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NationalInstituteonDrugAbuse(NIDA)

TheBrain&theActionsofCocaine,OpioidsandMarijuana

LastUpdatedJanuary2007https://www.drugabuse.gov

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TableofContents

TheBrain&theActionsofCocaine,OpioidsandMarijuana

SectionI:IntroductiontotheBrain

SectionII:IntroductiontotheRewardSystem

SectionIII:IntroductiontoDrugsofAbuse:Cocaine,Opiates(Heroin)andMarijuana(THC)

BackgroundInformationforthePresenter

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SectionI:IntroductiontotheBrain

1:Introduction

Introducethetopicofyourtalk.Indicatethatyouwillexplainhowthebrainbasicallyworksandhowdrugssuchascocaine,opiatesandmarijuanainteractwiththebrain'snormalactivities.Tellstudentsthatyouwillintroducetheconceptof"reward"whichisthepropertythatischaracteristicofmanyaddictivedrugs.Describethebrainasafunctionalunit;itismadeupofbillionsofnervecells(neurons)thatcommunicatewitheachotherusingelectricalandchemicalsignals.

2:Brainregionsandneuronalpathways

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Certainpartsofthebraingovernspecificfunctions.Pointtosensory,motor,associationandvisualcortextohighlightspecificfunctions.Pointtothehippocampustohighlighttheregionthatiscriticalformemory,forexample.Indicatethatnervecellsorneuronstravelfromoneareatoanotherviapathwaystosendandintegrateinformation.Show,forexample,therewardpathway.Startattheventraltegmentalarea(VTA)(inblue),followtheneuronalpathtothenucleusaccumbens(purple),andthenontothefrontalcortex.Explainthatthispathwaygetsactivatedwhenapersonreceivespositivereinforcementforcertainbehaviors("reward").Indicatethatyouwillexplainhowthishappenswhenapersontakesanaddictivedrug.

3:Neuronalstructure

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Remindthestudentthatpathwaysaremadeupofneurons.Describetheanatomyofaneuron(soma,dendrites,andaxonaremarkedwithtext).Statethatthisneuronisreal-asviewedthroughamicroscope.Explainthenormaldirectionofimpulseflow.Dendritesandsomareceivechemicalinformationfromneighboringneuronalaxons.Thechemicalinformationisconvertedtoelectricalcurrentswhichtraveltowardandconvergeonthesoma.Amajorimpulseisproduced(theactionpotential)andtravelsdowntheaxontowardtheterminal.Pointtotheterminal.

4:Thesynapseandsynapticneurotransmission

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Describethesynapseandtheprocessofchemicalneurotransmission.Indicatehowvesiclescontaininganeurotransmitter,suchasdopamine(thestars),movetowardthepresynapticmembraneasanelectricalimpulsearrivesattheterminal.Describetheprocessofdopaminerelease(showhowthevesiclesfusewiththepresynapticmembrane).Onceinsidethesynapticcleft,thedopaminecanbindtospecificproteinscalleddopaminereceptors(inblue)onthemembraneofaneighboringneuron.Introducetheideathatoccupationofreceptorsbyneurotransmitterscausesvariousactionsinthecell;activationorinhibitionofenzymes,entryorexitofcertainions.Statethatyouwilldescribehowthishappensinafewmoments.

5:Dopamineneurotransmission

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Usingtheclose-upofasynapse,continueusingdopamineforyourexampleofsynapticfunction.Explainthatitissynthesizedinthenerveterminalandpackagedinvesicles.Reiteratethestepsinneurotransmission.Showhowthevesiclefuseswiththemembraneandreleasesdopamine.Thedopaminemoleculescanthenbindtoadopaminereceptor(inblue).Afterthedopaminebinds,itcomesoffthereceptorandisremovedfromthesynapticcleftbyuptakepumps(alsoproteins)(inred)thatresideontheterminal.Thisprocessisimportantsothatnottoomuchdopamineisleftinthesynapticcleftatanyonetime.Alsopointoutthatthereisaneighboringneuron,whichreleasesanothercompoundcalledaneuromodulator.Inthiscaseitisan"endorphin"(blueflyingsaucers).Endorphinsbindtoopiatereceptors(ingreen)whichresideonthepost-synapticcellorinsomecasesontheterminalsofotherneurons(thisisnotshownsoitmustbepointedout).Theendorphinsaredestroyedbyenzymesratherthanremovedbyuptakepumps.

6:DopamineandtheproductionofcyclicAMP

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Usingtheclose-upview,explainwhathappenswhendopaminebindstoitsreceptor.Whendopaminebindstoitsreceptor,anotherproteincalledaG-protein(inpink)movesupclosetothedopaminereceptor.TheG-proteinsignalsanenzymetoproducecyclicadenosinemonophosphate(cAMP)molecules(ingreen)insidethecell.[SometimesthesignalcandecreaseproductionofcAMP,dependingonthekindofdopaminereceptorandG-proteinpresent.]Pointtothedopaminereceptor-G-protein/adenylatecyclasecomplex,andshowhowcAMPisgeneratedwhendopaminebindstoitsreceptor.IndicatethatcAMP(pointtothecyclic-lookingstructures)controlsmanyimportantfunctionsinthecellincludingtheabilityofthecelltogenerateelectricalimpulses.

7:Summaryofneuronaltransmission

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Usetheexampleoftwoneuronsmakingcontacttosummarizeneuronaltransmission.Pointtothecellonthetopandindicatethatelectricalimpulsesflowinthedirectiontowardtheterminal.Remindthestudentswhathappenswhenimpulsesreachtheterminal;neurotransmittersarereleased,theybindtotheirreceptors,andnewimpulsesaregeneratedinthecellonthebottom.Explainthatthisishowinformationtravelsfromneurontoneuron.

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SectionII:IntroductiontotheRewardSystem

1:Reward:drugself-administration

Introducetheconceptofpositivereinforcementorreward.Explainthatratswillpressalevertoself-administeraninjectionofcocaineorherointhatisinsertedintoeithertheperipheralbloodstream(leftimage)orintospecificbrainregions(rightimage).Theratkeepspressingtogetmorecocaineorheroinbecausethedrugsmaketheratfeelsogood.Thisiscalledpositivereinforcement,orreward.Naturalrewardsincludefood,water,andsex-eachisrequiredtomaintainsurvivalofourspecies.Animalsandpeoplewillcontinuetoexhibitabehaviorthatisrewarding,andtheywillceasethatbehaviorwhentherewardisnolongerpresent.Explainthatthereisactuallyapartofthebrainthatisactivatedbynaturalrewardsandbyartificialrewardssuchasaddictivedrugs.Thispartofthebrainiscalledtherewardsystem.Neuroscientistshavebeenabletopinpointtheexactpartsofthebraininvolved,withthehelpoftherats.Pointto

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thecartoonontherightandexplainthatratswillalsoself-administeraddictivedrugsdirectlyintotheirbrains,butonlyintoaspecificareaoftherewardsystem.Iftheinjectionneedleismovedlessthanamillimeterawayfromthiscrucialarea,theratwon'tpresstheleverformoredrug.Sobasedoninformationfromworkingwiththerats,scientistshavedrawnamapofthebrain,andlocatedthestructuresandpathwaysthatareactivatedwhenanaddictivedrugistakenvoluntarily.Tellthestudentsthatyouwillshowthemthis"map."

2:Therewardpathway

Tellstudentsthatthisisaviewofthebraincutdownthemiddle.Animportantpartoftherewardsystemisshownandthemajorstructuresarehighlighted:theventraltegmentalarea(VTA),thenucleusaccumbens(nuc.acc.)andtheprefrontalcortex.Also,thepathwayconnectingthesestructuresishighlighted.TheinformationtravelsfromtheVTAtothenucleusaccumbensandthenuptotheprefrontalcortex.Reiteratethatthispathwayisactivatedbyarewardingstimulus.[Notetoscientists-thisisnottheonlypathwayactivatedbyreward,otherstructuresareinvolvedtoo,butonlythispartofthepathwayisshownforsimplicity.]

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3:Injectionofcocaineintothenucleusaccumbens

Demonstratehowscientistslocatedthestructuresimportantfortheaddictivenatureofdrugs.Showthataratwillself-administercocainedirectlyintothenucleusaccumbens(ortheVTA)toactivatethepathway.PointtoanareaclosetothenucleusaccumbensorVTAandstatethatiftheinjectionisplacedinthisotherarea,theratwillnotpressthelevertoreceivethedrug.Indicatethatscientistsknowalotmorethanwherethedrugactstoproducerewardingeffects-theyalsoknowhowthedrugswork.Showexampleswithcocaine,heroin,andmarijuana.

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SectionIII:IntroductiontoDrugsofAbuse:Cocaine,Opiates(Heroin)andMarijuana(THC)

1:Localizationofcocaine"bindingsites"

Whenapersonsmokesorsnortscocaine,ittravelsquicklytothebrain.Althoughitreachesallareasofthebrain,itconcentratesinsomespecificareas.Thesearehighlightedwiththeturquoisesprinkles;theVTA,thenucleusaccumbens,andthecaudatenucleus(lighterturquoisesincethecaudateisinsidethehemisphere).Pointoutthatcocaineconcentratesespeciallyintherewardareasthatyouhavejustdiscussed.Cocaineaccumulationinotherareassuchasthecaudatenucleuscanexplainothereffectssuchasincreasedstereotypicbehaviors(pacing,nail-biting,scratching,etc..)

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2:Dopaminebindingtoreceptorsanduptakepumpsinthenucleusaccumbens

Explainthatcocaineconcentratesinareasofthebrainthatarerichindopaminesynapses.Reviewdopaminetransmissioninthenucleusaccumbens.Pointtodopamineinthesynapseandtodopamineboundtodopaminereceptorsandtouptakepumpsontheterminal.

3:Cocainebindingtouptakepumps:inhibitionofdopamineuptake

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Now,showwhathappenswhencocaineispresentinthesynapse.Cocaine(turquoise)bindstotheuptakepumpsandpreventsthemfromremovingdopaminefromthesynapse.Thisresultsinmoredopamineinthesynapse,andmoredopaminereceptorsareactivated.

4:IncreasedcAMPproducedinpost-synapticcell

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Inacloserview,showhowthisaffectsthefunctionofthecell.TheincreasedactivationofdopaminereceptorscausesincreasedproductionofcAMPinsidethepost-synapticcell.Thiscausesmanychangesinsidethecellthatleadtoabnormalfiringpatterns.

5:Summary:cocainebindinginnucleusaccumbensandactivationofrewardpathway

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Showthe"bigpicture,"Asaresultofcocaine'sactionsinthenucleusaccumbens(pointtothesprinklesofcocaineinthenuc.acc.),thereareincreasedimpulsesleavingthenucleusaccumbenstoactivatetherewardsystem.Indicatethatwithcontinueduseofcocaine,thebodyreliesonthisdrugtomaintainrewardingfeelings.Thepersonisnolongerabletofeelthepositivereinforcementorpleasurablefeelingsofnaturalrewards(food,water,sex).

6:Positronemissiontomography(PET)scanofapersononcocaine

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Cocainehasotheractionsinthebraininadditiontoactivatingreward.Scientistshavetheabilitytoseehowcocaineactuallyaffectsbrainfunctioninpeople.ThePETscanallowsonetoseehowthebrainusesglucose;glucoseprovidesenergytoeachneuronsoitcanperformwork.Thescansshowwherethecocaineinterfereswiththebrain'suseofglucose-oritsmetabolicactivity.Theleftscanistakenfromanormal,awakeperson.Theredcolorshowsthehighestlevelofglucoseutilization(yellowrepresentslessutilizationandblueshowstheleast).Therightscanistakenfromacocaineabuseroncocaine.Itshowsthatthebraincannotuseglucosenearlyaseffectively-showthelossofredcomparedtotheleftscan.Therearemanyareasofthebrainthathavereducedmetabolicactivity.Thecontinuedreductionintheneurons'abilitytouseglucose(energy)resultsindisruptionofmanybrainfunctions.

7:Localizationofopiatebindingsites

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Whenapersoninjectsheroinormorphine,ittootravelsquicklytothebrain.Pointtotheareaswhereopiatesconcentrate.TheVTA,nucleusaccumbens,caudatenucleusandthalamusarehighlighted.Theopiatesbindtoopiatereceptorsthatareconcentratedinareaswithintherewardsystem.Indicatethattheactionofopiatesinthethalamuscontributestotheirabilitytoproduceanalgesia.

8:Opiatesbindingtoopiatereceptorsinthenucleusaccumbens:increaseddopaminerelease

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Showhowopiatesactiviatetherewardsystemusingthenucleusaccumbensasanexample.Explainthattheactionisalittlemorecomplicatedthancocaine'sbecausemorethantwoneuronsareinvolved.Pointoutthatthreeneuronsparticipateinopiateaction:thedopamineterminal,anotherterminal(ontheright)containingadifferentneurotransmitter(probablyGABAforthosethatwouldliketoknow),andthepost-synapticcellcontainingdopaminereceptors.Showthatopiatesbindtoopiatereceptors(green)ontheneighboringterminalandthissendsasignaltothedopamineterminaltoreleasemoredopamine.[Incaseaninquisitivestudentaskshow,onetheoryisthatopiatereceptoractivationdecreasesGABArelease,whichnormallyinhibitsdopaminerelease,sodopaminereleaseisincreased.]

9:IncreasedcAMPproducedinpost-synapticcell

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Inacloserview,again,showhowthisaffectsthefunctionofthepost-synapticcell.Sincethereismoredopaminereleased,thereisincreasedactivationofdopaminereceptors,similartotheeffectofcocaine.ThiscausesincreasedproductionofcAMPinsidethepost-synapticcell,whichaltersthenormalactivityoftheneuron.

10:Summary:opiatebindinginnucleusaccumbensandactivationoftherewardpathway

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Showthe"bigpicture."Asaresultofopiateactionsinthenucleusaccumbens(pointtothesprinklesofopiatesinthenuc.acc.),thereareincreasedimpulsesleavingthenucleusaccumbenstoactivatetherewardsystem(pointtothefrontalcortex).Aswithcocaine,continueduseofopiatesmakesthebodyrelyonthepresenceofthedrugtomaintainrewardingfeelingsandothernormalbehaviors.Thepersonisnolongerabletofeelthebenefitsofnaturalrewards(food,water,sex)andcan'tfunctionnormallywithoutthedrugpresent.

11:LocalizationofTHCbindingsites

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Whenapersonsmokesmarijuana,theactiveingredient,cannabinoidsorTHC,travelsquicklytothebrain.PointtotheareaswhereTHC(magenta)concentrates.TheVTA,nucleusaccumbens,caudatenucleus,hippocampus,andcerebellumarehighlighted.THCbindstoTHCreceptorsthatareconcentratedinareaswithintherewardsystemaswellastheseotherareas.IndicatethattheactionofTHCinthehippocampusexplainsitsabilitytointerferewithmemoryandactionsinthecerebellumareresponsibleforitsabilitytocauseincoordinationandlossofbalance.

12:THCbindingtoTHCreceptorsinthenucleusaccumbens:increaseddopaminerelease

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[Notetoscientists-theinteractionofTHCwiththerewardsystemisnotfullyunderstoodatthispoint.Thefollowingdiscussionisbasedonrecentdata,butadditionaltheoriesmayemergeasweobtainmoredata.]StatethatscientistsknowtheleastaboutTHC.Overthelastfewyears,therehasbeenintensestudytodiscoverwhereandhowTHCworks.Onetheoryisthatitactsinasimilarwaytoopiates.Againusethenucleusaccumbensasanexample.Thesamethreeneuronsareprobablyinvolved:thedopamineterminal,anotherterminal(ontheright)containingadifferentneurotransmitter(probablyGABA),andthepost-synapticcellcontainingdopaminereceptors.AskthestudentsiftheycantellyouhowTHCmightwork.THCbindstoTHCreceptors(magenta)ontheneighboringterminalandthissendsasignaltothedopamineterminaltoreleasemoredopamine.[Again,itisprobablyapresynapticreceptoronGABAinterneuronsthatcontrolsdopaminerelease.]

13:IncreasedcAMPproducedinpost-synapticcell

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Inacloserview,showhowthisaffectsthefunctionofthepost-syanapticcell.Sincethereismoredopaminereleased,thereisincreasedactivationofdopaminereceptors.ThiscausesincreasedproductionofcAMPinsidethepost-synapticcellwhichaltersthenormalactivityoftheneuron.

14:Summary:THCbindinginnucleusaccumbensandactivationoftherewardpathway

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Showthe"bigpicture."AsaresultofTHCactionsinthenucleusaccumbens(pointtotheconcentrationofTHCinthenuc.acc.),thereareincreasedimpulsesleavingthenucleusaccumbenstoactivatetherewardsystem(pointtothefrontalcortex).Scientistsstilldon'tknowhowthecontinueduseofmarijuanaalterstherewardsystem.Indicatethatthisisanareaofintenseresearchbyneuroscientists.

15:Overallsummary:thesedrugsofabuseallactivatetherewardsystemviaincreasingdopamineneurotransmission

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Inthislastimage,thebindingofallthreedrugsisshowninoneoftherewardareas,thenucleusaccumbens.Summarizethateachdrugincreasestheactivityoftherewardpathwaybyincreasingdopaminetransmission.Thishappenseventhoughthedrugsactbydifferentmechanisms.Becauseofthewayourbrainsaredesigned,andbecausethesedrugsactivateaparticularbrainpathwayforreward,theyhavetheabilitytobeabused.Startadiscussion;askthestudentsiftheycanthinkofanyotherdrugsthatareabusedthatprobablyactivatetherewardsysteminthesameway.Answer:alcohol,nicotine,andamphetaminearegoodexamples.

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BackgroundInformationforthePresenter

Objectives

Theobjectiveoftheteachingpacketistoinformstudents(highschool)how3drugsofabuse(cocaine,opiates,marijuana)actuallyworkinthebrain.Thepacketisarrangedin3sections.Thefirstsectionintroducesthebrainandpresentssomebasicneurobiology,thesecondintroducestherewardpathwayandthethirdpresentsthemechanismofactionofeachdrugandhoweachaffectstherewardsystem.

BeforeEnteringtheClassroom

Arrangetotalkwiththeteacher(bytelephoneorinperson).

Obtaininformationontheagegroupandextentofbiologybackground.

Discussthesubjectsthatyouwillpresenttotheclass.

Ifpossible,meetwiththeteacher&reviewthepresentation;provideteacherwithsomebackgroundmaterialifrequested.

Solicitadvicefromtheteacheraboutteachingstrategies(e.g.whattodoifsomestudentsaredisruptiveornotlistening).

Readthenarrativescriptandpracticethepresentation-thisisdifferentfromascientificseminartopeers!

OnceintheClassroom

Introduceyourselftotheclass.

Talkbrieflyaboutyourpathtoyourcurrentjob.

Describewhatyoudo(simply).

Indicatetheobjectofyourpresentation.

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Invitequestionsduringyourpresentation.

Iftheopportunityarises,askquestionsofthestudents.

Bepreparedtodefineanywordsyouuse.

GeneralInstructions

Thepresentationshouldtakeapproximately30-40minutes(withoutquestions);itcanbepresentedin2classsessionsifsodesired.

Usethenarrativetextasaguide,itneednotberepeatedword-for-word.