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NationalInstituteonDrugAbuse(NIDA)

TheNeurobiologyofDrugAddiction

LastUpdatedJanuary2007

https://www.drugabuse.gov

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TableofContents

TheNeurobiologyofDrugAddiction

SectionI:IntroductiontotheBrain

SectionII:TheRewardPathwayandAddiction

SectionIII:TheActionofHeroin(Morphine)

SectionIV:TheActionofCocaine

BackgroundInformationforthePresenter

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SectionI:IntroductiontotheBrain

1:Introduction

Introducethepurposeofyourpresentation.Indicatethatyouwillexplainhowthebrainbasicallyworksandhowandwheredrugssuchasheroinandcocaineworkinthebrain.Tellyouraudiencethatyouwilldiscusstheconceptof"reward"whichisthepropertythatischaracteristicofmanyaddictivedrugs.

2:Thebrainandspinalcord

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Thecentralnervoussystemiscomposedofboththebrainandthespinalcord.Describethebrainasafunctionalunit;itismadeupofbillionsofnervecells(neurons)thatcommunicatewitheachotherusingelectricalandchemicalsignals.

3:Brainregionsandneuronalpathways

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Certainpartsofthebraingovernspecificfunctions.Pointtoareassuchasthesensory(blue),motor(orange)andvisualcortex(yellow)tohighlighttheirspecificfunctions.Pointtothecerebellum(pink)forcoordinationandtothehippocampus(green)formemory.Indicatethatnervecellsorneuronsconnectoneareatoanotherviapathwaystosendandintegrateinformation.Thedistancesthatneuronsextendcanbeshortorlong.Forexample,pointtotherewardpathway(deeporange).Explainthatthispathwayisactivatedwhenapersonreceivespositivereinforcementforcertainbehaviors("reward").Indicatethatyouwillexplainhowthishappenswhenapersontakesanaddictivedrug.Asanotherexample,pointtothethalamus(magenta).Thisstructurereceivesinformationaboutpaincomingfromthebody(magentalinewithinthespinalcord),andpassestheinformationuptothecortex.Telltheaudiencethatyoucanlookatthisinmoredetail.

4:Pathwayforsensationofpainandreactiontopain

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Thisisalongpathway,inwhichneuronsmakeconnectionsinboththebrainandthespinalcord.Explainwhathappenswhenoneslamsadooronone'sfinger.First,nerveendingsinthefingersensetheinjurytothefinger(sensoryneurons)andtheysendimpulsesalongaxonstothespinalcord(magentapathway).Pointtoeachpartofthepathwayasyouexplaintheflowofinformation.Theincomingaxonsformasynapsewithneuronsthatprojectuptothebrain.Theneuronsthattravelupthespinalcordthenformsynapseswithneuronsinthethalamus,whichisapartofthemidbrain(magentacircle).Thethalamusorganizesthisinformationandsendsittothesensorycortex(blue),whichinterpretstheinformationaspainanddirectsthenearbymotorcortex(orange)tosendinformationbacktothethalamus(greenpathway).Again,thethalamusorganizesthisincominginformationandsendssignalsdownthespinalcord,whichdirectmotorneuronstothefingerandotherpartsofthebodytoreacttothepain(e.g.,shakingthefingerorscreaming"ouch!").

5:Neuronalstructure

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Indicatethatthesepathwaysaremadeupofneurons.Thisimagecontainsrealneuronsfromthethalamus.Theyhavebeenfilledwithafluorescentdyeandviewedthroughamicroscope.Describetheanatomyofaneuron:pointtothecellbody(soma),dendrites,andaxon(markedwithtext).Attheendoftheaxonistheterminal,whichmakesaconnectionwithanotherneuron.[Note:theaxonhasbeendrawninforclarity,butactually,theaxonsoftheseneuronstraveltothecerebralcortex.]

6:Impulseflow

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Explainthenormaldirectionoftheflowofinformation(electricalandchemical).Anelectricalimpulse(theactionpotential)travelsdowntheaxontowardtheterminal.Pointtotheterminal.Theterminalmakesaconnectionwiththedendriteofneighboringneuron,whereitpassesonchemicalinformation.Theareaofconnectioniscalledthesynapse.Althoughthesynapsebetweenaterminalandadendrite(shownhere)isquitetypical,othertypesofsynapsesexistaswell.Forexample,asynapsecanoccurbetweenaterminalandasomaoraxon.

7:Thesynapseandsynapticneurotransmission

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Describethesynapseandtheprocessofchemicalneurotransmission.Asanelectricalimpulsearrivesattheterminal,ittriggersvesiclescontaininganeurotransmitter,suchasdopamine(inblue),tomovetowardtheterminalmembrane.Thevesiclesfusewiththeterminalmembranetoreleasetheircontents(inthiscase,dopamine).Onceinsidethesynapticcleft(thespacebetweenthetwoneurons)thedopaminecanbindtospecificproteinscalleddopaminereceptors(inpink)onthemembraneofaneighboringneuron.Thisisillustratedinmoredetailonthenextimage.

8:Dopamineneurotransmissionandmodulationbyendogenousopiates

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Usingtheclose-upofasynapse,continueusingdopamineforyourexampleofsynapticfunction.Explainthatitissynthesizedinthenerveterminalandpackagedinvesicles.Reiteratethestepsinneurotransmission.Showhowthevesiclefuseswiththemembraneandreleasesdopamine.Thedopaminemoleculescanthenbindtoadopaminereceptor(inpink).Afterthedopaminebinds,itcomesoffthereceptorandisremovedfromthesynapticcleftbyuptakepumps(alsoproteins)thatresideontheterminal(arrowsshowthedirectionofmovement).Thisprocessisimportantbecauseitensuresthatnottoomuchdopamineremainsinthesynapticcleftatanyonetime.Alsopointoutthatthereareneighboringneuronsthatreleaseanothercompoundcalledaneuromodulator.Neuromodulatorshelptoenhanceorinhibitneurotransmissionthatiscontrolledbyneurotransmitterssuchasdopamine.Inthiscase,theneuromodulatorisan"endorphin"(inred).Endorphinsbindtoopiatereceptors(inyellow)whichcanresideonthepost-synapticcell(shownhere)or,insomecases,ontheterminalsofotherneurons(thisisnotshownsoitmustbepointedout).Theendorphinsaredestroyedbyenzymesratherthanremovedbyuptakepumps

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SectionII:TheRewardPathwayandAddiction

1:Therewardpathwayandaddiction

Introducetheconceptofreward.Humans,aswellasotherorganismsengageinbehaviorsthatarerewarding;thepleasurablefeelingsprovidepositivereinforcementsothatthebehaviorisrepeated.Therearenaturalrewardsaswellasartificialrewards,suchasdrugs.

2:Naturalrewards

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Naturalrewardssuchasfood,water,sex,andnurturingallowtheorganismtofeelpleasurewheneating,drinking,procreating,andbeingnurtured.Suchpleasurablefeelingsreinforcethebehaviorsothatitwillberepeated.Eachofthesebehaviorsisrequiredforthesurvivalofthespecies.Remindyouraudiencethatthereisapathwayinthebrainthatisresponsibleforrewardingbehaviors.Thiscanbeviewedinmoredetailinthenextimage.

3:Therewardpathway

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Tellyouraudiencethatthisisaviewofthebraincutdownthemiddle.Animportantpartoftherewardpathwayisshownandthemajorstructuresarehighlighted:theventraltegmentalarea(VTA),thenucleusaccumbens,andtheprefrontalcortex.TheVTAisconnectedtoboththenucleusaccumbensandtheprefrontalcortexviathispathwayanditsendsinformationtothesestructuresviaitsneurons.TheneuronsoftheVTAcontaintheneurotransmitterdopamine,whichisreleasedinthenucleusaccumbensandintheprefrontalcortex(pointtoeachofthesestructures).Reiteratethatthispathwayisactivatedbyarewardingstimulus.[Note:thepathwayshownhereisnottheonlypathwayactivatedbyrewards,otherstructuresareinvolvedtoo,butonlythispartofthepathwayisshownforsimplicity.]

4:Activationoftherewardpathwaybyanelectricalstimulus

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Thediscoveryoftherewardpathwaywasachievedwiththehelpofanimalssuchasrats.Ratsweretrainedtopressaleverforatinyelectricaljolttocertainpartsofthebrain.Showthatwhenanelectrodeisplacedinthenucleusaccumbens,theratkeepspressingthelevertoreceivethesmallelectricalstimulusbecauseitfeelspleasurable.Thisrewardingfeelingisalsocalledpositivereinforcement.Pointtoanareaofthebrainclosetothenucleusaccumbens.Telltheaudiencethatwhentheelectrodeisplacedthere,theratwillnotpresstheleverfortheelectricalstimulusbecausestimulatingneuronsinanearbyareathatdoesnotconnectwiththenucleusaccumbensdoesnotactivatetherewardpathway.Theimportanceoftheneurotransmitterdopaminehasbeendeterminedintheseexperimentsbecausescientistscanmeasureanincreasedreleaseofdopamineintherewardpathwayaftertheratreceivesthereward.And,ifthedopaminereleaseisprevented(eitherwithadrugorbydestroyingthepathway),theratwon'tpressthebarfortheelectricaljolt.Sowiththehelpoftherats,scientistsfiguredoutthespecificbrainareasaswellastheneurochemicalsinvolvedintherewardpathway.

5:Addiction

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Nowthatyouhavedefinedtheconceptofreward,youcandefineaddiction.Addictionisastateinwhichanorganismengagesinacompulsivebehavior,evenwhenfacedwithnegativeconsequences.Thisbehaviorisreinforcing,orrewarding,asyouhavejustdiscussed.Amajorfeatureofaddictionisthelossofcontrolinlimitingintakeoftheaddictivesubstance.Themostrecentresearchindicatesthattherewardpathwaymaybeevenmoreimportantinthecravingassociatedwithaddiction,comparedtotherewarditself.Scientistshavelearnedagreatdealaboutthebiochemical,cellular,andmolecularbasesofaddiction;itisclearthataddictionisadiseaseofthebrain.Statethatyouwillprovidetwoexamplesoftheinteractionbetweendrugsthatareaddictive,theircellulartargetsinthebrain,andtherewardpathway.

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SectionIII:TheActionofHeroin(Morphine)

1:Theactionofheroin(morphine)

Heroinisanaddictivedrug,althoughnotallusersbecomeaddicted.Environmentandthepersonalityoftheuserareimportantinproducingaddiction.Heroinproduceseuphoriaorpleasurablefeelingsandcanbeapositivereinforcerbyinteractingwiththerewardpathwayinthebrain.Indicatethatyouwillexplainhowthishappens.

2:Localizationofopiatebindingsiteswithinthebrainandspinalcord

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Whenapersoninjectsheroin(ormorphine),thedrugtravelsquicklytothebrainthroughthebloodstream.Actually,heroincanreachthebrainjustasquicklyifitissmoked(seedescriptionofimage#25).Abusersalsosnortherointoavoidproblemswithneedles.Inthiscase,theheroindoesn'treachthebrainasquicklyasifitwereinjectedorsmoked,butitseffectscanlastlonger.Onceinthebrain,theheroinisconvertedtomorphinebyenzymes;themorphinebindstoopiatereceptorsincertainareasofthebrain.Pointtotheareaswhereopiatesbind(greendots).Partofthecerebralcortex,theVTA,nucleusaccumbens,thalamus,brainstem,andspinalcordarehighlighted.Showthatthemorphinebindstoopiatereceptorsthatareconcentratedinareaswithintherewardpathway(includingtheVTA,nucleusaccumbens,andcortex).Morphinealsobindstoareasinvolvedinthepainpathway(includingthethalamus,brainstem,andspinalcord).Bindingofmorphinetoareasinthepainpathwayleadstoanalgesia(lossofpain).

3:Morphinebindingwithintherewardpathway

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ReiteratethatmorphinebindstoreceptorsonneuronsintheVTAandinthenucleusaccumbens.Thisisshownherewithintherewardpathway.Indicatethatyouwillshowhowmorphineactivatesthispathwayonthenextimage.

4:Opiatesbindingtoopiatereceptorsinthenucleusaccumbens:increaseddopaminerelease

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Thisisaclose-upviewofasynapseinthenucleusaccumbens.Threetypesofneuronsparticipateinopiateaction:onethatreleasesdopamine(ontheleft),aneighboringterminal(ontheright)thatcontainsadifferentneurotransmitter(probablyGABAforthosewhowouldliketoknow),andthepost-synapticcellthatcontainsdopaminereceptors(inpink).Showthatopiatesbindtoopiatereceptors(yellow)ontheneighboringterminalandthissendsasignaltothedopamineterminaltoreleasemoredopamine.[Incasesomeoneaskshow,onetheoryisthatopiatereceptoractivationdecreasesGABArelease,whichnormallyinhibitsdopaminerelease,sodopaminereleaseisincreased.]

5:Ratsself-administerheroin

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Justasaratwillstimulateitselfwithasmallelectricaljolt(intotherewardpathway),itwillalsopressabartoreceiveheroin.Inthisimage,theratisself-administeringherointhroughasmallneedleplaceddirectlyintothenucluesaccumbens.Theratkeepspressingthebartogetmoreheroinbecausethedrugmakestheratfeelgood.Theheroinispositivelyreinforcingandservesasareward.Iftheinjectionneedleisplacedinanareanearbythenucleusaccumbens,theratwon'tself-administertheheroin.Scientistshavefoundthatdopaminereleaseisincreasedwithintherewardpathwayofratsself-administeringheroin.So,sincemoredopamineispresentinthesynapticspace,dopamine-dependentneurotransmissionisaugmented,causingtheactivationoftherewardpathway.

6:Definitionoftolerance

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Whendrugssuchasheroinareusedrepeatedlyovertime,tolerancemaydevelop.Toleranceoccurswhenthepersonnolongerrespondstothedruginthewaythatpersoninitiallyresponded.Statedanotherway,ittakesahigherdoseofthedrugtoachievethesamelevelofresponseachievedinitially.Forexample,inthecaseofheroinormorphine,tolerancedevelopsrapidlytotheanalgesiceffectsofthedrug.[Thedevelopmentoftoleranceisnotaddiction,althoughmanydrugsthatproducetolerancealsohaveaddictivepotential.]Tolerancetodrugscanbeproducedbyseveraldifferentmechanisms,butinthecaseofmorphineorheroin,tolerancedevelopsatthelevelofthecellulartargets.Forexample,whenmorphinebindstoopiatereceptors,ittriggerstheinhibitionofanenzyme(adenylatecyclase)thatorchestratesseveralchemicalsinthecelltomaintainthefiringofimpulses.Afterrepeatedactivationoftheopiatereceptorbymorphine,theenzymeadaptssothatthemorphinecannolongercausechangesincellfiring.Thus,theeffectofagivendoseofmorphineorheroinisdiminished.

7:Brainregionsmediatingthedevelopmentofmorphinetolerance

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Thedevelopmentoftolerancetotheanalgesiceffectsofmorphineinvolvesdifferentareasofthebrainseparatefromthoseintherewardpathway.Pointtothetwoareasinvolvedhere,thethalamus,andthespinalcord(greendots).Bothoftheseareasareimportantinsendingpainmessagesandareresponsiblefortheanalgesiceffectsofmorphine.Thepartsoftherewardpathwayinvolvedinheroinormorphineaddictionareshownforcomparison.

8:Definitionofdependence

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Withrepeateduseofheroin,dependencealsooccurs.Dependencedevelopswhentheneuronsadapttotherepeateddrugexposureandonlyfunctionnormallyinthepresenceofthedrug.Whenthedrugiswithdrawn,severalphysiologicreactionsoccur.Thesecanbemild(e.g.,forcaffeine)orevenlifethreatening(e.g.,foralcohol).Thisisknownasthewithdrawalsyndrome.Inthecaseofheroin,withdrawalcanbeveryseriousandtheabuserwillusethedrugagaintoavoidthewithdrawalsyndrome.

9:Brainregionsmediatingthedevelopmentofmorphinedependence

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Thedevelopmentofdependencetomorphinealsoinvolvesspecificareasofthebrain,separatefromtherewardpathway.Inthiscase,pointtothethalamusandthebrainstem(greendots).Thepartsoftherewardpathwayinvolvedinheroinormorphineaddictionareshownforcomparison.Manyofthewithdrawalsymptomsfromheroinormorphinearegeneratedwhentheopiatereceptorsinthethalamusandbrainstemaredeprivedofmorphine.

10:Addictionvsdependence

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Asyouhavejustexplained,differentpartsofthebrainareresponsiblefortheaddictionanddependencetoheroinandopiates.Reviewtheareasinthebrainunderlyingtheaddictiontomorphine(rewardpathway)andthoseunderlyingthedependencetomorphine(thalamusandbrainstem).Thus,itispossibletobedependentonmorphine,withoutbeingaddictedtomorphine.(Although,ifoneisaddicted,theyaremostlikelydependentaswell.)Thisisespeciallytrueforpeoplebeingtreatedchronicallywithmorphine,forexample,painassociatedwithterminalcancer.Theymaybedependent-ifthedrugisstopped,theysufferawithdrawalsyndrome.But,theyarenotcompulsiveusersofthemorphine,andtheyarenotaddicted.Finally,peopletreatedwithmorphineinthehospitalforpaincontrolaftersurgeryareunlikelytobecomeaddicted;althoughtheymayfeelsomeoftheeuphoria,theanalgesicandsedatingeffectspredominate.Thereisnocompulsiveuseandtheprescribeduseisshort-lived.

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SectionIV:TheActionofCocaine

1:Theactionofcocaine

Cocaineisalsoanaddictivedrug,andlikeheroin,notallusersbecomeaddicted.However,withtheadventofcrackcocaine(thefreebase),therateofaddictiontococainehasincreasedconsiderably.

2:Snortingvssmokingcocaine:differentaddictiveliabilities

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Historicallycocaineabuseinvolvedsnortingthepowderedform(thehydrochloridesalt).Whencocaineisprocessedtoformthefreebase,itcanbesmoked.Heatingthehydrochloridesaltformofcocainewilldestroyit;thefreebasecanbevolatilizedathightemperaturewithoutanydestructionofthecompound.Smokinggetsthedrugtothebrainmorequicklythandoessnorting.Showtheaudiencewhythishappens.Snortingrequiresthatthecocainetravelsfromthebloodvesselsinthenosetotheheart(purplearrow),whereitgetspumpedtothelungs(purplearrow)tobeoxygenated.Theoxygenatedblood(redarrows)carryingthecocainethentravelsbacktotheheartwhereitispumpedouttotheorgansofthebody,includingthebrain.However,smokingbypassesmuchofthis,thecocainegoesfromthelungsdirectlytotheheartanduptothebrain.Thefasteradrugwithaddictiveliabilityreachesthebrain,themorelikelyitwillbeabused.Thus,thetimebetweentakingthedrugandthepositivereinforcingorrewardingeffectsthatareproducedcandeterminethelikelihoodofabuse.

3:Localizationofcocaine"bindingsites"

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Whenapersonsmokesorsnortscocaine,itreachesallareasofthebrain,butitbindstositesinsomeveryspecificareas.Thesearehighlightedwiththeyellowdots:theVTA,thenucleusaccumbens,andthecaudatenucleus(thelargeststructure).Pointoutthatcocainebindsespeciallyintherewardareasthatyouhavejustdiscussed.Thebindingofcocaineinotherareassuchasthecaudatenucleuscanexplainothereffectssuchasincreasedstereotypic(orrepetitive)behaviors(pacing,nail-biting,scratching,etc..)

4:Dopaminebindingtoreceptorsanduptakepumpsinthenucleusaccumbens:theactionofcocaine

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ExplainthatcocainebindstositesinareasofthebrainthatarerichindopaminesynapsessuchastheVTAandthenucleusaccumbens.Reviewdopaminetransmissionintheclose-upofasynapseinthenucleusaccumbens.Pointtodopamine(insidetheterminal)thatisreleasedintothesynapticspace.Thedopaminebindstodopaminereceptorsandthenistakenupbyuptakepumpsbackintotheterminal.Nowshowwhathappenswhencocaineispresent(yellow).Cocainebindstotheuptakepumpsandpreventsthemfromtransportingdopaminebackintotheneuronterminal.Somoredopaminebuildsupinthesynapticspaceanditisfreetoactivatemoredopaminereceptors.Thisisthesameeffectthatyoushowedinanearlierimagewithmorphine,wheremorphineincreaseddopaminereleasefromtheterminaltoproducemoredopamineinthesynapticspace.

5:Cocainedependenceandactivationoftherewardpathway

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Reviewwherecocainebindswithintherewardpathway(theVTAandthenucleusaccumbens).Asaresultofcocaine'sactionsinthenucleusaccumbens(pointtothedotsofcocaineintheVTAandnucleusaccumbens),thereareincreasedimpulsesleavingthenucleusaccumbenstoactivatetherewardsystem.Thispathwaycanbeactivatedevenintheabsenceofcocaine(i.e.,duringcraving).Indicatethatwithrepeateduseofcocaine,thebodyreliesonthisdrugtomaintainrewardingfeelings.Thepersonisnolongerabletofeelthepositivereinforcementorpleasurablefeelingsofnaturalrewards(i.e.food,water,sex)--thepersonisonlyabletofeelpleasurefromthecocaine.Thustheuserbecomesdependentandwhenthecocaineisnolongerpresent,anhedonia(inabilitytofeelpleasure)anddepressionemergeaspartofawithdrawalsyndrome.Toavoidthis,theusergoesbacktothecocaine.Unliketheexampleformorphine,cocaineaddiction(i.e.,craving)anddependence(i.e.,anhedonia)bothinvolvestructuresintherewardpathway.

6:Ratsself-administercocaine

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Scientistshavemeasuredincreaseddopaminelevelsinthesynapsesoftherewardpathwayinratsself-administeringcocaine.Justastheydidforheroin,ratswillpressabartoreceiveinjectionsofcocainedirectlyintoareasoftherewardpathwaysuchasthenucleusaccumbensandtheVTA.Again,iftheinjectionneedleisplacedneartheseregions(butnotinthem),theratwillnotpressthebartoreceivethecocaine.Theabilityofratstoself-administercocaineisanexcellentpredictoroftheaddictivepotentialofthisdrug.

7:Summary:addictivedrugsactivatetherewardsystemviaincreasingdopamineneurotransmission

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Inthislastimage,therewardpathwayisshownalongwithseveraldrugsthathaveaddictivepotential.JustasheroinormorphineandcocaineactivatetherewardpathwayintheVTAandnucleusaccumbens,otherdrugssuchasnicotineandalcoholactivatethispathwayaswell,althoughsometimesindirectly(pointtotheglobuspallidus,anareaactivatedbyalcoholthatconnectstotherewardpathway).Althougheachdrughasadifferentmechanismofaction,eachdrugincreasestheactivityoftherewardpathwaybyincreasingdopaminetransmission.Becauseofthewayourbrainsaredesigned,andbecausethesedrugsactivatethisparticularbrainpathwayforreward,theyhavetheabilitytobeabused.Thus,addictionistrulyadiseaseofthebrain.Asscientistslearnmoreaboutthisdisease,theymayhelptofindaneffectivetreatmentstrategyfortherecoveringaddict.

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BackgroundInformationforthePresenter

Objectives

Theobjectiveoftheteachingpacketistoillustratetotheaudiencethebasicfunctionofthebrain,theneurobiologicalbasisforaddictionandtheactionsofheroinandcocaine.Thepacketisarrangedin4sections.Thefirstsectionintroducesthebrainandpresentssomebasicneurobiology,thesecondintroducestherewardpathwayandthethirdandfourthpresentthemechanismofactionofheroinandcocaineandhoweachaffectstherewardsystem.

BeforeUsingtheTeachingPacket

Knowyourtargetaudience.Bepreparedtoadjustyourpresentationdependingonthedegreeofeducationandtrainingofyouraudience.

Readthenarrativescriptandpracticethepresentation.Bepreparedtodefineanywordusedinthepresentation.Ifyouneedadditionalinformation,severalreferencematerialsarealsoincludedattheend.

GeneralInstructions

Thepresentationshouldtakeapproximately30-40minutes(withoutquestions).

Usethenarrativetextasaguide,itneednotberepeatedword-for-word.

AdditionalReferenceMaterial

1. G.HansonandP.J.Venturelli.DrugsandSociety,JonesandBarlettPublishers,Boston,1995.

2. O.RayandC.Ksir.Drugs,Society,andHumanBehavior,Mosby,St.Louis,1996.

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3. R.R.Levine,C.A.WalshandR.D.Schwartz.Pharmacology:DrugActionsandReactions,ParthenonPublishingGroup,NewYork,1996.

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