsomeglutamateandamino

butyricacid(GABA)receptors.Thesearetransmembraneproteins,withseveralsubunits,
usuallyfive,surroundingaporethroughthemembrane.Eachsubunithasfourtransmembrane
regions.Whentheligandbinds,thereisachangeinthethreedimensionalstructureofthe
complex,whichallowstheflowofionsthroughit.Theeffectonmembranepotentialdependson
theparticularionsthatareallowedtopass:thenicotinicAChreceptoriscomparatively
nonspecifictowardssodiumandpotassiumandcausesdepolarization,whereastheGABAA
receptorisachloridechannelandcauseshyperpolarization.

Fig.41.1.4
Mechanismofactionofionotropicreceptors.
Ionotropicreceptorsdirectlyopenionchannels(infact,theyarethemselvesionchannels).Thebeststudied
exampleisthenicotinicAChreceptor.Thisisatransmembraneprotein(A)consistingoffivenonidentical
subunits(B),eachonepassingrightthroughthemembrane.Thesubunitssurroundapore(C)that
selectivelyallowscertainionsthroughwhenitisopenedbyaligand(D).

Metabotropicreceptors
AllknownmetabotropicreceptorsarecoupledtoGproteins
Metabotropicreceptorsarecoupledtosecondmessengerpathwaysandactmoreslowlythan
ionotropicreceptors.AllknownmetabotropicreceptorsarecoupledtoGproteins(Chapter40)
and,likehormonereceptors,haveseventransmembraneregions.Typically,theythencouple
eithertoadenylatecyclase,alteringtheproductionofcyclicadenosinemonophosphate(cAMP),or

tothephosphatidylinositolpathway,whichalterscalciumfluxes.Ionchannelsthatareseparate
fromthereceptorarethenusuallymodifiedbyphosphorylation.Forinstance,theadrenergic
receptor,whichrespondstonorepinephrineandepinephrine(Fig.13.5),causesanincreasein
cAMP,whichstimulatesakinasetophosphorylateandactivateacalciumchannel.Someofthe
muscarinicclassofAChreceptorshavesimilareffectsonK+channels.

Regulationofneurotransmitters
Theactionoftransmittersmustbehaltedbytheirremovalfromthesynapticcleft
Whentransmittershaveservedtheirfunction,theymustberemovedfromthesynapticspace.
Simplediffusionisprobablythemajormechanismofremovalofneuropeptides.Enzymessuchas
acetylcholinesterase,whichcleavesACh,maydestroyanyremainingtransmitter.Surplus
transmittersmayalsobetakenbackupintothepresynapticneuronforreuse,andthisisamajor
routeofremovalforcatecholaminesandaminoacids.Interferencewithuptakecausesanincrease
intheconcentrationoftransmitterinthesynapticspacethisoftenhasusefultherapeutic
consequences.

Concentrationsofneurotransmittersmaybemanipulated
Theeffectsofneurotransmitterscanbealteredbychangingtheireffectiveconcentrationsorthe
numberofreceptors.Concentrationscanbealteredby:
changingtherateofsynthesis
alteringtherateofreleaseatthesynapse
blockingreuptake
blockingdegradation.
Changesinthenumberofreceptorsmaybeinvolvedinlongtermadaptationstothe
administrationofdrugs.

Classesofneurotransmitters
Aminoacids
Ithasbeenparticularlydifficulttoprovethataminoacidsaretrueneurotransmitterstheyare
presentinhighconcentrationsbecauseoftheirothermetabolicroles,andthereforesimple
measurementoftheirconcentrationsdidnotprovideconclusiveevidence.Pharmacologicstudies
ofresponsestodifferentanaloguesandthecloningofspecificreceptorsfinallyprovidedtheproof.

Glutamate
GlutamateisthemostimportantexcitatorytransmitterintheCNS
Glutamateactsonbothionotropicandmetabotropicreceptors.Clinically,thereceptor
characterizedinvitrobyNmethyldaspartate(NMDA)bindingisparticularlyimportant(
Fig.41.1.5(f0030)).

Fig.41.1.5
TheNMDAglutamatereceptor.
TheglutamatereceptorthatbindsNmethyldaspartate(NMDA)iscomplex.Thisreceptorisclinically
importantbecauseitmaycausedamagetoneuronsafterstroke(excitotoxicity).Itcontainsseveral
modulatorybindingsites,soitmaybepossibletodevelopdrugsthatcouldalteritsfunction.Glycineisan
obligatorycofactor,asarepolyaminessuchasspermine.Magnesiumphysiologicallyblocksthechannelat
therestingpotential,sothechannelcanopenonlywhenthecellhasbeenpartiallydepolarizedbyaseparate
stimulus.Itthereforecausesaprolongationoftheexcitation.Thisreceptoralsobindsphencyclidine(PCP).
Becausethisdrugofabusecancausepsychoticsymptoms,itispossiblethatdysfunctionofpathways
involvingNMDAreceptorscausessomeofthesymptomsofschizophrenia.

Thehippocampus(Fig.41.1.6(f0035))isanareaofthelimbicsystemofthebrainthatisinvolved
inemotionandmemory.Certainsynapticpathwaystherebecomemoreactivewhenchronically
stimulated,aphenomenonknownaslongtermpotentiation.Thisrepresentsapossiblemodelof
howmemoryislaiddown,anditrequiresactivationoftheNMDAreceptorandtheconsequent
influxofcalcium.

Fig.41.1.6
Limbicsystem.
Thelimbicsystemofthebrainisinvolvedinemotionsandmemory.Itconsistsofvariousareassurrounding
theupperbrainstem,includingthehippocampus,theamygdaloidbody,andthecingulategyrus.Removalof
thehippocampuspreventsthelayingdownofshorttermmemory,whileintactamygdaloidfunctionisrequired
fortheemotionoffear.

Glutamateisrecycledbyhighaffinitytransportersintobothneuronsandglialcells.Theglialcells
convertitintoglutamine,whichthendiffusesbackintotheneuron.Mitochondrialglutaminasein
theneuronregeneratesglutamateforreuse.

Glutamateandexcitotoxicity
Extracellularglutamateconcentrationisincreasedaftertraumaandstroke,duringsevere
convulsions,andinsomeorganicbraindiseasessuchasHuntington'schorea,AIDSrelated
dementia,andParkinson'sdisease.Thisisbecauseofreleaseofglutamatefromdamaged
cellsanddamagetotheglutamateuptakepathways.

Excessglutamateistoxictonervecells
TheactivationofNMDAreceptorallowscalciumentryintocells.Thisactivatesvariousproteases,
whichinturninitiatethepathwayofprogrammedcelldeathorapoptosis(seeChapter42).There
may,inaddition,bechangesinotherionotropicglutamatereceptorsthatalsocauseaberrant
calciumuptake.Uptakeofsodiumionsisalsoimplicatedandcausesswellingofcells.Activationof
NMDAreceptorsalsoincreasestheproductionofnitricoxide,whichmayinitselfbetoxic.Cell
deathinsomemodelsofexcitotoxicitycanbepreventedbyinhibitorsofnitricoxideproduction,
butthemechanismoftoxicityisnotclear.
AttemptsarebeingmadetodevelopdrugstoinhibitNMDAactivationandsuppressexcitotoxicity.
Thehopeisthatdamagecausedbystrokecanbelimitedorevenreversed.Unfortunately,manyof
thedrugshavesideeffectsbecausetheybindtothephencyclidinebindingsiteandhave
unpleasantpsychologiceffectssuchasparanoiaanddelusions.

Aminobutyricacid(GABA)
GABAissynthesizedfromglutamatebytheenzymeglutamatedecarboxylase
GABA(Fig.41.1.7(f0040))isthemajorinhibitorytransmitterinthebrain.Therearetwoknown
GABAreceptors:theGABAAreceptorisionotropicandtheGABABreceptorismetabotropic.The
GABAAreceptorconsistsoffivesubunitsthatarisefromseveralgenefamilies,givingan
enormousnumberofpotentialreceptorswithdifferentbindingaffinities.Thisreceptoristhe
targetforseveralusefultherapeuticdrugs.Benzodiazepinesbindtoitandcauseapotentiation
oftheresponsetoendogenousGABAthesedrugsreduceanxietyandalsocausemuscle
relaxation.BarbituratesalsobindtotheGABAreceptorandstimulateitdirectlyintheabsence
ofGABAbecauseofthislackofdependenceonendogenousligand,theyaremorelikelytocause
toxicsideeffectsinoverdose.

Fig.41.1.7
Synthesisofneurotransmittersandtheirprecursors.
Theaminoacidtyrosineistheprecursorofdopamine,norepinephrineandepinephrine.Tryptophanisthe
precursorofserotonin(5hydroxytryptamine),andhistaminederivesfromtheaminoacidhistidine.Choline,
anaminoalcoholistheprecursorofacetylcholine,andthecommonaminoacid,glutamicacid,isthe
precursoroftheGABA.

Glycine
Glycineisprimarilyfoundininhibitoryinterneuronsinthespinalcord,whereitblocksimpulses
travelingdownthecordinmotorneuronstostimulateskeletalmuscle.Theglycinereceptoron
motorneuronsisionotropicandisblockedbystrychninemotorimpulsescanthenbepassed
withoutnegativecontrol,whichaccountsfortherigidityandconvulsionscausedbythistoxin.

Catecholamines
Norepinephrine,epinephrine,anddopamine,knownascatecholamines,areallderivedfromthe
aminoacidtyrosine(Fig.41.1.7(f0040)).Incommonwithothercompoundscontainingamino
groups,suchasserotonin,theyarealsoknownasbiogenicamines.Nervesthatrelease
catecholamineshavevaricositiesalongtheaxon,insteadofasingleareaofreleaseattheend.
Transmitterisreleasedfromthevaricositiesanddiffusesthroughtheextracellularspaceuntilit
meetsareceptor.Thisallowsittoaffectawideareaoftissue,andthesecompoundsarebelievedto
haveageneralmodulatoryeffectonoverallbrainfunctionssuchasmoodandarousal.

Norepinephrineandepinephrine
Norepinephrine(alsoknownasnoradrenaline)isamajortransmitterinthe
sympatheticnervoussystem
Sympatheticnervesariseinthespinalcordandruntogangliasituatedclosetothecord,from
whichpostganglionicnervesruntothetargettissues.Norepinephrine(Fig.41.1.7(f0040))isthe
transmitterforthesepostganglionicnerves,whereasthetransmitterattheintermediategangliais
ACh.Stimulationofthesenervesisresponsibleforvariousfeaturesofthefightorflightresponse,
suchasstimulationoftheheartrate,sweating,vasoconstrictionintheskin,andbronchodilation.
TherearealsonorepinephrinecontainingneuronsintheCNS,largelyinthebrainstem(Fig.41.1.8
(f0045)).Theiraxonsextendinawidenetworkthroughoutthecortexandaltertheoverallstateof

alertnessorattention.Thestimulatoryeffectsofamphetaminesarecausedbytheirclose
chemicalsimilaritytocatecholamines.

CLINICALBOXAMANWITHASEVEREHEADACHEANDHYPERTENSION

A50yearoldmanhadbeensufferingfromdepressionforsomeyears.Hisconditionwas
treatedwithtranylcypromine,aninhibitorofmonoamineoxidasetypesAandB.He
developedasevere,throbbingheadacheandhisbloodpressurewasfoundtobe
200/110mmHg.Theonlyunusualoccurrencehadbeenthathehadattendedacocktailparty
thepreviouseveningatwhichheatecheesesnacksanddrankseveralglassesofredwine.

Comment.
Thepatientwasexperiencingahypertensivecrisiscausedbyaninteractionbetweenthefood
hehadeatenandthedrughewastreatedwithaMAOinhibitor.Thisdruginhibitsthe
mainenzymethatcatabolizescatecholamines.Severalfoods,includingcheese,pickled
herringandredwine,containanaminecalledtyramine,whichissimilarinstructureto
naturalaminetransmittersandisalsobrokendownbyMAO.Ifthisenzymeisnot
functional,theconcentrationsoftyramineincreaseanditstartstoactasaneurotransmitter.
Thiscancauseahypertensivecrisis,asitdidinthispatient.

Fig.41.1.8
NorepinephrineneuronsintheCNS.
Norepinephrinecontainingneuronsariseinthelocusceruleusinthebrainstemandaredistributed
throughoutthecortex.

Epinephrine(alsoknownasadrenaline)isproducedbytheadrenalmedullaunderthe
influenceofAChcontainingnerves,analogoustothesympatheticpreganglionicnerves
Epinephrineismoreactivethannorepinephrineontheheartandlungs,causesredirectionof
bloodfromtheskintoskeletalmuscle,andhasimportantstimulatoryeffectsonglycogen
metabolismintheliver.Inresponsetoepinephrine,asuddenextrasupplyofglucoseisdelivered
tomuscle,theheartandlungsworkhardertopumpoxygenroundthecirculation,andthebodyis
thenpreparedtorunortodefenditself(Chapter21).Epinephrineisnotessentialforlife,
however,asitispossibletoremovetheadrenalmedullawithoutseriousconsequences.
Thereceptorsfornorepinephrineandepinephrinearecalledadrenoceptors(seeFig.13.5).
Theyaredividedintoandreceptorclassesandsubclassesonthebasisoftheirpharmacology.
Epinephrineactsonallclassesofthereceptorsbutnorepinephrineismorespecificfor
receptors.Blockers,suchasatenolol,areusedtotreathypertensionandchestpain(angina)

inischemicheartdiseasebecausetheyantagonizethestimulatoryeffectsofcatecholamineson
theheart.Nonspecificblockershavelimiteduse,althoughthemorespecific1blockers,such
asprazosin,and2blockers,suchasclonidine,canbeusedtotreathypertension.Certain
subclassesofreceptorsarefoundinparticulartissuesforinstance,the2receptorispresent
inlungand2receptoragonistssuchassalbutamolarethereforeusedtoproducebronchial
dilatationinasthmawithoutstimulatingthe1receptorintheheart.
Norepinephrineistakenupintocellsbyahighaffinitytransporterandcatabolizedbytheenzyme
monoamineoxidase(MAO).FurtheroxidationandmethylationbycatecholamineO
methyltransferase(COMT)converttheproductstometanephrinesandvanillylmandelic
acid(4hydroxy3methoxymandelicacid)(Fig.41.1.9(f0050)),whichcanbemeasuredinthe
urineasindicesofthefunctionoftheadrenalmedulla.Theyareparticularlyincreasedinpatients
whohavethetumoroftheadrenalmedullaknownaspheochromocytoma.Thistumorcauses
hypertensionbecauseofthevasoconstrictoractionofthecatecholaminesitproduces.

ADVANCEDCONCEPTBOXDEPRESSIONASADISEASEOFAMINE
NEUROTRANSMITTERS:THEANTIDEPRESSANTS

Monoamineoxidase(MAO)inhibitorspreventthecatabolismofcatecholaminesand
serotonin.Theythereforeincreasetheconcentrationsofthesecompoundsatthesynapse
andincreasetheactionofthetransmitters.Compoundswiththispropertyare
antidepressants.Reserpine,anantihypertensivedrugthatdepletescatecholamines,
causeddepressionandisnolongerinuse.Thesefindingsgaverisetotheaminetheoryof
depression:thisstatesthatdepressioniscausedbyarelativedeficiencyofamine
neurotransmittersatcentralsynapses,andpredictsthatdrugswhichincreaseamine
concentrationsshouldimprovesymptomsofthecondition.
Insupportofthistheory,tricyclicantidepressantsinhibittransportofbothnorepinephrine
andserotoninintoneurons,therebyincreasingtheconcentrationofaminesinthesynaptic
cleft.Selectiveserotoninreuptakeinhibitors(SSRIs),suchasfluoxetine(Prozac),
arealsohighlyeffectiveantidepressants.However,asthesymptomsofdepressiondonot
resolveforseveraldaysaftertreatmentisstarted,itislikelythatlongtermadaptationsof
concentrationsoftransmittersandtheirreceptorsareatleastasimportantasacutechanges
inamineconcentrationsinthesynapticcleft.
Thisroleofmonoaminesindepressionisundoubtedlyanoversimplification.Thus,cocaine
isalsoaneffectivereuptakeinhibitorbutisnotanantidepressant,andamphetaminesboth
blockreuptakeandcausereleaseofcatecholaminesfromnerveterminals,butcausemania
ratherthanreliefofdepression.

CLINICALBOXA56YEAROLDWOMANPRESENTEDWITHSEVEREHYPERTENSION:
PHEOCHROMOCYTOMA

A56yearoldwomanpresentedwithseverehypertension.Shesufferedfromattacksof
sweating,headaches,andpalpitations.Herhighbloodpressurehadnotrespondedto
treatmentwithanangiotensinconvertingenzymeinhibitorandadiuretic.Asampleofurine
wastakenformeasurementofcatecholaminesandmetabolites.Therateofexcretionof
norepinephrinewas1500nmol/24h(253mg/24h)(referencerange<900nmol/24h,
<152mg/24h),thatofepinephrine620nmol/24h(113mg/24h)(referencerange
<230nmol/24h,<42mg/24h)andthatofvanillylmandelicacid60mmol/24h
(11.9mg/24h)(referencerange<35.5mmol/24h<7.0mg/24h)(seeFig.41.1.9(f0050)).

Comment.
Thepatienthadapheochromocytomawhichisatumoroftheadrenalmedullathatsecretes
catecholamines.Bothnorepinephrineandepinephrinemaybesecreted:nor
epinephrine
causeshypertensionbyactivating1adrenoceptorsonvascularsmoothmuscle,and
epinephrineincreasesheartratebyactivating1adrenoceptorsontheheartmuscle.
Hypertensionmaybeparoxysmalandsevere,leadingtostrokeorheartfailure.
Diagnosisismadebymeasuringcatecholaminesinplasmaorurine,ortheirmetabolites,
suchasmetanephrinesandvanillylmandelicacid,inurine.Thetumorisusuallylocalizedby
radiologictechniquessuchasnuclearmagneticresonance(NMR)orcomputedtomography
(CT)scanning.
Althoughthisisararecauseofhypertension,comprisingonlyabout1%ofcases,itisvery
importanttorememberit,astheconditionisdangerousandoftenamenabletosurgical
cure.

Fig.41.1.9
Catabolismofcatecholamines.
Catecholaminesaredegradedbyoxidationoftheaminogroupbytheenzymemonoamineoxidase(MAO),
andbymethylationbycatecholamineOmethyltransferase(COMT).Thepathwayshownisfor
norepinephrinebutthepathwaysforepinephrine,dopamine,and5HTareanalogous.

Dopamine
Dopamineisbothanintermediateinthesynthesisofnorepinephrineanda
neurotransmitter

Itisamajortransmitterinnervesthatinterconnectthenucleiofthebasalgangliainthebrainand
controlvoluntarymovement(Fig.41.1.10(f0055)).DamagetothesenervescausesParkinson's
disease,whichischaracterizedbytremoranddifficultiesininitiatingandcontrollingmovement.
Dopamineisalsofoundinpathwaysaffectingthelimbicsystemsofthebrain,whichareinvolved
inemotionalresponsesandmemory.Defectsindopaminergicsystemsareimplicatedin
schizophrenia,becausemanyantipsychoticdrugsusedtotreatthisdiseasehavebeenfoundto
bindtodopaminereceptors.

Fig.41.1.10
Dopamineinthenigrostriataltract.
Nervescontainingdopamineruninwelldefinedtracts.Oneofthemostimportanttracts,thenigrostriatal,
connectsthesubstantianigrainthemidbrainwiththebasalgangliabelowthecortex.Damagetothiscauses
Parkinson'sdisease,withlossoffinecontrolofmovement.

Intheperiphery,dopaminecausesvasodilatationanditisthereforeusedclinicallytostimulate
renalbloodflow,andisimportantinthetreatmentofrenalfailure(Chapter23).Thecatabolism
ofdopamineiscomparabletonorepinephrine.However,themajormetaboliteformedis
homovanillicacid(HVA).

CLINICALBOXTYROSINEHYDROXYLASEANDAROMATICAMINOACIDDECARBOXYLASE
(AADC)DEFICIENCIES:INHERITEDCAUSESOFIMPAIREDBIOGENICAMINEMETABOLISM

Tyrosinehydroxylaseisthefirststepindopaminebiosynthesis,andinheriteddisorders
affectingtheactivityofthisenzymeresultinbraindopaminedeficiency.Anumberofclinical
phenotypeshavebeendescribedandincludeaprogressivegaitdisorderandinfantile
parkinsonism.Treatmentoftyrosinehydroxylasedeficiencyisbytheadministrationofl
dopa.Inordertopreventthedecarboxylationofldopatodopamineintheblood(by
peripheralaromaticaminoaciddecarboxylaseAADC),aninhibitor(whichdoesnotaffect
theactivityofthebrainAADCenzyme)isgivenatthesametimeastheldopa.Such
inhibitionoptimizesthetransportofldopaacrossthebloodbrainbarrier.Withinthe
brain,AADCcanthenconverttheldopatodopamine.

AADCcatalyzestheconversionofldopatodopamineand5hydroxytryptophanto
serotonin.Consequently,aninbornerrorofmetabolismaffectingtheactivityofthisenzyme
resultsinabraindeficiencyofbothdopamineandserotonin.PatientswithAADCdeficiency
haveaclinicalpicturethatincludesaseveremovementdisorder,abnormaleyemovements
andneurologicimpairment.TreatmentofAADCdeficiencyconsistsofpreventingthe
degradationofanydopamineandserotoninthatmaybeproducedbyresidualAADC
activity,i.e.bytheuseofmonoamineoxidaseinhibitors.Inaddition,dopamineagonists
suchaspergolideandbromocriptineareusedtomimictheeffectsofdopamine.

CLINICALBOXLOSSOFACTIVITYOFADOPAMINETRANSPORTERLEADSTOA
CLINICALPICTURESUGGESTIVEOFADOPAMINEDEFICIENCYSTATE

Dopaminereleasedintothesynapticcleftistakenback,viathedopaminetransporter(DAT
SLC6A3)intopresynapticneuronswhereitcanberecycled.Autosomalrecessivemutations
arenowdocumentedthataffecttheDAT.Thisresultsinanintra
cellularneuronaldopamine
deficiencyandamarkedincreaseinextracellularlevelsoftheneurotransmitter.This
excessdopamineismetabolizedtohomovanillicacid(HVA)vianonneuronal
monoamineoxidaseandcatecholOmethyltransferase.AmarkedlyelevatedCSF
concentrationofHVAisastrongindicatorofDATdeficiency.Serumprolactinmayalsobe
elevatedinthisdisorder.Clinically,patientswithDATmutationscanpresentwith
parkinsonismdystonia,associatedwithaneyemovementdisorderandpyramidaltract
features.Currently,thereisnotanadequatetreatment.

CLINICALTESTBOXSERUMHORMONECONCENTRATIONCANPOINTTOCENTRAL
NEUROTRANSMITTERDEFICIENCY:PROLACTINANDDOPAMINE

Hypothalamicdopamineisaninhibitorofthereleaseofprolactinfromthepituitary.
Consequently,aprofounddeficiencyofcentraldopaminecanleadtoelevationsinthe
concentrationofserumprolactin.However,criticaltotheuseofthisperipheralbiomarkeris
theadoptionofappropriateagerelatedreferenceintervals,because,forinstance,theserum
prolactinconcentrationdeclinesmarkedlyduringthefirstyearoflife.Whilstserum
prolactinmaynotbeelevatedinallcasesofcentraldopaminedeficiency,documented
elevationshavebeennotedintheinheriteddisordersoftetrahydrobiopterinmeta
bolism,
andintyrosinehydroxylaseandaromaticaminoaciddecarboxylasedeficiencystates.
Furthermore,correctionofthecentraldopaminedeficitcanbeaccompaniedbyaloweringof
theserumprolactinconcentration,therebyenablingthemonitoringoftreatmentefficacy.

Serotonin(5hydroxytryptamine)
Serotonin,alsocalled5hydroxytryptamine(5HT),isderivedfromtryptophan(Fig.
41.1.7(f0040))

Inaddition,serotoninbiosynthesishasanumberofbiochemicalsimilaritiestodopamine
synthesis.Thus,tryptophanhydroxylase,liketyrosinehydroxylase,displaysacofactor
requirementfortetrahydrobiopterin(BH4)(seebelow).Furthermore,5hydroxytryptophanis
convertedtoserotoninbydopadecarboxylase(alsoknownasaromaticaminoaciddecarboxylase).
Serotoninergicneuronsareconcentratedintheraphenucleiintheupperbrainstem(Fig.41.1.11
(f0060)),butprojectuptothecerebralcortexanddowntothespinalcord.Theyaremoreactive

whensubjectsareawakethanwhentheyareasleep,andserotoninmaycontrolthedegreeof
responsivenessofmotorneuronsinthespinalcord.Inaddition,itisimplicatedinsocalled
vegetativebehaviorssuchasfeeding,sexualbehavior,andtemperaturecontrol.

ADVANCEDCONCEPTBOXDOPAMINEANDSEROTONINRECEPTORS

Multiplereceptorshavebeenisolatedfordopamineandsero
tonin.Notallthosethathave
beenclonedhaveyetbeenshowntobefunctional,butthepossiblerelevanceintermsof
drugdevelopmentisobvious.Insomecases,specificmanipulationofparticularreceptors
canbeexploitedtherapeutically.
Therearefiveknowndopaminereceptors,fallingintotwomaingroups(D1like:D1and
D5,andD2like:D2,D3,andD4)thatdifferintheirsignalingpathways.D1receptors
increasetheproductionofcAMP,whereasD2receptorsinhibitit.Antipsychoticdrugssuch
asphenothiazinesandhaloperidoltendtoinhibitD2likereceptors,suggestingthat
excessivedopamineactivitymaybeimportantincausingthesymptomsofschizophrenia.
TheD2receptorisamajorreceptorinthenervesthatinterconnectthebasalganglia.Asitis
knownthatdestructionofthesenervescausesParkinson'sdisease,itisnotsurprising
thatantipsychoticdrugsthatinhibittheD2receptortendtohavethesideeffectofcausing
abnormalmovements.Drug,suchasclozapinethatbindpreferentiallytotheD4receptor
appeartobefreeofsuchsideeffects,althoughthatparticulardrugalsobindstoseveral
otherreceptors.
Morethanadozenserotonin(5HT)receptorshavebeenisolatedusingmolecular
biologicaltechniques.Theyhavebeendividedintoclassesandsubclassesonthebasisof
theirpharmacologicpropertiesandtheirstructures.Mostaremetabotropic,althoughthe5
HT3receptorisionotropicandmediatesafastsignalintheentericnervoussystem.The5
HT1Areceptorisfoundonmanypresynapticneurons,whereitactsasanauto
receptorto
inhibitthereleaseof5HT.
Ingeneral,increasingthebrainconcentrationof5HTappearstoincreaseanxiety,
whereasreducingitsconcentrationishelpfulintreatingthecondition.Theantidepressant
buspironeactsasanagonistat5HT1Areceptors,andpresumablycausesadecreasein
productionof5HT.InadditiontoitseffectsontheD4dopaminereceptor,clozapinebinds

stronglytothe5HT2Areceptor,anditmaybethatacombinationofahighlevelof5HT2A
antagonismandlowD2bindingactivityisdesirablefordrugsthatcanbeusedtotreat
schizophreniawiththeminimumfrequencyofsideeffects.The5HT3blockerondansetron
isanantiemetic,extensivelyusedtopreventvomitingduringchemotherapy.Migrainecan
betreatedwithsumatriptan,a5HT1Dagonist.
Thecentralroleof5HTincontrollingbrainfunctionandthehugenumberofassociated
receptorssuggestthatitmaypossibletotailoralargenumberofdrugstotreatspecific
disorders,andthatpharmacologicmanipulationofthefunctionofthenervoussystemis
probablystillinitsinfancy.

CLINICALBOXA60YEAROLDMANWHOSUFFEREDATTACKSOFFLUSHINGAND
DIARRHEA:CARCINOIDSYNDROME

A60yearoldmancomplainedofattacksofflushing,associatedwithanincreasedheart
rate.Healsohadtroublesomediarrheaandabdominalpain,andhadlostweight.The
symptomssuggestedadiagnosisofcarcinoidsyndromecausedbyexcessivesecretionof
serotoninandothermetabolicallyactivecompoundsfromatumor.Toconfirmthis,aurine
samplewastakenformeasurementof5hydroxyindoleaceticacid(5HIAA),themajor
metaboliteof5HTtheconcentrationwasfoundtobe120mmol/24h(23mg/24h)
(referencerange1052mmol/24h,314mg/24h).

Comment.
Thepatienthadthecarcinoidsyndrome,whichiscausedbytumorsofenterochromaffin
cells,usuallyoriginatingintheileum,thathavemetastasizedtotheliver.Thesecellsare
relatedtothecatecholamineproducingchromaffincellsintheadrenalmedullaandconvert
tryptophantoserotonin(5HT).Serotoninitselfisbelievedtocausediarrhea,butother
mediators,suchashistamineandbradykinin,maybemoreimportantintheflushing
attacks.Theurinaryconcentrationof5HIAAprovidesausefuldiagnostictestandcanbe
usedtomonitortheresponseofthecancertotreatment.

Fig.41.1.11
SerotoninergicnervesintheCNS.
Serotonincontainingnervesariseintheraphenuclei,partofthereticularformationintheupperbrainstem.In
commonwiththosecontainingnorepinephrine,theyaredistributedwidely.

Acetylcholine
Acetylcholine(ACh)isthetransmitteroftheparasympatheticautonomicnervous
systemandofthesympatheticganglia(Fig.41.1.3(f0020))
Stimulationoftheparasympatheticsystemproduceseffectsthatarebroadlyoppositetothoseof
thesympatheticsystem,suchasslowingoftheheartrate,bronchoconstriction,andstimulationof
intestinalsmoothmuscle.AChalsoactsatneuromuscularjunctions,wheremotornervescontact
skeletalmusclecellsandcausethemtocontract.Apartfromtheseroles,AChmaybeinvolvedin
learningandmemory,asneuronscontainingthistransmitteralsoexistinthebrain.
AChissynthesizedfromcholinebytheenzymecholineacetyltransferase.Afteritissecretedinto
thesynapticcleft,itislargelybrokendownbyacetylcholinesterase.Theremainderistakenback
upintothenervecellbytransporterssimilartothoseforamines.
TherearetwomainclassesofAChreceptors:nicotinicandmuscarinic(seeChapter41.2,Fig.
41.2.3).

BothrespondtoAChbutcanbedistinguishedbytheirassociatedagonistsandantagoniststhey
arequitedifferentstructurallyanddifferintheirmechanismsofaction.
Nicotinicreceptorsareionotropic.Theybindnicotineandarefoundongangliaand
attheneuromuscularjunction.WhenAChornicotinebinds,aporeopens,whichallows
bothNa+andK+topassthrough.Becausetheactionoftheligandonthechannelisdirect,
actionisrapid.
Muscarinicreceptors,respondingtothefungaltoxinmuscarine,are
metabotropic.Theyaremuchmorewidespreadinthebrainthanarenicotinicreceptors,
andarealsothemajorreceptorsfoundonsmoothmuscleandglandsinnervatedby
parasympatheticnerves.Atropinespecificallyinhibitsthesereceptors.Thereareseveral
separatemuscarinicreceptors,differingintheirtissuedistributionandsignalingpathways.
Asyet,noclearpatternhasemergedastotheirspecificfunctions.
Clinically,AChagonists,incommonwithacetylcholinesteraseinhibitors,areusedtotreat
glaucoma,aneyediseasecharacterizedbyhighintraocularpressure,byincreasingthetoneof
themusclesofaccommodationoftheeye.Theyarealsousedtostimulateintestinalfunctionafter
surgery.Ontheotherhand,whenacetylcholinesteraseisinhibitedbyorganophosphate
insecticidesornervegases,atoxicsyndromeiscausedbytheresultingexcessofACh.There
maybediarrhea,increasedsecretoryactivityofseveralglands,andbroncho
constriction.This
syndromecanbeantagonizedbyatropine,althoughlongertermtreatmentinvolvestheuseof
drugsthatcanremovetheinsecticidefromtheenzyme,suchaspralidoxime.

CLINICALBOXAWOMANWITHOCCASIONALDOUBLEVISIONANDACHANGEINHER
VOICE:MYASTHENIAGRAVIS

A35yearoldwomannoticedthatshehaddifficultyinkeepinghereyesopen.Shealsohad
periodsofdoublevisionwhenhervoicewasindistinctandnasalandshehaddifficulty
swallowing.Herphysiciansuspectedmyasthenia,adiseaseofnervemuscleconduction.
Theserumtiterofantiacetylcholinereceptorantibodieswasmeasuredandfoundtobe
elevated.

Comment.
Thepatientwassufferingfrommyastheniagravis.Thisisadiseasethatmanifestsitselfas
weaknessofvoluntarymusclesandiscorrectedbytreatmentwithacetylcholinesterase
inhibitors.Itiscausedbyautoantibodiesdirectedagainstthenicotinicacetylcholine
receptor,whichcirculateinserum.Becauseoftheseautoantibodies,transmissionofnerve
impulsestomuscleismuchlessefficientthannormal.
Drugsthatinhibitacetylcholinesteraseincreasetheconcentrationofacetylcholineinthe
synapticspace,whichcompensatesforthereducednumberofreceptors.Improvementin
nervemuscleconductioninresponsetoedrophoniumcanbeusedasadiagnostictestbut
requiresseveralprecautionslongactingacetylcholinesteraseinhibitorssuchas
pyridostigminecanbeusedtotreatthedisease,butcorticosteroidsareofteneffective.

Nitricoxidegas
Inautonomicandentericnerves,nitricoxide(NO)isproducedfromargininebythe
tetrahydrobiopterindependentnitricoxidesynthases
NOhasanumberofattributedphysiologicfunctionsincludingrelaxationofbothvascularand
intestinalsmoothmuscle,andthepossibleregulationofmitochondrialenergyproduction.
Furthermore,withinthebrain,NOmayhavearoleinmemoryformation.However,excessiveNO
formationhasbeenimplicatedintheneurodegenerativeprocessassociatedwithParkinson's
andAlzheimer'sdisease.WhilsttheexactmechanismwherebyexcessiveNOcausesneuronal
deathisnotknown,agrowingbodyofevidencesuggeststhatirreversibledamagetothe
mitochondrialelectrontransportchainmaybeanimportantfactor.

NOisnotstoredinvesicles,butreleaseddirectlyintotheextracellularspace
Consequently,NOdoesnot,inthestrictestsense,meetallthecurrentcriteriatobelabeledasa
neurotransmitter.NOitselfdiffusescomparativelyeasilybetweencells,andbindsdirectlytoheme
groupsintheenzymeguanylatecyclase,stimulatingtheproductionofcyclicguanosine
monophosphate.

Othersmallmolecules
ATPandotherpurinecontainingmoleculesderivedfromitarenowknowntohave
transmitterfunctions

ATPispresentinsynapticvesiclesofsympatheticnerves,alongwithnorepinephrine,andis
responsibleforrapidexcitatorypotentialsinsmoothmuscle.Adenosinereceptorsarewidespread
inthebrainandinvasculartissue.AdenosineislargelyinhibitoryintheCNS,andinhibitionof
adenosinereceptorsisbelievedtounderliethestimulatoryeffectsofcaffeine.

Studyofhistamineinnervesiscomplicatedbythelargeamountsthatarepresentin
mastcells
Histamineisfoundinasmallnumberofneurons,mainlyinthehypothalamus,althoughtheir
projectionsarewidespreadthroughoutthebrain.Ithasbeenshowntocontrolthereleaseof
pituitaryhormones,arousal,andfoodintake.Antihistaminesdesignedtocontrolallergies
causedbyreleasefrommastcellsactontheH1receptorandtendtobesedative,suggestingthat
othercentralfunctionsalsoprobablyexist.ThehistaminereceptorinthestomachisoftheH
2classtherefore,theH2inhibitors,suchascimetidineandranitidine,thatareusedtotreat
pepticulcershavenoeffectonallergy.

CLINICALBOXDEFICIENCYOFPYRIDOXALPHOSPHATE:ACAUSEOFNEONATAL
EPILEPSY

Pyridoxalphosphate(PLP),thebiologicallyactiveformofvitaminB6Chapter11),isutilized
asacofactorbymorethan100enzymes,includingreactionscatalyzedbyaromaticamino
aciddecarboxylase(AADC),threoninedehydrataseandtheglycinecleavagesystem.Vitamin
B6ispresentinthehumanbodyasanumberofvitamersthatareprecursorstoPLP.A
pivotalenzymeintheformationofPLPispyridox(am)ine5phosphateoxidase(PNPO).
Thisenzymecatalyzestheconversionoftheprecursorspyridoxinephosphateand
pyridoxaminephosphatetoPLP.DeficiencyofPNPOresultsindecreasedavailabilityofPLP
and,suchpatients,whenpresentingintheneonatalperiod,haveaclinicalpicturethat
includessevereepilepsy.BiochemicalanalysisofCSFrevealselevatedthreonine,glycineand
evidenceofimpairedAADCactivity.Inaddition,theCSFconcentrationofPLPisdecreased.
Treatment,whichcanbeparticularlyeffective,isbytheadministrationofPLP.

Peptides
Manypeptidesactasneurotransmitters
Itisanopenquestionwhetherallthepeptidesthathavebeendescribedarereallytrue
neurotransmitters.Nevertheless,morethan50smallpeptideshavenowbeenshowntoinfluence
neuralfunction.AllknownpeptidereceptorsaremetabotropicandcoupledtoGproteins(Chapter
40),andsoactcomparativelyslowly.Therearenospecificuptakepathwaysordegradative

enzymes,andthemainrouteofdisposalissimplediffusionfollowedbycleavagebyanumberof
peptidasesintheextracellularfluid.Thisallowsapeptidetoaffectanumberofneuronsbeforeit
isfinallydegraded.

Vasoactiveintestinalpeptide(VIP)isoneofmanypeptidesthataffectthefunctionofthe
intestinethroughtheentericnervoussystem.Itwasoriginallydescribedasaguthormonethat
affectedbloodflowandfluidsecretion,butitisnowknowntobeanimportantenteric
neuropeptide,inhibitingsmoothmusclecontraction.Italsocausesvasodilatationinseveral
secretoryglands,andpotentiatesstimulationbyACh.

Manyneuropeptidesbelongtoamultigenefamily
Theopioidpeptidesandopioidreceptorsprovideagoodexampleofamultigenefamily.They
aretheendogenousligandsforopiateanalgesicssuchasmorphineandcodeine.Thecontrolof
painiscomplex,andopioidpeptidesandreceptorsarefoundbothinthespinalcordandinthe
brainitself.Thereareatleastthreegenesthatcodeforthesepeptides,andeachcontainsthe
sequencesforseveralactivemolecules:
proopiomelanocortincontainsendorphin,whichbindstoopiatereceptors,and
alsoadrenocorticotropichormone(ACTH)andthemelanocytestimulatinghormones
(MSH),whicharepituitaryhormones(Chapter39)
proenkephalinAcontainsthesequencesforMetandLeuenkephalins,whichbindto
receptorsandareinvolvedinpainregulationatlocallevelsinthebrainandspinalcord
prodynorphincontainssequencesfordynorphinandseveralotherpeptides,whichbind
totheclassofreceptors.
Opiatesaffectpleasurepathwaysinthebrain,whichexplainstheireuphorianteffects,andthey
alsohavesideeffects,suchasrespiratorydepression,thatlimittheiruse.Inexcess,theycause
contractionofthemusclesoftheeye,resultinginpinpointpupils.Ithasbeenshownthat
endorphinsarereleasedafterstrenuousexercise,givingthesocalledjoggershigh.Itis
hopedthatincreasedknowledgeofthespecificopioidreceptorsandneuralopioidpathwayswill
allowthedevelopmentofanalgesicswithfewersideeffectsandlesslikelihoodofabuse.
SubstancePisanotherexampleofamemberofamultigenefamily,knownasthetachykinin
family.Itispresentinafferentfibersofsensorynervesandtransmitssignalsinresponsetopain.
Itisalsoinvolvedinsocalledneurogenicinflammationstimulatedbynerveimpulses,andisan
importantneurotransmitterintheintestine.

Neuropeptidescanactasneuromodulators
Somepeptidesdoactastrueneurotransmitters,buttheyalsohavemanyotheractions.Theyoften
altertheactionofothertransmitters,actingasneuromodulators,buthavenoactionoftheirown.
Forinstance,VIPenhancestheeffectofAChonsalivaryglandsecretionincatsubmandibular
glands(glandslocatedunderthejawbone)bycausingvasodilatationandpotentiatingthe
cholinergiccomponent.NPYcausesinhibitionofthereleaseofnorepinephrineatautonomic
nerveterminals,actingatpresynapticautoreceptors,andpotentiatestheactionofnorepinephrine
incertainarterieswhilehavingonlyweakactionsitself.Opioidpeptidesalsoarecapableof
modulatingneurotransmitterrelease.

Summary

Neuronscommunicateatsynapsesbymeansofneurotransmitters.
Alargenumberofcompounds,whetheroflowmolecularweight,suchasthebiogenic
amines,orlargerpeptides,canactasneurotransmitters.
Theyactonspecificreceptorsandthereisnormallymorethanonereceptorforeach
neurotransmitter.
Thepresenceofseveraltransmittersinthesamenervesandtheidentificationofmultiple
receptorssuggestthatthereisahighdegreeofflexibilityandcomplexityinthesignalsthat
canbeproducedinthenervoussystem.
ACTIVELEARNING

1.Doesnitricoxidemeetallthecriteriatobedefinedasatrueneurotransmitter?
2.Explainhowaneurotransmittersuchasserotonincanhavesomanydiverseeffects
withinthecentralnervoussystem.
3.Explainhowneurotransmitterscanbeexcitatoryorinhibitory.
4.Whatneurotransmittertypesarelikelytobecomedeficientinthebrainofapatient
withaninbornerroraffectingtyrosinehydroxylase,aromaticaminoacid
decarboxylaseandtetrahydrobiopterinmetabolism?
5.Discussthefactorsthatneedtoconsideredwhenestablishingadiagnosticmethod
fordisordersofdopamineandserotoninmetabolism.
6.Explaintheconceptofionotropicandmetabotropicreceptors.

Furtherreading
Aitkenhead,Heales,2013.AitkenheadH,HealesSJ:Establishmentofpaediatricagerelated
referenceintervalsforserumprolactintoaidinthediagnosisofneurometabolicconditions
affectingdopaminemetabolism.AnnClinBiochem201350:pp.156158.
Clayton,2006.ClaytonPT:B6responsivedisorders:amodelofvitamindependency.JInherit
MetabDis200629:pp.317326.
Hyland,2007.HylandK:Inheriteddisordersaffectingdopamineandserotonin:critical
neurotransmittersderivedfromaromaticaminoacids.JNutr2007137:pp.1568S1572S.
Kurianetal,2011.KurianMA,ZhenJ,MeyerE,et.al.:Clinicalandmolecularcharacterisationof
hereditarydopaminetransporterdeficiencysyndrome:anobservationalcohortandexperimental
study.LancetNeurol201110:pp.5462.
Lam,Hyland,Heales,2007.LamAAJ,HylandK,HealesSJR:Tetrahydrobiopterinavailability,

nitricoxidemetabolismandglutathionestatusinthehph1mouse:implicationsforthe
pathogenesisandtreatmentoftetrahydrobiopterindeficiencystates.JInheritMetabDis2007
30:pp.256262.

Websites
TheAADCResearchTrust.www.aadcresearch.org(http://www.aadcresearch.org)
DatabasesofPKUandPNDvariationsthiswebsitehostsdatabasesofpediatricneurotransmitter
disorders(PND).www.BioPKU.org(http://www.BioPKU.org)
ThePNDAssociationisadiseaseorganizationrepresentingchildrenandfamilieswhoareaffected
byapediatricneurotransmitterdisease.www.pndassoc.org(http://www.pndassoc.org)

Copyright2015Elsevier,Inc.Allrightsreserved.