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Basic&ClinicalPharmacology,13e>

CHAPTER21:Introductiontothe
PharmacologyofCNSDrugs
JohnA.GrayRogerA.Nicoll

INTRODUCTION
Drugsactinginthecentralnervoussystem(CNS)wereamongthefirsttobediscoveredbyprimitivehumansand
arestillthemostwidelyusedgroupofpharmacologicagents.Theseincludemedicationsusedtotreatawide
rangeofneurologicandpsychiatricconditionsaswellasdrugsthatrelievepain,suppressnausea,andreduce
fever,amongothersymptoms.Inaddition,manyCNSactingdrugsareusedwithoutprescriptiontoincreasethe
senseofwellbeing.

Duetotheircomplexity,themechanismsbywhichvariousdrugsactintheCNShavenotalwaysbeenclearly
understood.Inrecentdecades,however,dramaticadvanceshavebeenmadeinthemethodologyofCNS
pharmacology.Itisnowpossibletostudytheactionofadrugonindividualneuronsandevensinglereceptors
withinsynapses.Theinformationobtainedfromsuchstudiesisthebasisforseveralmajordevelopmentsinstudies
oftheCNS.First,itisclearthatnearlyalldrugswithCNSeffectsactonspecificreceptorsthatmodulatesynaptic
transmission.Whileafewagentssuchasgeneralanestheticsandalcoholmayhavenonspecificactionson
membranes(althoughtheseexceptionsarenotfullyaccepted),eventhesenonreceptormediatedactionsresultin
demonstrablealterationsinsynaptictransmission.

Second,drugsareamongthemostvaluabletoolsforstudyingCNSfunction,fromunderstandingthemechanism
ofconvulsionstothelayingdownoflongtermmemory.Bothagoniststhatmimicnaturaltransmitters(andinmany
casesthataremoreselectivethantheendogenoussubstances)andantagonistsareextremelyusefulinsuch
studies.Third,unravelingtheactionsofdrugswithknownclinicalefficacyhasledtosomeofthemostfruitful
hypothesesregardingthemechanismsofdisease.Forexample,informationabouttheactionofantipsychotic
drugsondopaminereceptorshasprovidedthebasisforimportanthypothesesregardingthepathophysiologyof
schizophrenia.Studiesoftheeffectsofavarietyofagonistsandantagonistsonaminobutyricacid(GABA)
receptorshaveresultedinnewconceptspertainingtothepathophysiologyofseveraldiseases,includinganxiety
andepilepsy.

AfullappreciationoftheeffectsofadrugontheCNSrequiresanunderstandingofthemultiplelevelsofbrain
organization,fromgenestocircuitstobehavior.Thischapterprovidesanintroductiontothefunctionalorganization
oftheCNSanditssynaptictransmittersasabasisforunderstandingtheactionsofthedrugsdescribedinthe
followingchapters.

ORGANIZATIONOFTHECNS
TheCNScomprisesthebrainandspinalcordandisresponsibleforintegratingsensoryinformationandgenerating
motoroutputandotherbehaviorsneededtosuccessfullyinteractwiththeenvironmentandenhancespecies
survival.Thehumanbraincontainsabout100billioninterconnectedneuronssurroundedbyvarioussupporting
glialcells.ThroughouttheCNS,neuronsareeitherclusteredintogroupscallednucleiorarepresentinlayered
structuressuchasthecerebellumorhippocampus.Connectionsamongneuronsbothwithinandbetweenthese
clustersformthecircuitrythatregulatesinformationflowthroughtheCNS.

Neurons

Neuronsareelectricallyexcitablecellsthatprocessandtransmitinformationviaanelectrochemicalprocess.There
aremanytypesofneuronsintheCNS,andtheyareclassifiedinthefollowingways:byfunction,bylocation,and
bytheneurotransmittertheyrelease.Thetypicalneuronpossessesacellbody(orsoma)andspecialized

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processescalleddendritesandaxons(Figure211).Dendrites,whichformhighlybranchedcomplexdendritic
trees,receiveandintegratetheinputfromotherneuronsandconductthisinformationtothecellbody.Theaxon
carriestheoutputsignalofaneuronfromthecellbody,sometimesoverlongdistances.Neuronsmayhave
hundredsofdendritesbutgenerallyhaveonlyoneaxon,thoughaxonsmaybranchdistallytocontactmultiple
targets.Theaxonterminalmakescontactwithotherneuronsatspecializedjunctions,calledsynapses,where
neurotransmitterchemicalsarereleasedthatinteractwithreceptorsonotherneurons.

FIGURE211

NeuronsandgliaintheCNS.Atypicalneuronhasacellbody(orsoma)thatreceivesthesynapticresponsesfrom
thedendritictree.Thesesynapticresponsesareintegratedattheaxoninitialsegment,whichhasahigh
concentrationofvoltagegatedsodiumchannels.Ifanactionpotentialisinitiated,itpropagatesdowntheaxonto
thesynapticterminals,whichcontactotherneurons.Theaxonoflongrangeprojectionneuronsisinsulatedbya
myelinsheathderivedfromspecializedmembraneprocessesofoligodendrocytes,analogoustotheSchwanncells
intheperipheralnervoussystem.AstrocytesperformsupportiverolesintheCNS,andtheirprocessesareclosely
associatedwithneuronalsynapses.(seeFigures214and217).

Neuroglia

Inadditiontoneurons,therearealargenumberofnonneuronalsupportcells,calledneurogliaorglia,thatperform
avarietyofessentialfunctionsintheCNS.Astrocytesarethemostabundantglialcellsinthebrainandplay
homeostaticsupportroles,includingprovidingmetabolicnutrientstoneuronsandmaintainingextracellularion
concentrations.Inaddition,astrocyteprocessesarecloselyassociatedwithneuronalsynapseswheretheyare
involvedintheremovalandrecyclingofneurotransmittersafterreleaseandplayincreasinglyappreciatedrolesin
regulatingneurotransmission(seebelow).

OligodendrocytesarecellsthatwraparoundtheaxonsofprojectionneuronsintheCNSformingthemyelinsheath
(Figure221).SimilartotheSchwanncellsinperipheralneurons,themyelinsheathcreatedbythe
oligodendrocytesinsulatestheaxonsandincreasesthespeedofsignalpropagation.Damagetooligodendrocytes
occursinmultiplesclerosisandthusisatargetofdrugdiscoveryefforts.

MicrogliaarespecializedmacrophagesderivedfromthebonemarrowthatarefoundintheCNSandarethemajor
immunedefensesysteminthebrain.Thesecellsareactivelyinvolvedinneuroinflammatoryprocessesinmany
pathologicalstatesincludingneurodegenerativediseases.

BloodBrainBarrier

Thebloodbrainbarrier(BBB)isaprotectivefunctionalseparationofthecirculatingbloodfromtheextracellular
fluidoftheCNSthatlimitsthepenetrationofsubstances,includingdrugs.Thisseparationisaccomplishedbythe
presenceoftightjunctionsbetweenthecapillaryendothelialcellsaswellasasurroundinglayerofastrocyteend
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feet.Therefore,toentertheCNS,drugsmusteitherbehighlyhydrophobicorengagespecifictransport
mechanisms.Forexample,thesecondgenerationantihistaminescauselessdrowsinessbecausetheywere
developedtobesignificantlymorepolarthanolderantihistamines,limitingtheircrossingoftheBBB(seeChapter
16).Manynutrients,suchasglucoseandtheessentialaminoacids,havespecifictransportersthatallowthemto
crosstheBBB.lDOPA,aprecursoroftheneurotransmitterdopamine,canenterthebrainusinganaminoacid
transporter,whereasdopaminecannotcrosstheBBB.Thus,anorallyadministereddrug,lDOPA,butnot
dopamine,canbeusedtoboostCNSdopaminelevelsinthetreatmentofParkinsonsdisease.Somepartsofthe
brain,thesocalledcircumventricularorgans,lackanormalBBB.Theseincluderegionsthatsampletheblood,
suchastheareapostremavomitingcenter,andregionsthatsecreteneurohormonesintothecirculation.

IONCHANNELS&NEUROTRANSMITTERRECEPTORS
Themembranesofneuronscontaintwotypesofchannelsdefinedonthebasisofthemechanismscontrollingtheir
gating(openingandclosing):voltagegatedandligandgatedchannels(Figure212AandB).Voltagegated
channelsrespondtochangesinthemembranepotentialofthecell.Thevoltagegatedsodiumchanneldescribed
inChapter14fortheheartisanexampleofthistypeofchannel.Innervecells,thesechannelsarehighly
concentratedontheinitialsegmentoftheaxon(Figure211),whichinitiatestheallornothingfastactionpotential
andalongthelengthoftheaxonwheretheypropagatetheactionpotentialtothenerveterminal.Therearealso
manytypesofvoltagesensitivecalciumandpotassiumchannelsonthecellbody,dendrites,andinitialsegment,
whichactonamuchslowertimescaleandmodulatetherateatwhichtheneurondischarges.Forexample,some
typesofpotassiumchannelsopenedbydepolarizationofthecellresultinslowingoffurtherdepolarizationandact
asabraketolimitfurtheractionpotentialdischarge.Plantandanimaltoxinsthattargetvariousvoltagegatedion
channelshavebeeninvaluableforstudyingthefunctionsofthesechannels(seeBox:NaturalToxins:Toolsfor
CharacterizingIonChannelsTable211).

TABLE211Sometoxinsusedtocharacterizeionchannels.
ChannelTypes ModeofToxinAction Source
Voltagegated
Sodiumchannels
Tetrodotoxin(TTX) Blockschannelfromoutside Pufferfish
Batrachotoxin(BTX) Slowsinactivation,shiftsactivation Colombianfrog
Potassiumchannels
Apamin BlockssmallCaactivatedKchannel Honeybee
Charybdotoxin BlocksbigCaactivatedKchannel Scorpion
Calciumchannels
Omegaconotoxin(CTXGVIA) BlocksNtypechannel Pacificconesnail
Agatoxin(AGAIVA) BlocksPtypechannel Funnelwebspider
Ligandgated
NicotinicAChreceptor
Bungarotoxin Irreversibleantagonist Marinesnake
GABAAreceptor
Picrotoxin Blockschannel SouthPacificplant
Glycinereceptor
Strychnine Competitiveantagonist Indianplant
AMPAreceptor
Philanthotoxin Blockschannel Wasp

FIGURE212

TypesofionchannelsandneurotransmitterreceptorsintheCNS.Ashowsavoltagegatedchannelinwhicha
voltagesensorcomponentoftheproteincontrolsthegating(brokenarrow)ofthechannel.Bshowsaligandgated
channelinwhichthebindingoftheneurotransmittertotheionotropicchannelreceptorcontrolsthegating(broken
arrow)ofthechannel.CshowsaGproteincoupled(metabotropic)receptor,which,whenbound,activatesa
heterotrimericGprotein.DandEshowtwowaysmetabotropicreceptorscanregulateionchannels.Theactivated
Gproteincaninteractdirectlytomodulateanionchannel(D)ortheGproteincanactivateanenzymethat
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generatesadiffusiblesecondmessenger(E),eg,cAMP,whichcaninteractwiththeionchannelorcanactivatea
kinasethatphosphorylatesandmodulatesachannel.

NaturalToxins:ToolsforCharacterizingIonChannels

Evolutionistirelessinthedevelopmentofnaturaltoxins.Avastnumberofvariationsarepossiblewithevena
smallnumberofaminoacidsinpeptides,andpeptidesmakeuponlyoneofabroadarrayoftoxiccompounds.For
example,thepredatorymarinesnailgenusConusincludesover3000differentspecies.Eachspecieskillsor
paralyzesitspreywithavenomthatcontains50200differentpeptidesorproteins.Furthermore,thereislittle
duplicationofpeptidesamongConusspecies.Otheranimalswithusefultoxinsincludesnakes,frogs,spiders,
bees,wasps,andscorpions.Plantspecieswithtoxic(ortherapeutic)substancesarereferredtoinseveralother
chaptersofthisbook.

Sincemanytoxinsactonionchannels,theyprovideawealthofchemicaltoolsforstudyingthefunctionofthese
channels.Infact,muchofourcurrentunderstandingofthepropertiesofionchannelscomesfromstudiesutilizing
onlyasmallpercentageofthehighlypotentandselectivetoxinsthatarenowavailable.Thetoxinstypicallytarget
voltagesensitiveionchannels,butanumberofveryusefultoxinsblockionotropicneurotransmitterreceptors.
Table211listssomeofthetoxinsmostcommonlyusedinresearch,theirmodeofaction,andtheirsource.

Neurotransmittersexerttheireffectsonneuronsbybindingtotwodistinctclassesofreceptor.Thefirstclassis
referredtoasligandgatedchannels,orionotropicreceptors.Thesereceptorsconsistofmultiplesubunits,and
bindingoftheneurotransmitterliganddirectlyopensthechannel,whichisanintegralpartofthereceptorcomplex
(seeFigure226).Thesechannelsareinsensitiveoronlyweaklysensitivetomembranepotential.Activationof
thesechannelstypicallyresultsinabrief(afewmillisecondstotensofmilliseconds)openingofthechannel.
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LigandgatedchannelsareresponsibleforfastsynaptictransmissiontypicalofhierarchicalpathwaysintheCNS
(seefollowingtext).

Thesecondclassofneurotransmitterreceptorisreferredtoasmetabotropicreceptors(Figure212C).These
areseventransmembraneGproteincoupledreceptorsofthetypedescribedinChapter2.Thebindingof
neurotransmittertothistypeofreceptordoesnotresultinthedirectgatingofachannel.Rather,bindingtothe
receptorengagesaGprotein,whichresultsintheproductionofsecondmessengersthatmediateintracellular
signalingcascadessuchasthosedescribedinChapter2.

Inneurons,activationofmetabotropicneurotransmitterreceptorsoftenleadstothemodulationofvoltagegated
channels.Theseinteractionscanoccurentirelywithintheplaneofthemembraneandarereferredtoas
membranedelimitedpathways(Figure212D).Inthiscase,theGprotein(oftenthesubunit)interactsdirectly
withavoltagegatedionchannel.Ingeneral,twotypesofvoltagegatedionchannelsarethetargetsofthistypeof
signaling:calciumchannelsandpotassiumchannels.WhenGproteinsinteractwithcalciumchannels,theyinhibit
channelfunction.Thismechanismaccountsfortheinhibitionofneurotransmitterreleasethatoccurswhen
presynapticmetabotropicreceptorsareactivated.Incontrast,whenthesereceptorsarepostsynaptic,theyactivate
(causetheopeningof)potassiumchannels,resultinginaslowpostsynapticinhibition.Metabotropicreceptorscan
alsomodulatevoltagegatedchannelslessdirectlybythegenerationofdiffusiblesecondmessengers(Figure
212E).Aclassicexampleofthistypeofactionisprovidedbytheadrenoceptor,whichgeneratescAMPviathe
activationofadenylylcyclase(seeChapter2).Whereasmembranedelimitedactionsoccurwithinmicrodomainsin
themembrane,secondmessengermediatedeffectscanoccuroverconsiderabledistances.Finally,animportant
consequenceoftheinvolvementofGproteinsinreceptorsignalingisthat,incontrasttothebriefeffectof
ionotropicreceptors,theeffectsofmetabotropicreceptoractivationcanlasttensofsecondstominutes.
MetabotropicreceptorspredominateinthediffuseneuronalsystemsintheCNS(seebelow).

THESYNAPSE&SYNAPTICPOTENTIALS
ThecommunicationbetweenneuronsintheCNSoccursthroughchemicalsynapsesinthemajorityofcases.(A
fewinstancesofelectricalcouplingbetweenneuronshavebeendocumented,andsuchcouplingmayplayarolein
synchronizingneuronaldischarge.However,itisunlikelythattheseelectricalsynapsesareanimportantsiteof
drugaction.)Theeventsinvolvedinsynaptictransmissioncanbesummarizedasfollows.

Anactionpotentialpropagatingdowntheaxonofthepresynapticneuronentersthesynapticterminalandactivates
voltagesensitivecalciumchannelsinthemembraneoftheterminal(seeFigure63).Thecalciumchannels
responsibleforthereleaseofneurotransmitteraregenerallyresistanttothecalciumchannelblockingagents
discussedinChapter12(verapamil,etc)butaresensitivetoblockadebycertainmarinetoxinsandmetalions(see
Tables211and124).Ascalciumflowsintotheterminal,theincreaseinintraterminalcalciumconcentration
promotesthefusionofsynapticvesicleswiththepresynapticmembrane.Theneurotransmittercontainedinthe
vesiclesisreleasedintothesynapticcleftanddiffusestothereceptorsonthepostsynapticmembrane.The
neurotransmitterbindstoitsreceptorandopenschannels(eitherdirectlyorindirectlyasdescribedabove)causing
abriefchangeinmembraneconductance(permeabilitytoions)ofthepostsynapticcell.Thetimedelayfromthe
arrivalofthepresynapticactionpotentialtotheonsetofthepostsynapticresponseisapproximately0.5ms.Most
ofthisdelayisconsumedbythereleaseprocess,particularlythetimerequiredforcalciumchannelstoopen.

FIGURE213

Postsynapticpotentialsandactionpotentialgeneration.A(top)showsthevoltagerecordeduponentryofa
microelectrodeintoapostsynapticcellandsubsequentrecordingofarestingmembranepotentialof60mV.
Stimulationofanexcitatorypathway(E1,left)generatestransientdepolarizationcalledanexcitatorypostsynaptic
potential(EPSP).Simultaneousactivationofmultipleexcitatorysynapses(E1+E2,middle)increasesthesizeof
thedepolarization,sothatthethresholdforactionpotentialgenerationisreached.Alternatively,atrainofstimuli
fromasingleinputcantemporallysummatetoreachthethreshold(E1+E1,right).B(bottom)demonstratesthe
interactionofexcitatoryandinhibitorysynapses.Ontheleft,asuprathresholdexcitatorystimulus(E3)evokesan
actionpotential.Inthecenter,aninhibitorypathway(I)generatesasmallhyperpolarizingcurrentcalledan
inhibitorypostsynapticpotential(IPSP).Ontheright,ifthepreviouslysuprathresholdexcitatoryinput(E3)isgiven
shortlyaftertheinhibitoryinput(I),theIPSPpreventstheexcitatorypotentialfromreachingthreshold.

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ThefirstsystematicanalysisofsynapticpotentialsintheCNSwasintheearly1950sbyEcclesandassociates,
whorecordedintracellularlyfromspinalmotorneurons.Whenamicroelectrodeentersacell,thereisasudden
changeinthepotentialrecordedbytheelectrode,whichistypicallyabout60mV(Figure213).Thisistheresting
membranepotentialoftheneuron.Twotypesofpathwaysexcitatoryandinhibitoryimpingeonthemotor
neuron.

Whenanexcitatorypathwayisstimulated,asmalldepolarizationorexcitatorypostsynapticpotential(EPSP)is
recorded.Thispotentialisduetotheexcitatorytransmitteractingonanionotropicreceptor,causinganincreasein
cationpermeability.Asadditionalexcitatorysynapsesareactivated,thereisagradedsummationoftheEPSPsto
increasethesizeofthedepolarization(Figure213,top,spatialsummation,middle).Whenasufficientnumberof
excitatorysynapsesareactivated,theexcitatorypostsynapticpotentialdepolarizesthepostsynapticcellto
threshold,andanallornoneactionpotentialisgenerated.Alternatively,ifthereisarepetitivefiringofanexcitatory
input,thetemporalsummationoftheEPSPsmayalsoreachtheactionpotentialthreshold(Figure213,top,right).

Whenaninhibitorypathwayisstimulated,thepostsynapticmembraneishyperpolarizedowingtotheselective
openingofchloridechannels,producinganinhibitorypostsynapticpotential(IPSP)(Figure213,bottom,
middle).However,becausetheequilibriumpotentialforchloride(seeChapter14)isonlyslightlymorenegative
thantherestingpotential(~65mV),thehyperpolarizationissmallandcontributesonlymodestlytotheinhibitory
action.Theopeningofthechloridechannelduringtheinhibitorypostsynapticpotentialmakestheneuronleaky
sothatchangesinmembranepotentialaremoredifficulttoachieve.Thisshuntingeffectdecreasesthechangein
membranepotentialduringtheexcitatorypostsynapticpotential.Asaresult,anexcitatorypostsynapticpotential
thatevokedanactionpotentialunderrestingconditionsfailstoevokeanactionpotentialduringtheinhibitory
postsynapticpotential(Figure213,bottom,right).Asecondtypeofinhibitionispresynapticinhibition.Itwasfirst
describedforsensoryfibersenteringthespinalcord,whereexcitatorysynapticterminalsreceivesynapsescalled
axoaxonicsynapses(describedlater).Whenactivated,axoaxonicsynapsesreducetheamountoftransmitter
releasedfromtheterminalsofsensoryfibers.Itisinterestingthatpresynapticinhibitoryreceptorsarepresenton
almostallpresynapticterminalsinthebraineventhoughaxoaxonicsynapsesappeartoberestrictedtothespinal
cord.Inthebrain,transmittercanspilloutofthesynapseandactivatepresynapticreceptors,eitheronthesame
synapse(autoreceptors)oronneighboringsynapses.

SITESOFDRUGACTION
VirtuallyallthedrugsthatactintheCNSproducetheireffectsbymodifyingsomestepinchemicalsynaptic
transmission.Figure214illustratessomeofthestepsthatcanbealtered.Thesetransmitterdependentactions
canbedividedintopresynapticandpostsynapticcategories.

FIGURE214

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Sitesofdrugaction.Schematicdrawingofstepsatwhichdrugscanaltersynaptictransmission.(1)Action
potentialinpresynapticfiber(2)synthesisoftransmitter(3)storage(4)metabolism(5)release(6)reuptakeinto
thenerveendingoruptakeintoaglialcell(7)degradation(8)receptorforthetransmitter(9)receptorinduced
increaseordecreaseinionicconductance(10)retrogradesignaling.

Drugsactingonthesynthesis,storage,metabolism,andreleaseofneurotransmittersfallintothepresynaptic
category.Synaptictransmissioncanbedepressedbyblockadeoftransmittersynthesisorstorage.Forexample,
reserpinedepletesmonoaminesynapsesoftransmittersbyinterferingwithintracellularstorage.Blockadeof
transmittercatabolisminsidethenerveterminalcanincreasetransmitterconcentrationsandhasbeenreportedto
increasetheamountoftransmitterreleasedperimpulse.Drugscanalsoalterthereleaseoftransmitters.The
stimulantamphetamineinducesthereleaseofcatecholaminesfromadrenergicsynapses(seeChapters6,9,and
32).CapsaicincausesthereleaseofthepeptidesubstancePfromsensoryneurons,andtetanustoxinblocksthe
releaseoftransmitters.AfteraCNStransmitterhasbeenreleasedintothesynapticcleft,itsactionisterminated
eitherbyuptakeorbydegradation.Formostneurotransmitters,thereareuptakemechanismsintothesynaptic
terminalandalsointosurroundingneuroglia.Cocaine,forexample,blockstheuptakeofcatecholaminesat
adrenergicsynapsesandthuspotentiatestheactionoftheseamines.Acetylcholine,however,isinactivatedby
enzymaticdegradation,notreuptake.Anticholinesterasesblockthedegradationofacetylcholineandthereby
prolongitsaction(seeChapter7).NouptakemechanismhasbeenfoundforanyofthenumerousCNSpeptides,
andithasyettobedemonstratedwhetherspecificenzymaticdegradationterminatestheactionofpeptide
transmitters.

Inthepostsynapticregion,thetransmitterreceptorprovidestheprimarysiteofdrugaction.Drugscanacteitheras
neurotransmitteragonists,suchastheopioids,whichmimictheactionofenkephalin,ortheycanblockreceptor
function.ReceptorantagonismisacommonmechanismofactionforCNSdrugs.Anexampleisstrychnines
blockadeofthereceptorfortheinhibitorytransmitterglycine.Thisblock,whichunderliesstrychninesconvulsant
action,illustrateshowtheblockadeofinhibitoryprocessesresultsinexcitation.Drugscanalsoactdirectlyonthe
ionchannelofionotropicreceptors.Forexample,theanestheticketamineblockstheNMDAsubtypeofglutamate
ionotropicreceptorsbybindingintheionchannelpore.Inthecaseofmetabotropicreceptors,drugscanactatany
ofthestepsdownstreamofthereceptor.Perhapsthebestexampleisprovidedbythemethylxanthines,whichcan

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modifyneurotransmitterresponsesmediatedthroughthesecondmessengercAMP.Athighconcentrations,the
methylxanthineselevatethelevelofcAMPbyblockingitsmetabolismandtherebyprolongitsaction.

Thetraditionalviewofthesynapseisthatitfunctionslikeavalve,transmittinginformationinonedirection.
However,itisnowclearthatthesynapsecanalsogeneratesignalsthatfeedbackontothepresynapticterminalto
modifytransmitterrelease.Endocannabinoidsarethebestdocumentedexampleofsuchretrogradesignaling.
Postsynapticactivityleadstothesynthesisandreleaseofendocannabinoids,whichthenbindtoreceptorsonthe
presynapticterminal.Althoughthegasnitricoxide(NO)haslongbeenproposedasaretrogrademessenger,its
physiologicroleintheCNSisstillnotwellunderstood.

TheselectivityofCNSdrugactionisbasedontwoprimaryfactors.First,withafewexceptions,different
neurotransmittersarereleasedbydifferentgroupsofneurons.Thesetransmittersareoftensegregatedinto
neuronalsystemsthatsubservebroadlydifferentCNSfunctions.Thatthissegregationoccurshasprovided
neuroscientistswithapowerfulpharmacologicapproachforanalyzingCNSfunctionandtreatingpathologic
conditions.Second,thereisamultiplicityofreceptorsforeachneurotransmitter.Forexample,atleast14different
serotoninreceptorsareencodedbydifferentgenes.Thesereceptorsalsooftenhavedifferentialcellular
distributionsthroughouttheCNS,allowingforthedevelopmentofdrugsthatselectivelytargetparticularreceptors
andCNSfunctions.

CELLULARORGANIZATIONOFTHEBRAIN
MostoftheneuronalsystemsintheCNScanbedividedintotwobroadcategories:hierarchicalsystemsand
nonspecificordiffuseneuronalsystems.

HierarchicalSystems

Hierarchicalsystemsincludeallthepathwaysdirectlyinvolvedinsensoryperceptionandmotorcontrol.These
pathwaysaregenerallyclearlydelineated,beingcomposedoflargemyelinatedfibersthatcanoftenconductaction
potentialsatarateofmorethan50m/s.Theinformationistypicallyphasicandoccursinburstsofaction
potentials.Insensorysystems,theinformationisprocessedsequentiallybysuccessiveintegrationsateachrelay
nucleusonitswaytothecortex.Alesionatanylinkincapacitatesthesystem.

Withineachnucleusandinthecortex,therearetwotypesofcells:relayorprojectionneuronsandlocalcircuit
neurons(Figure215A).Theprojectionneuronsformtheinterconnectingpathwaysthattransmitsignalsoverlong
distances.Theircellbodiesarerelativelylarge,andtheiraxonscanprojectlongdistancesbutalsoemitsmall
collateralsthatsynapseontolocalinterneurons.Theseneuronsareexcitatory,andtheirsynapticinfluences,which
involveionotropicreceptors,areveryshortlived.Theexcitatorytransmitterreleasedfromthesecellsis,inmost
instances,glutamate.

FIGURE215

HierarchicalpathwaysintheCNS.Ashowspartsofthreeexcitatoryrelayneurons(blue)andtwotypesoflocal
inhibitoryinterneuronpathways,recurrentandfeedforward.Theinhibitoryneuronsareshowningray.Bshowsthe
pathwayresponsibleforaxoaxonicpresynapticinhibitioninwhichtheaxonofaninhibitoryneuron(gray)synapses
ontothepresynapticaxonterminalofanexcitatoryfiber(blue)toinhibititsneurotransmitterrelease.

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Localcircuitneuronsaretypicallysmallerthanprojectionneurons,andtheiraxonsarborizeintheimmediate
vicinityofthecellbody.Mostoftheseneuronsareinhibitory,andtheyreleaseeitherGABAorglycine.They
synapseprimarilyonthecellbodyoftheprojectionneuronsbutcanalsosynapseonthedendritesofprojection
neuronsaswellaswitheachother.Twocommontypesofpathwaysfortheseneurons(Figure215A)include
recurrentfeedbackpathwaysandfeedforwardpathways.Aspecialclassoflocalcircuitneuronsinthespinalcord
formsaxoaxonicsynapsesontheterminalsofsensoryaxons(Figure215B).Althoughthereareagreatvarietyof
synapticconnectionsinthesehierarchicalsystems,thefactthatalimitednumberoftransmittersareusedbythese
neuronsindicatesthatanymajorpharmacologicmanipulationofthissystemwillhaveaprofoundeffectonthe
overallexcitabilityoftheCNS.Forinstance,selectivelyblockingGABAAreceptorswithadrugsuchaspicrotoxin
resultsingeneralizedconvulsions.Thus,althoughthemechanismofactionofpicrotoxinisspecificinblockingthe
effectsofGABA,theoverallfunctionaleffectappearstobequitenonspecific,becauseGABAmediatedsynaptic
inhibitionissowidelyutilizedinthebrain.

NonspecificorDiffuseNeuronalSystems

Neuronalsystemscontainingmanyoftheotherneurotransmitters,includingthemonoaminesandacetylcholine,
differinfundamentalwaysfromthehierarchicalsystems.Theseneurotransmittersareproducedbyonlyalimited
numberofneuronswhosecellbodiesarelocatedinsmalldiscretenuclei,ofteninthebrainstem.Forexample,
noradrenergiccellbodiesarefoundprimarilyinacompactcellgroup,calledthelocuscaeruleus,locatedinthe
caudalpontinecentralgraymatterandnumberonlyapproximately1500neuronsoneachsideofthebraininthe
rat.However,fromtheselimitednuclei,theseneuronsprojectwidelyanddiffuselythroughoutthebrainandspinal
cord(Figure216).Becausetheaxonsfromthesediffuselyprojectingneuronsarefineandunmyelinated,they
conductveryslowly,atabout0.5m/s.Theaxonsbranchrepeatedlyandareextraordinarilydivergent.Branches
fromthesameneuroncaninnervateseveralfunctionallydifferentpartsoftheCNS,synapsingontoandmodulating
neuronswithinthehierarchicalsystems.Intheneocortex,thesefibershaveatangentialorganizationandtherefore
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caninfluencelargeareasofcortex.Inaddition,mostneurotransmittersutilizedbydiffuseneuronalsystems,
includingnorepinephrine,actpredominantlyonmetabotropicreceptorsandthereforeinitiatelonglastingsynaptic
effects.Basedontheseobservations,itisclearthatthemonoaminesystemscannotbeconveyingtopographically
specifictypesofinformationrather,vastareasoftheCNSmustbeaffectedsimultaneouslyandinaratheruniform
way.Itisnotsurprising,then,thatthesesystemshavebeenimplicatedinsuchglobalfunctionsassleepingand
waking,attention,appetite,andemotionalstates.

FIGURE216

DiffuseneurotransmitterpathwaysintheCNS.Foreachoftheneurotransmitterpathwaysshown,thecellbodies
arelocatedindiscretebrainstemorbasalforebrainnucleiandprojectwidelythroughouttheCNS.Thesediffuse
systemslargelymodulatethefunctionofthehierarchicalpathways.Serotoninneurons,forexample,arefoundin
themidlineraphenucleiintheforebrainandsendextraordinarilydivergentprojectionstonearlyallregionsofthe
CNS.Otherdiffuselyprojectingneurotransmitterpathwaysincludethehistamineandorexinsystems(notshown).
VTA,ventraltegmentalareaSN,substantianigraA1A7,adrenergicbrainstemnucleiMSN,medialseptal
nucleusDB,diagonalbandofBrocaC5C8,cholinergicbrainstemnuclei.

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CENTRALNEUROTRANSMITTERS
Becausedrugselectivityisbasedonthefactthatdifferentpathwaysusedifferenttransmitters,aprimarygoalof
neuroscientistshasbeentoidentifytheneurotransmittersinCNSpathways.Establishingthatachemical
substanceisatransmitterhasbeenfarmoredifficultforcentralsynapsesthanforperipheralsynapses.The
followingcriteriahavebeenestablishedfortransmitteridentification.

1.Localization:Asuspectedtransmittermustresideinthepresynapticterminalofthepathwayofinterest.

2.Release:Asuspectedtransmittermustbereleasedfromaneuroninresponsetoneuronalactivityandina
calciumdependentmanner.

3.Synapticmimicry:Applicationofthecandidatesubstanceshouldproducearesponsethatmimicstheaction
ofthetransmitterreleasedbynervestimulation,andapplicationofaselectiveantagonistshouldblockthe
response.

Usingthecriteriaabove,avastnumberofsmallmoleculeshavebeenisolatedfromthebrain,andstudiesusinga
varietyofapproachessuggestthattheagentslistedinTable212areneurotransmitters.Abriefsummaryofthese
compoundsfollows.

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TABLE212Summaryofneurotransmitterpharmacologyinthecentralnervoussystem.
Receptor
Subtypesand Receptor
Transmitter Anatomy Mechanisms
Preferred Antagonists
Agonists
Cellbodiesatalllevels Muscarinic(M1): Pirenzepine, Excitatory:inK+
Acetylcholine
longandshortconnections muscarine atropine conductanceIP3,DAG
Muscarinic(M2):
Atropine, Inhibitory:K+
muscarine, methoctramine conductancecAMP
bethanechol
Dihydro
MotoneuronRenshawcell Excitatory:cation
Nicotinic:nicotine erythroidine,
synapse conductance
bungarotoxin
Cellbodiesatalllevels
Dopamine short,medium,andlong D1:dihydrexidine Phenothiazines Inhibitory(?):cAMP
connections
Inhibitory(presynaptic):
D2:bromocriptine Phenothiazines, Ca2+Inhibitory
butyrophenones (postsynaptic):inK+
conductance,cAMP
Supraspinalandspinal
GABA
interneuronsinvolvedin GABAA:muscimol Bicuculline, Inhibitory:Cl
preandpostsynaptic picrotoxin conductance
inhibition
Inhibitory(presynaptic):
GABAB:baclofen 2OHsaclofen Ca2+conductance
Inhibitory(postsynaptic):
K+conductance
NMethyld 2Amino5 Excitatory:cation
Relayneuronsatalllevels
Glutamate aspartate(NMDA): phosphonovalerate, conductance,particularly
andsomeinterneurons
NMDA dizocilpine Ca2+
Excitatory:cation
AMPA:AMPA NBQX
conductance
Kainate:kainic Excitatory:cation
ACET
acid,domoicacid conductance
Inhibitory(presynaptic):
Metabotropic:
Ca2+conductance,
ACPD, MCPG
quisqualate cAMPExcitatory:K+
conductance,IP3,DAG
Spinalinterneuronsand
Glycine somebrainstem Taurine,alanine Strychnine Inhibitory:Cl
interneurons conductance
5 Cellbodiesinmidbrain 5HT1A:
Hydroxytryptamine andponsprojecttoall
Metergoline, Inhibitory:K+
eptapirone spiperone conductance,cAMP
(serotonin) levels

5HT2A:LSD Excitatory:K+
Ketanserin
conductance,IP3,DAG
5HT3:2methyl5 Excitatory:cation
Ondansetron
HT conductance

5HT4:cisapride Piboserod Excitatory:K+

conductance

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Receptor
Subtypesand Receptor
Transmitter Anatomy Mechanisms
Preferred Antagonists
Agonists
Cellbodiesinponsand
1:phenylephrine Prazosin Excitatory:K+
Norepinephrine brainstemprojecttoall
conductance,IP3,DAG
levels
Inhibitory(presynaptic):
2:clonidine Ca2+conductance
Yohimbine
Inhibitory:K+
conductance,cAMP
1:isoproterenol, Excitatory:K+
Atenolol,practolol
dobutamine conductance,cAMP
Inhibitory:mayinvolve
2:albuterol Butoxamine inelectrogenicsodium
pumpcAMP
H1:2(m
Cellsinventralposterior Excitatory:K+
Histamine fluorophenyl) Mepyramine
hypothalamus conductance,IP3,DAG
histamine
H2:dimaprit Ranitidine Excitatory:K+
conductance,cAMP
H3:Rmethyl
Thioperamide Inhibitoryautoreceptors
histamine
Inhibitory(presynaptic):
Cellbodiesatalllevels
Opioidpeptides
longandshortconnections
Mu:bendorphin Naloxone Ca2+conductance,
cAMP
Inhibitory(postsynaptic):
Delta:enkephalin Naloxone
K+conductance,cAMP
Kappa:dynorphin, Inhibitory(postsynaptic):
Naloxone
salvanorinA K+conductance,cAMP
OX1:orexinA
Cellbodiesin Suvorexant
excitatory,Glutamateco
Orexins hypothalamusproject
OX2:orexinsA release
widely Suvorexant
andB
Primarysensoryneurons, NK1:substanceP
Excitatory:K+
Tachykinins cellbodiesatalllevels methylester, Aprepitant
conductance,IP3,DAG
longandshortconnections aprepitant
NK2:neurokininA Saredutant
NK3:neurokininB Osanetant
CB1:anandamide, Inhibitory(presynaptic):
Endocannabinoids Widelydistributed 2 Rimonabant Ca2+conductance,
arachidonyglycerol cAMP

Note:Manyothercentraltransmittershavebeenidentified(seetext).

ACET,(S)1(2amino2carboxyethyl)3(2carboxy5phenylthiophene3ylmethyl)5methylpyrimidine2,4dione
ACPD,trans1aminocyclopentyl1,3dicarboxylateAMPA,DLamino3hydroxy5methylisoxazole4
propionatecAMP,cyclicadenosinemonophosphateCQNX,6cyano7nitroquinoxaline2,3dioneDAG,
diacylglycerolIP3,inositoltrisphosphateLSD,lysergicaciddiethylamideMCPG,methyl4
carboxyphenylglycineNBQX,2,3dihydroxy6nitro7sulfamoylbenzo(f)quinoxaline.

AminoAcidNeurotransmitters

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Theaminoacidsofprimaryinteresttothepharmacologistfallintotwocategories:theacidicaminoacidglutamate
andtheneutralaminoacidsglycineandGABA.AllthreecompoundsarepresentinhighconcentrationsintheCNS
andareextremelypotentmodifiersofneuronalexcitability.

A.Glutamate

Excitatorysynaptictransmissionismediatedbyglutamate,whichispresentinveryhighconcentrationsin
excitatorysynapticvesicles(~100mM).GlutamateisreleasedintothesynapticcleftbyCa2+dependent
exocytosis.Thereleasedglutamateactsonpostsynapticglutamatereceptorsandisclearedbyglutamate
transporterspresentonsurroundingglia(Figure217).Inglia,glutamateisconvertedtoglutaminebyglutamine
synthetase,releasedfromtheglia,takenupbythenerveterminal,andconvertedbacktoglutamatebytheenzyme
glutaminase.Thehighconcentrationofglutamateinsynapticvesiclesisachievedbythevesicularglutamate
transporter(VGLUT).

FIGURE217

Schematicdiagramofaglutamatesynapse.Glutamineisimportedintotheglutamatergicneuron(A)and
convertedintoglutamatebyglutaminase.Theglutamateisthenconcentratedinvesiclesbythevesicular
glutamatetransporter.Uponreleaseintothesynapse,glutamatecaninteractwithAMPAandNMDAionotropic
receptorchannels(AMPAR,NMDAR)andwithmetabotropicreceptors(mGluR)onthepostsynapticcell(B).
Synaptictransmissionisterminatedbyactivetransportoftheglutamateintoaneighboringglialcell(C)bya
glutamatetransporter.Itisconvertedintoglutaminebyglutaminesynthetaseandtransportedbackintothe
glutamatergicaxonterminal.

Almostallneuronsthathavebeentestedarestronglyexcitedbyglutamate.Thisexcitationiscausedbythe
activationofbothionotropicandmetabotropicreceptors,whichhavebeenextensivelycharacterizedbymolecular

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cloning.Theionotropicreceptorsaredividedintothreesubtypesbasedontheactionofselectiveagonists:
amino3hydroxy5methylisoxazole4propionicacid(AMPA),kainicacid(KA),andNmethyldaspartate(NMDA).
Alltheionotropicreceptorsarecomposedoffoursubunits.AMPAreceptors,whicharepresentonallneurons,are
heterotetramersassembledfromfoursubunits(GluA1GluA4).ThemajorityofAMPAreceptorscontaintheGluA2
subunitandarepermeabletoNa+andK+,butnottoCa2+.SomeAMPAreceptors,typicallypresentoninhibitory
interneurons,lacktheGluA2subunitandarealsopermeabletoCa2+.

KainatereceptorsarenotasuniformlydistributedasAMPAreceptors,beingexpressedathighlevelsinthe
hippocampus,cerebellum,andspinalcord.Theyareformedfromanumberofsubunitcombinations(GluK1
GluK5).AlthoughGluK4andGluK5areunabletoformchannelsontheirown,theirpresenceinthereceptor
changesthereceptorsaffinityandkinetics.SimilartoAMPAreceptors,kainatereceptorsarepermeabletoNa+
andK+andinsomesubunitcombinationscanalsobepermeabletoCa2+.

NMDAreceptorsareasubiquitousasAMPAreceptors,beingpresentonessentiallyallneuronsintheCNS.All
NMDAreceptorsrequirethepresenceofthesubunitGluN1.ThechannelalsocontainsoneortwoGluN2subunits
(GluN2AGluN2D).UnlikeAMPAandkainatereceptors,allNMDAreceptorsarehighlypermeabletoCa2+aswell
astoNa+andK+.NMDAreceptorfunctioniscontrolledinanumberofintriguingways.Inadditiontoglutamate
binding,thechannelalsorequiresthebindingofglycinetoaseparatesite.Thephysiologicroleofglycinebinding
isunclearbecausetheglycinesiteappearstobesaturatedatnormalambientlevelsofglycine.Anotherimportant
featureisthatwhileAMPAandkainatereceptoractivationresultsinchannelopeningatrestingmembrane
potential,NMDAreceptoractivationdoesnot.ThisisduetothevoltagedependentblockoftheNMDAporeby
extracellularMg2+.Onlywhentheneuronisstronglydepolarized,asoccurswithintenseactivationofthesynapse
orbyactivationofneighboringsynapses,isMg2+expelledandthechannelopened.Thus,therearetwo
requirementsforNMDAreceptorchannelopening:Glutamatemustbindthereceptorandthemembranemustbe
depolarized.TheriseinintracellularCa2+thataccompanieschannelopeningresultsinalonglastingenhancement
insynapticstrengththatisreferredtoaslongtermpotentiation(LTP).Thechange,whichisonemajortypeof
synapticplasticity,canlastformanyhoursorevendaysandisgenerallyacceptedasanimportantcellular
mechanismunderlyinglearningandmemory.

ThemetabotropicglutamatereceptorsareGproteincoupledreceptorsthatactindirectlyonionchannelsviaG
proteins.Metabotropicreceptors(mGluR1mGluR8)havebeendividedintothreegroups(I,II,andIII).Avarietyof
agonistsandantagonistshavebeendevelopedthatinteractselectivelywiththedifferentgroups.GroupIreceptors
aretypicallylocatedpostsynapticallyandactivatephospholipaseC,leadingtoinositoltrisphosphatemediated
intracellularCa2+release.Incontrast,groupIIandgroupIIIreceptorsaretypicallylocatedonpresynapticnerve
terminalsandactasinhibitoryautoreceptors.ActivationofthesereceptorscausestheinhibitionofCa2+channels,
resultingininhibitionoftransmitterrelease.Thesereceptorsareactivatedonlywhentheconcentrationof
glutamaterisestohighlevelsduringrepetitivestimulationofthesynapse.Activationofthesereceptorsalsocauses
theinhibitionofadenylylcyclaseanddecreasescAMPgeneration.

B.GABAandGlycine

BothGABAandglycineareinhibitoryneurotransmitters,whicharetypicallyreleasedfromlocalinterneurons.
Interneuronsthatreleaseglycinearerestrictedtothespinalcordandbrainstem,whereasinterneuronsreleasing
GABAarepresentthroughouttheCNS,includingthespinalcord.Itisinterestingthatsomeinterneuronsinthe
spinalcordcanreleasebothGABAandglycine.Glycinereceptorsarepentamericstructuresthatareselectively
permeabletoCl.Strychnine,whichisapotentspinalcordconvulsantandhasbeenusedinsomeratpoisons,
selectivelyblocksglycinereceptors.

GABAreceptorsaredividedintotwomaintypes:GABAAandGABAB.Inhibitorypostsynapticpotentialsinmany
areasofthebrainhaveafastandslowcomponent.ThefastcomponentismediatedbyGABAAreceptorsandthe
slowcomponentbyGABABreceptors.Thedifferenceinkineticsstemsfromthedifferencesincouplingofthe
receptorstoionchannels.GABAAreceptorsareionotropicreceptorsand,likeglycinereceptors,arepentameric
structuresthatareselectivelypermeabletoCl.Thesereceptorsareselectivelyinhibitedbypicrotoxinand
bicuculline,bothofwhichcausegeneralizedconvulsions.AgreatmanysubunitsforGABAAreceptorshavebeen
clonedthisaccountsforthelargediversityinthepharmacologyofGABAAreceptors,makingthemkeytargetsfor
clinicallyusefulagents(seeChapter22).GABABreceptorsaremetabotropicreceptorsthatareselectively
activatedbytheantispasticdrugbaclofen.ThesereceptorsarecoupledtoGproteinsthat,dependingontheir
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cellularlocation,eitherinhibitCa2+channelsoractivateK+channels.TheGABABcomponentoftheinhibitory
postsynapticpotentialisduetoaselectiveincreaseinK+conductance.Thisinhibitorypostsynapticpotentialis
longlastingandslowbecausethecouplingofreceptoractivationtoK+channelopeningisindirectanddelayed.
GABABreceptorsarelocalizedtotheperisynapticregionandthusrequirethespilloverofGABAfromthesynaptic
cleft.GABABreceptorsarealsopresentontheaxonterminalsofmanyexcitatoryandinhibitorysynapses.Inthis
case,GABAspillsoverontothesepresynapticGABABreceptors,inhibitingtransmitterreleasebyinhibitingCa2+
channels.Inadditiontotheircouplingtoionchannels,GABABreceptorsalsoinhibitadenylylcyclaseanddecrease
cAMPgeneration.

Acetylcholine

AcetylcholinewasthefirstcompoundtobeidentifiedpharmacologicallyasatransmitterintheCNS.Eccles
showedintheearly1950sthatexcitationofspinalcordRenshawcellsbyrecurrentaxoncollateralsfromspinal
motorneuronswasblockedbynicotinicantagonists.Furthermore,Renshawcellswereextremelysensitiveto
nicotinicagonists.Thisearlysuccessatidentifyingatransmitterforacentralsynapsewasfollowedby
disappointmentbecauseitremainedthesolecentralsynapseforwhichthetransmitterwasknownuntilthelate
1960s,whencomparabledatabecameavailableforGABAandglycine.Themotoraxoncollateralsynapse
remainsoneofthebestdocumentedexamplesofacholinergicnicotinicsynapseinthemammalianCNS,despite
theratherwidespreaddistributionofnicotinicreceptorsasdefinedbyinsituhybridizationstudies.

MostCNSresponsestoacetylcholinearemediatedbyalargefamilyofGproteincoupledmuscarinicreceptors.At
afewsites,acetylcholinecausesslowinhibitionoftheneuronbyactivatingtheM2subtypeofreceptor,which
openspotassiumchannels.Afarmorewidespreadmuscarinicactioninresponsetoacetylcholineisaslow
excitationthatinsomecasesismediatedbyM1receptors.Thesemuscariniceffectsaremuchslowerthaneither
nicotiniceffectsonRenshawcellsortheeffectofaminoacids.Furthermore,thisM1muscarinicexcitationis
unusualinthatacetylcholineproducesitbydecreasingthemembranepermeabilitytopotassium,ie,theopposite
ofconventionaltransmitteraction.

EightmajorCNSnucleiofacetylcholineneuronshavebeencharacterizedwithdiffuseprojections.Theseinclude
neuronsintheneostriatum,themedialseptalnucleus,andthereticularformationthatappeartoplayanimportant
roleincognitivefunctions,especiallymemory.PreseniledementiaoftheAlzheimertypeisreportedlyassociated
withaprofoundlossofcholinergicneurons.However,thespecificityofthislosshasbeenquestionedbecausethe
levelsofotherputativetransmitters,eg,somatostatin,arealsodecreased.

MonoamineNeurotransmitters

Monoaminesincludethecatecholamines(dopamineandnorepinephrine)and5hydroxytryptamine.Thediamine
neurotransmitter,histamine,hasseveralsimilaritiestothesemonoamines.Althoughthesecompoundsarepresent
inverysmallamountsintheCNS,theycanbelocalizedusingextremelysensitivehistochemicalmethods.These
pathwaysarethesiteofactionofmanydrugsforexample,theCNSstimulantscocaineandamphetamineappear
toactprimarilyatcatecholaminesynapses.Cocaineblocksthereuptakeofdopamineandnorepinephrine,
whereasamphetaminescausepresynapticterminalstoreleasethesetransmitters.

A.Dopamine

Themajorpathwayscontainingdopaminearetheprojectionlinkingthesubstantianigratotheneostriatumandthe
projectionlinkingtheventraltegmentalregiontolimbicstructures,particularlythelimbiccortex.Thetherapeutic
actionoftheantiparkinsonismdruglevodopaisassociatedwiththeformerarea(seeChapter28),whereasthe
therapeuticactionoftheantipsychoticdrugsisthoughttobeassociatedwiththelatter(seeChapter29).In
addition,dopaminecontainingneuronsintheventralhypothalamusplayanimportantroleinregulatingpituitary
function.Fivedopaminereceptorshavebeenidentified,andtheyfallintotwocategories:D1like(D1andD5)and
D2like(D2,D3,D4).Alldopaminereceptorsaremetabotropic.Dopaminegenerallyexertsaslowinhibitoryaction
onCNSneurons.Thisactionhasbeenbestcharacterizedondopaminecontainingsubstantianigraneurons,
whereD2receptoractivationopenspotassiumchannelsviatheGicouplingprotein.

B.Norepinephrine

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Mostnoradrenergicneuronsarelocatedinthelocuscaeruleusorthelateraltegmentalareaofthereticular
formation.Althoughthedensityoffibersinnervatingvarioussitesdiffersconsiderably,mostregionsoftheCNS
receivediffusenoradrenergicinput.Allnoradrenergicreceptorsubtypesaremetabotropic.Whenappliedto
neurons,norepinephrinecanhyperpolarizethembyincreasingpotassiumconductance.Thiseffectismediatedby
2receptorsandhasbeencharacterizedmostthoroughlyonlocuscaeruleusneurons.Inmanyregionsofthe
CNS,norepinephrineactuallyenhancesexcitatoryinputsbybothindirectanddirectmechanisms.Theindirect
mechanisminvolvesdisinhibitionthatis,inhibitorylocalcircuitneuronsareinhibited.Thedirectmechanism
involvesblockadeofpotassiumconductancesthatslowneuronaldischarge.Dependingonthetypeofneuron,this
effectismediatedbyeither1orreceptors.Facilitationofexcitatorysynaptictransmissionisinaccordancewith
manyofthebehavioralprocessesthoughttoinvolvenoradrenergicpathways,eg,attentionandarousal.

C.5Hydroxytryptamine

Most5hydroxytryptamine(5HT,serotonin)pathwaysoriginatefromneuronsinthemidlineraphenucleiofthe
ponsandupperbrainstem.5HTiscontainedinunmyelinatedfibersthatdiffuselyinnervatemostregionsofthe
CNS,butthedensityoftheinnervationvaries.5HTactsonmorethanadozenreceptorsubtypes.Exceptforthe
5HT3receptor,allofthesereceptorsaremetabotropic.Theionotropic5HT3receptorexertsarapidexcitatory
actionataverylimitednumberofsitesintheCNS.InmostareasoftheCNS,5HThasastronginhibitoryaction.
Thisactionismediatedby5HT1Areceptorsandisassociatedwithmembranehyperpolarizationcausedbyan
increaseinpotassiumconductance.Ithasbeenfoundthat5HT1AreceptorsandGABABreceptorsactivatethe
samepopulationofpotassiumchannels.Somecelltypesareslowlyexcitedby5HTowingtoitsblockadeof
potassiumchannelsvia5HT2or5HT4receptors.Bothexcitatoryandinhibitoryactionscanoccuronthesame
neuron.5HThasbeenimplicatedintheregulationofvirtuallyallbrainfunctions,includingperception,mood,
anxiety,pain,sleep,appetite,temperature,neuroendocrinecontrol,andaggression.Giventhebroadrolesof5HT
inCNSfunctionandtherichmoleculardiversityof5HTreceptors,itisnotsurprisingthatmanytherapeuticagents
targetthe5HTsystem(seeChapters16,29,30,and32).

D.Histamine

IntheCNS,histamineisexclusivelymadebyneuronsinthetuberomammillarynucleus(TMN)intheposterior
hypothalamus.Theseneuronsprojectwidelythroughoutthebrainandspinalcordwheretheymodulatearousal,
attention,feedingbehavior,andmemory(seeChapter16).Therearefourhistaminereceptors(H1toH4),allof
whicharemetabotropic.Centrallyactingantihistaminesaregenerallyusedfortheirsedativepropertiesand
antagonismofH1receptorsisacommonsideeffectofmanydrugsincludingsometricyclicantidepressantsand
antipsychotics.

Neuropeptides

AgreatmanyCNSpeptideshavebeendiscoveredthatproducedramaticeffectsbothonanimalbehaviorandon
theactivityofindividualneurons.Inmanycases,peptidehormonesdiscoveredintheperiphery(seeChapter17)
alsoactasneurotransmittersintheCNS.Asmostofthesepeptideswereinitiallynamedaccordingtotheir
peripheralfunctions,thenamesareoftenunrelatedtotheirCNSfunction.Thepathwaysformanyofthepeptides
havebeenmappedwithimmunohistochemicaltechniquesandincludeopioidpeptides(eg,enkephalins,
endorphins),neurotensin,substanceP,somatostatin,cholecystokinin,vasoactiveintestinalpolypeptide,
neuropeptideY,andthyrotropinreleasinghormone.

Unliketheclassicalneurotransmittersabove,whicharepackagedinsmallsynapticvesicles,neuropeptidesare
generallypackagedinlarge,densecorevesicles.Asintheperipheralautonomicnervoussystem,peptidesoften
coexistwithaconventionalnonpeptidetransmitterinthesameneuron,butthereleaseoftheneuropeptidesand
thesmallmoleculeneurotransmitterscanbeindependentlyregulated.Releasedneuropeptidesmayactlocallyor
maydiffuselongdistancesandbindtodistantreceptors.Mostneuropeptidereceptorsaremetabotropicand,like
monoaminereceptors,primarilyservemodulatoryrolesinthenervoussystem.Neuropeptideshavebeen
implicatedinawiderangeofCNSfunctionsincludingreproduction,socialbehaviors,appetite,arousal,pain,
reward,andlearningandmemory.Thus,neuropeptidesandtheirreceptorsareactivetargetsofdrugdiscovery
efforts.

AgoodexampleoftheapproachesusedtodefinetheroleofthesepeptidesintheCNScomesfromstudieson
substancePanditsassociationwithsensoryfibers.SubstancePiscontainedinandreleasedfromsmall

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unmyelinatedprimarysensoryneuronsinthespinalcordandbrainstemandcausesaslowexcitatorypostsynaptic
potentialintargetneurons.Thesesensoryfibersareknowntotransmitnoxiousstimuli,anditistherefore
surprisingthatalthoughsubstancePreceptorantagonistscanmodifyresponsestocertaintypesofpaintheydo
notblocktheresponse.Glutamate,whichisreleasedwithsubstancePfromthesesynapses,presumablyplaysan
importantroleintransmittingpainstimuli.SubstancePiscertainlyinvolvedinmanyotherfunctionsbecauseitis
foundinmanyareasoftheCNSthatareunrelatedtopainpathways.

Orexin

Orexinsarepeptideneurotransmittersproducedinneuronsinthelateralandposteriorhypothalamusthat,likethe
monoaminesystems,projectwidelythroughouttheCNS.Orexinsarealsocalledhypocretinsbecauseofthenear
simultaneousdiscoverybytwoindependentlaboratories.Likemostneuropeptides,orexinisreleasedfromlarge,
densecorevesiclesandbindtotwoGproteincoupledreceptors,OX1andOX2.Orexinneuronsalsorelease
glutamateandarethusexcitatory.Theorexinsystem,likethemonoaminesystems,projectswidelythroughoutthe
CNStoinfluencephysiologyandbehavior.Inparticular,orexinneuronsexhibitfiringpatternsassociatedwith
wakefulnessandprojecttoandactivatemonoamineandacetylcholineneuronsinvolvedinsleepwakecycles(see
alsoChapter22).Animalslackingorexinoritsreceptorshavenarcolepsyanddisruptedsleepwakepatterns.In
additiontopromotingwakefulness,theorexinsystemisinvolvedinenergyhomeostasis,feedingbehaviors,
autonomicfunction,andreward.

OtherSignalingSubstances

A.Endocannabinoids

Theprimarypsychoactiveingredientincannabis,9tetrahydrocannabinol(9THC),affectsthebrainmainlyby
activatingaspecificcannabinoidreceptor,CB1.CB1receptorsareexpressedathighlevelsinmanybrainregions,
andtheyareprimarilylocatedonpresynapticterminals.Severalendogenousbrainlipids,includinganandamide
and2arachidonylglycerol(2AG),havebeenidentifiedasCB1ligands.Theseligandsarenotstored,asare
classicneurotransmitters,butinsteadarerapidlysynthesizedbyneuronsinresponsetodepolarizationand
consequentcalciuminflux.Activationofmetabotropicreceptors(eg,byacetylcholineandglutamate)canalso
activatetheformationof2AG.Infurthercontradistinctiontoclassicneurotransmitters,endogenouscannabinoids
canfunctionasretrogradesynapticmessengers:Theyarereleasedfrompostsynapticneuronsandtravel
backwardacrosssynapses,activatingCB1receptorsonpresynapticneuronsandsuppressingtransmitterrelease.
Thissuppressioncanbetransientorlonglasting,dependingonthepatternofactivity.Cannabinoidsmayaffect
memory,cognition,andpainperceptionbythismechanism.

B.NitricOxide

TheCNScontainsasubstantialamountofnitricoxidesynthase(NOS)withincertainclassesofneurons.This
neuronalNOSisanenzymeactivatedbycalciumcalmodulin,andactivationofNMDAreceptors,whichincreases
intracellularcalcium,resultsinthegenerationofnitricoxide.Althoughaphysiologicrolefornitricoxidehasbeen
clearlyestablishedforvascularsmoothmuscle,itsroleinsynaptictransmissionandsynapticplasticityremains
controversial.Nitricoxidediffusesfreelyacrossmembranesandthushasbeenhypothesizedtobearetrograde
messenger,althoughthishasnotbeendemonstratedconclusively.Perhapsthestrongestcaseforaroleofnitric
oxideinneuronalsignalingintheCNSisforlongtermdepressionofsynaptictransmissioninthecerebellum.

C.Purines

Receptorsforpurines,particularlyadenosine,ATP,UTP,andUDP,arefoundthroughoutthebody,includingthe
CNS.HighconcentrationsofATParefoundinandreleasedfromcatecholinergicsynapticvesicles,andATPmay
beconvertedtoadenosineextracellularlybynucleotidases.AdenosineintheCNSactsonmetabotropicA1
receptors.PresynapticA1receptorsinhibitcalciumchannelsandinhibitreleaseofbothaminoacidand
monoaminetransmitters.ATPcoreleasedwithotherneurotransmitterscanbindtotwoclassesofreceptors.The
P2XfamilyofATPreceptorscomprisesnonselectiveligandgatedcationchannels,whereastheP2Yfamilyis
metabotropic.ThephysiologicalrolesforcoreleasedATPremainelusive,butpharmacologicalstudiessuggest
thesereceptorsareinvolvedinmemory,wakefulness,andappetite,andmayplayrolesinmultipleneuropsychiatric
disorders.

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