醫(yī)學神經(jīng)生物學：Noradrenaline (NA NE)

Noradrenaline(NA/NE)Catechol兒茶酚Catecholamine

兒茶酚胺

8.1PATHWAYSinCNScellbodylocationprojectionpathway

MajorNoradrenergic(blue),Dopaminergic(red)andSerotonergic(green)PathwaysintheCNS

locuscoeruleus(LC藍斑)complex---A4,A6

lateraltegmentalnuclei外側(cè)被蓋核

---A1,A3,A5,A7,A2

LocationofNAcellbodiesA1–A7:Brainstem(腦干）Noradrenalinepathwaysinratbrain

projectionpathwaysofNAneuronsThelocuscoeruleuscomplexLateraltegmentalnucleiBrainstemnuclei(sensory)HippocampusCerebralcortexSpinalcordCerebellumThalamusHypothalamus(paraventricularnucleus)AmygdalaSeptumBrainstemnuclei(motor)Hypothalamus(allnuclei)NAconcentrationinCNScortex:0.1g/ghippocampus:0.25g/ghypothalamus:0.2g/gPonsmedulla:0.35g/gNAconcentrationindifferentbrainareasoftheratisinkeepingwiththedistributionofitspathways.SynthesisStorageReleaseReuptakeMetabolism8.2NEUROCHEMISTRYSimilartothelifecycleofdopamineSynthesisforDAincytoplasmofCAneuronsSynthesisforNAinvesiclesofNAneuronsDopamine--hydroxylase(DH)8.2.1

SYNTHESISNADAPrecursor:Tyrosine(tyr)tyrEnzymes:

tyrosinehydroxylase(TH)*TH*Dopadecarboxylase(DDC)DDCDopamine--hydroxylase(DH)vesiclecytosolNAergicneurons

DAergic

SYNTHESIS*rate-limitingenzymeNAsynthesisissimilartothatofDADopamine--hydroxylase(DH,多巴胺

羥化酶)

vesicle-boundenzyme：DANAonlywithintheNAstoragevesiclesrequiresCu2+andvitaminClowsubstratespecifichighaffinity

SYNTHESISControlsofsynthesis

SYNTHESISRate-limitingTyrDopaDATHDDCNADHdisruptedby:reserpinetetrabenazineStoredinNAvesicles8.2.2

STORAGEVMAT:vesicularmonoaminetransporter8.2.3

RELEASEVesicularexocytosisRegulationofrelease

RELEASE

2Areceptor(autoreceptor)Inhibitionofthereleaseprocess---(terminalreceptors)Depressionofneuronalfiring---(cellbodiesreceptors)receptor(presynaptic):augmentthereleaseOtherheteroceptors:

GABABinhibitNAreleaseGABAAaugmentNArelease8.2.3

REUPTAKETopologicalmodelofthehNET12transmembranedomainsN-terminal,C-terminal----inplasmaNAspecificationNa+/Cl-dependentMembranepotentiationdependentBlockedbytricycleantidepressantsand

cocaine,amphetamine

Transporterinthemembraneofneuralcellsnoradrenalinetransporter(NET)TricyclicAntidepressants6-OHDA:

ToxinsforbothDAandNAneuronsBetakenupintonerveterminalsbyDATandNETOxidisedanddegeneratetheterminals------

chemicalsympathectomyNEUROTOXINS幾種轉(zhuǎn)運體的比較8.2.4

METABOLISMDeamination(去氨基化）O-methylation（氧位甲基化）Twoimportantenzymesinvolved:

monoamineoxidase(MAO，單胺氧化酶）catechol-O-methyltransferase(COMT，兒茶酚胺氧位甲基移位酶）MAO:

deaminationenzymeinthe

membraneofmitochondriareactioninthe

cytosolplasmaSubtypes:

MAOA–moreactiveinNAand5-HTneurons

MAOB

–dominantenzyme

forDA

Inhibitors:

tranylcypromine（反苯環(huán)丙胺）,

deprenyl(丙烷苯丙胺）

COMT:

O-methylation

extracellularenzyme

reactionoutsidecellsinhibitors:pyragallol,catechol(tootoxicforclinicaluse)entacapone,tolcapone(mainlyinPDtreatment)

METABOLISM

METABOLISMMAOCOMTNMN3,4-dihydroxyphenylglycolaldehydeVMAMAODOMACOMTMHPGMAODHPGCOMTCytosol：MAOCOMTSynapticcleft：COMTMAO8.3RECEPTORSOFNA

---adrenoceptors

GPr.CoupledReceptorsPharmacologically：

1(Gq)(Gs)1

2(Gi)2Structurally：

1

1A

2

2A

1

1B

2B

2

1D

2C

3

4？ReceptordistributioninCNS

1A:cortex,hippocampus

1B:cortex,brainstem

2A:cortex,brainstem,midbrain,spinalcord（autoreceptor)

2B:diencephalon

2C:basalganglia,cortex,cerebellum,hippocampus

1:olfactorynucleus,cortex,cerebellarnuclei,spinalcord

2:olfactorybulb,hippocampus,cerebellarcortexPredictedaminoacidsequenceoftheb-adrenoceptor7trans-membranedomainsN-terminusisextracellularC-terminusisintracellularFundamentalNeuroscience1999byM.J.Zigmond,F.E.Bloom,S.C.Landis,J.L.Roberts&L.R.Squire.AcademicPress,SanDiegoCA,USA.ISBN:0-12-780870-1Signalingtransduction

1：Gq/11PLCIP3+DAGCa2+PKC

2：Gi/oACcAMPPKACa2+

K+

：GsACcAMPPKA8.4CENTRALFUNCTIONSEmotion,motivation,cognition……

EmotionInadequatenoradrenergictransmission:depressionModeratenoradrenergicactivity:provokesattentiveinterestthatisvitalforappropriatecognitivefunctionExcessivenoradrenergicactivation:anxietyoragitationThereareanumberofwaysinwhichdrugsinterferewithcatecholaminemetabolism:

inhibitingenzymesresponsibleforconvertingprecursormolecules:---alpha-methyl-para-tyrosine,disulphiram

disruptingthestorageofCAinsynapticvesicles:---reserpine,

tetrabenazine

inhibitingthereuptakeofCAfromthesynapticcleft:---

cocaine,amphetamine,tricyclicantidepressants（NE）drugsinterferewithcatecholaminemetabolism(CONT):

inhibitingenzymesresponsibleforMAO:---MAOI(iproniazid)

enhancingthereleaseofCAintothesynapticcleft:---amphetamine,

2antagonist(forautoreceptor)

agonist&antagonistneutotoxins兒茶酚胺(catecholamine,CA)多巴胺（Dopamine,DA)去甲腎上腺素（Noradrenaline,norepinephrine,NA或NE)腎上腺素（adrenaline,epinephrine,A或E)吲哚胺(indolamine)5-羥色胺（Serotonine,5-HT)5-羥色胺（5-Hydroxytryptamine，5-HT)5-HT（5-羥色胺），

Serotonin（血清緊張素，血清素）Indolamine（吲哚胺）causemarkedvasoconstrictionincardiovascularsystem----serotonin

InCNS:一種負責控制情緒及快樂的化學物質(zhì)中樞和外周5-HT可看作兩個獨立的系統(tǒng)5-羥色胺（5-HT，Serotonin)中樞神經(jīng)系統(tǒng)5-HT的遞質(zhì)通路(DistributioninCNS)5-HT的神經(jīng)化學(Neurochemistry)

合成（Synthesis）儲存（Storage）釋放（Release）重攝?。≧euptake）降解代謝，酶解失活（Metabolism）

5-HT受體(Receptors)5-HT在中樞神經(jīng)系統(tǒng)中的功能(Centralfunctions)1.DISTRIBUTIONinCNScellbodylocationprojectionpathway

caudalgroup（尾側(cè)）---B1-B5

rostralgroup(喙側(cè))---B6-B9Locationof5-HTcellbodiesB1–B9:Raphenuclei中縫核B1-B5projectsmainlytobrainstemnuclei,thenucleiofsomecranialnervesandthespinalcord--servingakeyroleinregulationofmotoractivity,autonomicfunctionandnociceptionB6-B9projectsrostrally,generallyipsilaterally,insixfibretracts.innervatemostofthebrain,includingthecerebellumDorsalRaphenucleus(DRN)(B6andB7)MedianRaphenucleus(MRN)(B5andB8)LocuscoeruleusSubstantianigraStriatumNucleusaccumbensThalamuscortexHypothalamusBrainstemnucleiAmygdalaFrontalcortexhippocampusCingluatecortexSeptalnucleiOccipitalcortexSynthesis（合成）

Storage（儲存）

Release（釋放）

Reuptake（重攝取）

Metabolism（降解代謝，酶解失活）2.NEUROCHEMISTRY

（神經(jīng)化學）2.1

SYNTHESIS（合成）1.hydroxylation（羥基化）2.decarboxylation（脫羧）色氨酸（Trp)5-羥色氨酸(5-HTP)5-羥色胺(5-HT)色氨酸羥化酶(TPH)5-羥色氨酸脫羧酶（5-HTPDC）5-HT能神經(jīng)元內(nèi)合成

SYNTHESIS色氨酸羥化酶(TPH)Cytoplasmicenzyme：

Trp

5-hydroxytryptophanRate-limitingstepLimitingfactor:tryptophan（色氨酸）

Km=50

M>[腦內(nèi)色氨酸]Fe2+,O2,andtetrahydropterine(BH4)Substrate-specificInhibitors:desferrioxamine(去鐵草酰胺);dopamine;PCPATrp:rate-limitingfactor!TrpbloodBBBbrainLNAAcarriers:largeneutralaminoacidscarriers（大分子中性氨基酸轉(zhuǎn)運體：forTrp,Phe,Leu,Ile,Val轉(zhuǎn)運）TrpTPH正常情況下，腦內(nèi)TPH遠未飽和TPHTPHNeurochemistryofSerotonin

dietaryavailabilityFM&QFig9.4FM&QFig9.5highcarbo(碳水化合物）

andlowproteindietisbestforincreasing5-HT.

SYNTHESIS5-HTPdecarboxylase(5-羥色氨酸脫羧酶)solubleenzyme：

5-hydroxytryptophan5-HTKm=10

MSubstrate-specificL-aromaticaminoaciddecarboxylase(AADC)–thesameenzymeinvolvedinthebiosynthesisofcatecholamines

SYNTHESISControlof5-HTsynthesis1,brainTrplevel---rate-limitingfactor2,brain5-HTlevel---negativefeedback3,TPH（色氨酸羥化酶）

rapid:activityslow:expressionEvidence:Neuronaldepolarization

phosphorylation:NeuronaldepolarizationTPHactivation

Ca2+/calmodulin-dependentproteinkinaseinhibitorPhosphorylationofTPH----anincreaseinactivityCa2+/calmodulin-dependentproteinkinaseIIcAMP-dependentproteinkinase(PKA)

SYNTHESIS2.2

STORAGE(儲存）

Vesicularstorage(30-35mmdiameter)（囊泡儲存）

Vesiclescontainingserotonin-bindingproteins(SBP),

formamacromolecularcomplexwith5-HT

SBPcanbesecretedintothesynapsealongwith5-HT

VMAT（囊泡單胺轉(zhuǎn)運體）：質(zhì)子泵產(chǎn)生的[H+]

梯度作為能量

STORAGE2.3

RELEASE（釋放）

胞裂外排（exocytosis)Autoreceptorssuppress5-HTrelease:

5-HT1Areceptors:onthecellbodiesofneuronsintheRaphenuclei;5-HT1B/1Dreceptors:ontheirterminals

Heteroceptorsmodify5-HTrelease:nAChR:increasereleasefromstriatalsynaptosomes;

2Aadrenoceptors:depresscorticalreleaseReleasingagent:fenfluramine2.4

REUPTAKE（重攝?。﹕erotonintransporter(SERT)

Na+/Cl-dependenttransporterSERThaslargenumberofpotentialphosphorylationsitesandcanbephosphorylatedbyPKAandPKC.InvitroSERTphosphorylationbyPKCleadstotheinternalizationoftheproteinandtoareductioninserotoninreuptake.“uptake-1”and“uptake-2”.FM&QFig9.1DependentonNa+andCl-bindingNa+andCl-arebroughtintothecellalongwith5-HTandK+isextrudedDrugsthatblock5-HTreuptakebindtothe5-HTbindingsiteEnergysuppliedbyNa+/K+dependentATPasePhosphorylationofSERTAtleast8phosphorylationsiteRapid,short-termregulationPKA,PKC:internalization

(decreasethereuptakeof5-HT)Inhibitorsof5-HTtransporter(SERT)

TCA（Tricyclicantidepressants，三環(huán)類抗抑郁藥）:

clomipramine(氯丙咪嗪)，…Selectiveserotoninreuptakeinhibitor(SSRIs):fluoxetine,sertraline,fluvoxamine,paroxetine,citalopramCocaine（可卡因）

Amphetamine（安非他命）

Fenfluramine（芬弗拉明）(DAT,SERT)MDMA（ecstasy，搖頭丸）：neurotoxinfor5-HTneuron(similartotheeffectofMPTPonDAneuron)（SERT底物，刺激腦部快速釋放大量的5-HT）Imagingofbindingabilityof

SERTindepressionbrain[123I]-ADAM:

AhighselectivebindingligandofSERTCanbeimagedbySPECTFordetectionofthebindingabilityofSERTindepressionpatientbeforeandaftertreatmentImagingofserotonintransportersanditsblockadebycitalopraminpatientswithmajordepressionusinganovelSPECTligand[123I]-ADAM.JNeuralTransm(2006)113:659–670(A)showsaspecifictraceraccumulationinthemidbrain;whereasthescanatweek1aftercitalopramtreatment(B)demonstratesnovisibleuptakeof[123I]ADAMduetotheSERTblockade2.5

METABOLISM（酶解失活）MAOA-CHO-COOH5-HT5-HIAA（5-羥吲哚乙酸）醛脫氫酶MOAI（-）NCNCNH2COOHCOOHNH2OHNCNH2OHHTryptophan5-Hydroxytryptophan5-HydroxytryptamineNCCOOH5-OHIndoleAcetaldehyde5-HydroxyIndoleAceticAcidTryptophanhydroxylase5-OHTryptophandecarboxylaseMAOAldehydedehydrogenase(Ratelimiting)Indiet.ActiveCNStransport7distinctfamilies14distinctsubtypeshavebeenclonedsofar3.RECEPTORS（5-HT受體）Thepharmacologyof5-HTisextremelycomplex,withitsactionsbeingmediatedbyalargeanddiverserangeof5-HTreceptors-manyofwhichhavepoorlycharacterisedphysiologicalfunctions.AllareGproteincoupledreceptorsexcept5-HT35-HT3

:ligand-gatedionchannels:5-HT3A，5-HT3B，5-HT3CSplicevariants:5-HT3,5-HT4,5-ht6,5-HT7

RNAeditedisoforms:5-HT2C

Differentcentraldistributionandfunction5HT1A:roleinanxiety/depression5HT1D:roleinmigraine5HT2:roleinCNSvariousbehaviors,andincardiovascularsystem5-HT3:roleinnauseaandvomitingesp.duetoChemotherapy.5-HT1A:hippocampus,septum,amygdala,dorsalraphe,cortex5-HT1B:substantianigra,basalganglia5-HT1D:substantianigra,striatum,accumbens,hippocampuslessthan5-HT1B5-ht1E,5-ht1F：lackofspecificligands5-HT1Areceptors:somatodendriticautoreceptorsresideonserotonergiccellbodiesanddendritesreducecellfiringandcurtailsthesynthesisandreleaseof5-HT5-HT1B/1Dreceptors:resideonpresynapticnerveterminaldecreasethelocalsynthesisandreleaseof5-HTAutoreceptorsonsomatodendritesandterminals5-HT2A:cortex,olfactorytubercle,claustrum5-HT2B:notlocatedinbrain(lackofspecificligands)5-HT2C:basalganglia,choroidplexus,substantianigra5-HT3receptor:Spinalcord,cortex,hippocampus,brainstemnucleialigand-gatedionchannelthatishomologoustootherreceptorionophores.nonselectivecationchannel;triggersarapid,transientdepolarizingcurrentthatiscarriedbyNa+andK+.5-HT4:hippocampus,nucleusaccumbens,striatum,substantianigra5-ht5A:cortex,hippocampus,cerebellum5-ht5B:hippocampus5-ht6:striatum,olfactorytubercle,cortex,hippocampus5-HT7:hypothalamus,thalamus,cortex,suprachiasmaticnucleusSerotoninAgonists（受體激動劑）Sumatriptan(舒馬曲坦):5-HT1Dagonist;antimigraineBuspirone(丁螺環(huán)酮)

:5-HT1AagonistforanxietyCisapride(西沙比利):5-HT4agonistto↑GImotilityanddecreaseGEreflux(RemovedfromUSmarketduetofatalarrhythmias)LSD:5HT1Aagonist–hallucinogen(致幻劑)SerotoninAntagonists（受體拮抗劑）Methysergide（二甲麥角新堿）andCyproheptadine（賽庚啶）:5HT2antagonists.Incarcinoid,migraine.Ketanserin（酮舍林,凱坦生）:5HT2andAlphaantagonist–usedasantihypertensive.Ondansetron（奧坦西?。?5-HT3antagonistforchemotherapyinducednauseaandvomitingClozapine（氯氮平）:5HT2A/2Cantagonist:forschizophrenia.Interferencewith5-HTsystemashiftbacktolessselectivecompoundsInterferencewith5-HTsystem

Levelsofserotonininthebraincanbemanipulatedby:InhibittryptophanuptakeintoCNS:exclusionoftryptophanfromthedietInhibitsynthesis:p-chlorophenylalanine(irreversible)（TPH）Inhibitneuronalre-uptake:cocaine,SSRI(e.g.fluoxetine),TCA(e.g.imipramine丙咪嗪)Inhibitstorage-deplete:reserpineInhibitmetabolism:MAOinhibitorsPromoterelease:p-chloroamphetamine-thendepletes(e.g.fenfluramineto↓appetite)Neurotoxins:5,6-DHT/5,7-DHTNon-selectiveAlthoughserotonincanmediatenumeroustherapeuticactions,toomuchserotonincancausedangeroustoxicity.

Theblindmenandtheelephant.5-HT,5-hydroxytryptamineorserotonin;CBF,cerebralbloodflow;GI,gastrointestinal.FigureadaptedfromawoodblockprintbyKatsushikaHokusai(1760–1849).4.CENTRALFUNCTIONSPainperception（projectionfrominferiorgroupneuronstospinalcord)Sleep/WakefulnessVariousbehaviorsnormal/abnormal:

depression,schizophrenia,obsessivecompulsivebehavior,etc.……DepressionOldManwithhisHeadinhisHandsVanGogh,1882Someveryfamouspeoplehavesufferedfromdepression,forexample:LudwigvanBeethoven

VincentvanGogh

BorisYeltsinSirWinstonChurchill

Depression–CatecholamineHypothesisFifteenpercentofindividualsprescribed

reserpine

forhypertensiondevelopeddepression.MAOI’sbeingprescribedfortuberculosis(肺結(jié)核）werefoundtoelevatemood.Cocaineandamphetamine,whichincreasecatacholamines,elevatemood.NEisfoundinabundanceinthelimbicsystems（大腦邊緣系）andisthoughttoregulatemood.DepressedindividualsshowlowlevelsofMHPG,ametaboliteofNE.TricyclicantidepressantdrugswerefoundtoinhibitthereuptakeofNE.(抑郁癥可能與CA的功能不足/降低有關(guān)）ProblemswiththeCatacholamineHypothesisTryicyclicantidepressantdrugsrequiredseveraldaysorweekstoalleviatethesymptomsofdepression.Healthyindividualsdidnotshowelevatedmoodwithtricyclicantidepressants.Cocaineandamphetaminearenotgoodantidepressants.Non-tricylcicantidepressantsthatspecificallyaffected5-HTwerefoundtobeclinicallyaffectiveinalleviatingthesymptomsofdepression.Depression-SerotoninHypothesis

(抑郁癥可能與5-HT的功能不足/降低有關(guān)）Themostclinicallyeffectiveantidepressantsarethosethataremostselectiveforreuptakeof5-HT(SSRI’s).Thedatathatpreviouslyweretakeninsupportofthecatacholaminehypothesiscouldalsosupporttheroleof5-HTbecausereserpine,MAOI'sandtricyclicsalsoaffect5-HT.

ButtheeffectsofSSRI’salsotakedaysorweekseventhoughthebiochemicalactionon5-HTreuptakeisimmediate.Depression-SupportfortheSerotoninHypothesisDepressedindividualshave:Lowerlevelsofplasmatryptophan.LowerCSFlevelsof5HIAA.Decreasedplatelet（血小板）5-HTuptakesuggestinglowerlevelsof5-HTrelease.Bluntedresponsivenesstoserotoninagonistchallengesuggestingdecreased5-HTresponsiveness.SpecificTreatmentsforDepressionAlleffectiveantidepressantsactbyincreasingtheactivityofoneorbothoftheseneurotransmittersystem