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Drugs,AddictionandRewardChapter5PsychoactiveDrugsAddictionTheRoleofGenesinAddiction
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Drugs,Addiction,andRewardFigure5.1:HonoredeBalzacdiedofheartattackafterabusingcoffee• Adrugisanysubstancethatchangesthebodyoritsfunctioning.• Agonistsmimicsorenhancesaneurotransmitter.• Antagonistsmayreducereleaseofneurotransmitterorblockreceptors.
• Psychoactivedrugsarethosethathavepsychologicaleffects,suchasanxietyrelieforhallucinations.
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PsychoactiveDrugsTerms
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• Addictionisidentifiedby:• preoccupationwithobtainingadrug;• compulsiveuseofthedruginspiteofadverseconsequences;
• ahightendencytorelapseafterquitting.• Withdrawal
• negativereactionthatoccurswhendruguseisstopped.• oftenincludeeffectsoppositeofthedrugitself
• Tolerance:• Personbecomeslessresponsivetothedrug,requiringincreasingamountsofthedrugtoproducethesameresults
• killedabout½ofheroinusersinalongtermstudy,andisasignificantreasonforoverdose.
PsychoactiveDrugsAnOverview• Opiates
• Analgesic:painrelief;• Hypnotic:sleep-inducing;
• Euphoria:strongfeelingsofhappiness.
• Depressants• Sedation:calming,reducesagitationandirritability
• Anxiolytic:anxietyreduction
• Hypnotic:sleepinducing
• Stimulants• Increasedarousalandalertness
• Euphoria• Psychedelics
• Perceptualdistortionsandhallucinations
• Marijuana• Temporarymemory,cognitive,andIQdeficits;
• Impairedprefrontalfunctioning.
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PsychoactiveDrugsOpiates.Figure5.2:Opiatesarederivedfromtheopiumpoppy
• Opiateshavehighabusepotential,sincetheymimicendogenousopioids(naturalpainkillersoranalgesicscalledendorphins)
• Examples• Morphine• Heroinwassynthesizedfrommorphine• Oxycontinisasyntheticopiate,calledanopioid
• ExamplesinFiction• WizardofOzfieldofpoppies• GameofThrones’ “MilkofthePoppy”
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PsychoactiveDrugsOpiates:TheDangersofHeroin
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• Heroinisparticularlydangerousbecause:• itproducesintenseeuphoria• itcrossesthebloodbrainbarrier• tolerancedevelopsrapidly,increasingthechanceofoverdose.
• Conditionedorlearnedtolerancealsoisaproblem.• Alearnedassociationdevelopsbetweentoleranceandtheenvironmentinwhichitdevelops.
• Whenadrugistakeninadifferentsetting,itismorelikelytoresultinanoverdose.
SOURCE: (top) WikiPedia User Fuse809, licensed under the Creative Commons Attribution Share-Alike 3.0 Unported. (bottom) WikiPedia User NEUROtiker, image in public domain
PsychoactiveDrugsOpiatesandEndorphins
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• Endorphins• producepainreliefbystimulatingtheseopioidreceptors
• andproduceadditionalpositiveeffectsbyindirectlystimulatingdopaminepathways.
PsychoactiveDrugsDepressants
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• Depressantsaredrugsthatreducenervoussystemactivity.• Sedation:calming,reducesagitationandirritability• Anxiolytic:anxietyreduction• Hypnotic:sleepinducing
• Alcohol,orethanol,isthemostcommonlyusedandabuseddepressant.• Ithasbeenusedthroughouthistoryasapartofculturalandsocialpractices.
• However,controlledgroupdrinkinghasbeenreplacedbyuncontrolledindividualconsumption.
• itisinvolvedin1/3ofallU.S.trafficfatalities
PsychoactiveDrugsDepressants:Alcohol
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• Alcoholhasmanyeffectsonbehavior.• Itcanactasastimulantbyturningoffcorticalinhibition,reducingsocialconstraintsandanxiety.
• Athigherdosesalcoholproducessedativeandhypnoticeffects.• IntheU.S.andCanadaapersonisconsideredtooimpairedtodriveatabloodalcoholconcentrationof0.08%.
• Alcoholhasnegativeeffectsonhealth.• Acuteeffectsincludealcohol-inducedcomaordeath.• Insomeusersitincreasestendenciestowardaggressiveness.• ChroniceffectsincludeliverdamageandbraindamageassociatedwithKorsakoff’ssyndrome.
• Withdrawalisdangerous,andmayproduceaconditionknownasdeliriumtremens—hallucinations,delusions,confusion,and,inextremecases,seizuresandpossibledeath.
PsychoactiveDrugsDepressants:Figure5.3:AnAlcoholicBrainvs.ANormalBrain
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PsychoactiveDrugsDepressants:Figure5.4:Alcohol’seffectonneurotransmittersystems• Inhibitsglutamate(excitatorytransmitter).
• ActsatthealcoholpartoftheGABAAreceptorcomplex(inhibitoryeffects)
• Thecombinedeffectissedation,anxiolytic,musclerelaxation,andinhibitionofcognitiveandmotorskills.• Alcohol’spleasurableeffectslikelyduetostimulationofopiate,serotonin,andcannabinoidreceptors.
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PsychoactiveDrugsDepressants:Figure5.4:BarbituratesandBenzodiazepines• Barbiturates
• Oncethedrugofchoicefortreatinganxietyandinsomnia.
• Atprescribeddosestheyarenotaddictive,buttolerancemayleadtoincreasedconsumption,whichleadstoaddictionandpossibleoverdoses
• TheycanopenchloridechannelswithoutGABA.
• Benzodiazepinesaresaferdrugsfortreatinganxiety.• Effectsduetodecreasedactivityinavarietyofsystems,whichareduetotheenhancementofGABAactivity.
• Rohypnolhasareputationasadaterapedrug.
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PsychoactiveDrugsStimulants:Figure5.6:AdvertisementforCocainefromAround1900• Stimulantsactivatethecentralnervoussystemtoproducearousal,increasedalertness,relievesfatigue,decreasedappetite,&elevatedmood.
• Cocaine:Extractedfromthecocaplant,• Blocksdopamine&serotoninreuptake• Dopamineremovesinhibitiononlowerstructures
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SOURCE: The National Library of Medicine
PsychoactiveDrugsFigure5.7:ANormalBrainandaBrainonCocaine.• Cocainewasbelievedtobesafe,andwasfoundinover-the-countermedicationsandeveninCocaCola.• Freudinitiallypraisedtheeffectsofcocaine,butreversedhisopinionwhenhenoteditsdangers.
• Usershavedeficitsinexecutivefunctionsthatinvolvethepre-frontalcortex.
• Addictiveduetointenseeuphoriaandcravingduringabstinence.
• Difficulttotreatbecausemanyusershavepsychologicaldisorders...and
• Alsodifficulttotreatbecauseusersoftenabuseotherdrugs.
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SOURCE: Photo courtesy of Nora Vollow, Ph.D. Volkow ND, Hitzemann R, Wang GJ, Fowler JS, Wolf AP, Dewey SL. Long-term frontal brain metabolic changes in cocaine abusers. Synapse 11: 184-190, 1992.
PsychoactiveDrugs
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• Amphetaminesareagroupofsyntheticdrugsthatproduceeuphoriaandincreaseconfidenceandconcentration.• ExamplesincludeBenzedrine,Dexadrine,andmethamphetamine.
• Amphetaminesincreasethereleaseofnorepinephrineanddopamine.
• Heavyusecancausesymptomsthatresembleschizophrenia.
• Amphetamineshavebeenusedinweight-lossdrugs,topostponesleep,andtotreatnarcolepsy(adisorderofexcessivedaytimesleepiness).
PsychoactiveDrugs
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• Nicotineistheprimarypsychoactiveandaddictiveagentintobacco.• Itstimulatesnicotinicacetylcholinereceptors.• Intheperiphery,itactivatesmusclesandmaycausetwitching.
• Centrally,itproducesincreasedalertnessandfasterresponsetostimulation.
• Withdrawalsymptomsaremild,buttheycontributetoa7%increaseinworkplaceaccidentsduringtheUnitedKingdom’s“NoSmokingDay.”
• Only20%ofattemptstostoparesuccessfulaftertwoyears.
PsychoactiveDrugsSmoking
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• Thedangersofsmokingaremostlyduetothecompoundsintobaccosmoke,notnicotine.• Theseinclude
• variouscancers(damagesacancersuppressinggene)• Buerger’sdisease(constrictsbloodvessels)• Reducedbirthweight
• Smokingistheprimarycauseofpreventabledeathintheworld.• 438,000deathsannuallyintheU.S.• 4millionworldwide• Freudfounditeasiertogiveupcocainethancigars.
PsychoactiveDrugsCaffeine
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• Caffeineistheactiveingredientincoffee.• Itproducesarousal,increasedalertness,anddecreasedsleepiness.
• Itblocksreceptorsfortheneuromodulatoradenosine,increasingthereleaseofdopamineandacetylcholine.
• Becauseadenosinehassedativeanddepressiveeffects,blockingitsreceptorscontributestoarousal.
• Withdrawalsymptomsincludeheadaches,fatigue,anxiety,shakiness,andcraving.
PsychoactiveDrugsPsychedelics(Hallucinogens)
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• Psychedelicdrugsarecompoundsthatcauseperceptualdistortions.• Oftenreferredtoashallucinogenic,theyaremostnotedforproducingperceptualdistortions.
• Light,color,anddetailsareintensified.• Objectsmaychangeshape,soundsmayevokevisualexperiences,andlightmayproduceauditorysensations.
• Examples• LSD• Mushrooms• Mescaline• PCP• Ecstasy
PsychoactiveDrugsPsychedelics(Hallucinogens)
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• Ecstasy(orMDMA)isapopulardrugamongyoungpeople.• Psychomotorstimulantatlowdoses(releasesdopamine)• Hallucinatoryathigherdoses(releasesserotonin)• Chronicusemaycauseimpairmentinserotoninfunctioning
• Cognitivedeficitssuchasmemoryloss• Inmonkeys,MDMAdestroysserotonergicneurons.
• Phencyclidine(PCP):• Addictivethroughactivatingdopaminepathways• Inhibitsglutamatereceptors,causing“modelpsychosis,”withsignificantimplicationsfortheoriesofschizophrenia.
PsychoactiveDrugsPsychedelics(Hallucinogens).Fig5.8:BrainDamageInducedbyEcstasyUse
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PsychoactiveDrugsFigure5.9:AMarijuanaPlant• Marijuana:driedleavesandflowersofCannabissativa.
• Delta-9-tetrahydrocannabinol(THC)• Bindstoendogenouscannabinoidreceptors.• Cannabinoidsregulatepresynaptictransmitters.
• EffectsonBrainandMind• Mildlyaddictive• Memory,cognitive,IQdeficits• Hippocampus,amygdalareductions(possible)• Impairedprefrontalfunctioninginoffspringwhensmokedduringpregnancy
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Addiction
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• Addictionandwithdrawalareindependentprocesses;theyevenoccurindifferentpartsofthebrain.• Thedesiretoavoidwithdrawalsymptomsdoesnotfullyexplainaddiction.
• Howdoesoneexplaininitialdruguse?Probablytheeuphoriaassociatedwithblockingdopaminereuptake.
• Addictswillpurposefullygothroughwithdrawalinordertoresettheirtolerancelevel.
• Theaddictivenessofadrugisnotrelatedtotheseverityofthewithdrawalsymptoms.
AddictionRewardandDopamine
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• Ahypothesizedbasisforaddictionisreward.• Rewardisthepositiveeffectanobjectorcondition(drug,food,sex,etc.)hasontheuser.
• Themesolimbocorticaldopaminesystemisusuallyconsideredthemajorrewardsystem.• Majorstructuresarethenucleusaccumbens,medialforebrainbundle,andventraltegmentalarea(VTA).
• ManyabuseddrugscreateeuphoriabyblockingthereuptakeofDopamine.
• VirtuallyallabuseddrugsincreasedopamineintheVTA.• Thedopaminesystemisimplicatedintherewardingeffectsofdrugs,food,sex,andelectricalstimulationofthebrain(ESB).
AddictionFigure5.10:TheMesolimbocorticalDopamineSystem
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AddictionDrugUseasaReinforcer
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• Rewardisanincompleteexplanationofaddiction.• Overtime,dopaminereleasetoarewardingstimulusceases;itreturnsifanexpectedrewardisomitted.
• Researcherssuggestthatdopaminesignalsrewardanderrorsinprediction.
• Detectingerrorsinpredictioniscriticaltolearning.• Errorsinpredictionthatlearningtheoristsconsiderimportant:
• Therewardisunexpectedorbetterthanexpected.• Therewardisomittedorisworsethanexpected.
• Moderntheorysuggeststhatdruguseisareinforcer
Addiction
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• Learningproducesbrainchanges,creatinglifelongaddiction• Learningispartoftheaddictiveprocess• Increaseddendritelengthandcomplexityinnucleusaccumbens
• Hyperactivityinareasinvolvedinlearningandemotionduringcraving(whenpresentedwithdrugparaphernalia).
• Additionalbrainchangesamounttopathology• Malformeddendritesassociatedwithfrontaldysfunction.
ApprovedmedicationsDrug Medication Action
AlcoholismAntabuse Preventsdigestionofalcohol,toxic
sideeffectsincreasenausea.
Acamprosate,Topiramate
ReducecravingthroughGNeurotransmiters
Nicotine
Gum,Patch,Electroniccigarette Reducenicotineintake
Buproprion Blockreuptake,reducingnicotinerewardandwithdrawal
Heroin&Opiates
Naltrexone Opiateantagonist
Methadone Opiateagonist(bad)
Buprenorphine Opiateagonist(bad)28
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AddictionAgonisticandAntagonisticTreatments
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• Drugaddictiontendstobelifelong;severalstrategieshavebeendevelopedtopreventrelapse.• Agonistictreatmentsmimicthedrug’seffects.
• Example:Methadoneforopiateaddiction,thenicotinepatch.• Thesereplacethedrug,whichhelpswithmotivation.
• Antagonistictreatmentsblockdrugeffects.• Examples:Naltrexoneisusedforopiateandalcoholaddiction;baclofenandrimonabantinterferewiththedopaminepathway.
• Antagonistictreatmentsdon’treplacethedrug,socompliancedependsontheaddict’smotivationtoquit.
AddictionAversiveandAnti-DrugTreatments
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• Aversivetreatmentscauseanunpleasantreactionwhentheaddictusesthedrug.• Example:Antabuse(thatblockstheenzymealdehydedehydrogenaseorALDH)foralcoholaddictioncausesimmediatehangovereffects.
• Treatmentcompliancedependsontheaddict’smotivationtoquit.
• Anti-drugvaccinesstimulatetheimmunesystemtomakeantibodiesthatdegrade/destroythedrug.
• Havefewersideeffectsthanotherpharmacologicaltreatments.
• Havelongerlastingeffectsthanotherpharmacologicaltreatments.
AddictionEffectivenessandAcceptanceofPharmacologicalTreatment
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• Behavioralmanagementforheroinaddictionhasa10%to30%successrate;combinedwithmethadone,successrisesto60-80%.
• Pharmacologicaltreatmentiscontroversialduetobeliefthatrecoveryshouldinvolvetheexerciseofwillandthatitiswrongtogiveanaddictanotherdrug,suchasmethadone.
• Drugtreatmentiscosteffective:Addictioncosts$544billionayearintheU.S.,buteverydollarinvestedintreatmentsaves$4to$12.
TheRoleofGenesinAddictionTable5.2:DistinguishedCharacteristicsofTwoTypesofAlcoholism
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CharacteristicFeatures Type1(orlate-onset)
Type2(orearly-onset)
Ageofonset(years) After25 Before25
Alcoholseeking Infrequent Frequent
Fighting/arrestswhiledrinking Infrequent Frequent
PsychologicalDependence Frequent Infrequent
Guiltandfearaboutdependence Frequent Infrequent
NoveltySeeking Low High
Harmavoidance High Low
Rewarddependence High Low
Representative heritabilities for drug abuse • Alcoholism: 50-60% • Hallucinogens: 50% • Cocaine: 72%
TheRoleofGenesinAddiction
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• Genesthatcontributetoaddictiongenerally• areinvolvedwithneurotransmittersystemsoraffecthowtheindividualrespondstothedrug.
• Manyaddictshavereducednumbersofdopaminereceptors.
• KnockoutmicelackingeitheroftwoHomergenes,whichregulateglutamateactivity,aremoresusceptibletococaine.
• MicelackingtheClockgenereleasemoredopamineinrewardareasofthebrainandaremorevulnerabletococaine’seffects.
• IndividualswiththeGalleleforanopioidreceptorreportgreaterintoxicationandare3xmorelikelytohaveahistoryofalcoholism.
TheRoleofGenesinAddiction
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• Peoplewhodonotrespondtothenegativeeffectsofalcohol,suchasmotorimpairment,are4xmorelikelytobecomealcoholiclater.• Theinheritableabilitytoeliminatealdehydeisassociatedwithalcoholismandvulnerabilitytootherdrugs.
• Ageneticdeficiencyintheabilitytometabolizenicotineprotectssomepeoplefromnicotineaddiction.
• Anumberofgenesarecommontodrugdependenceandthepersonalitycharacteristicsassociatedwithit—impulsivity,risktaking,noveltyseeking,andstressresponsiveness.
TheRoleofGenesinAddiction
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• Genesinvolvedinalcoholaddictionalterthewaythebrainfunctions,asindicatedbystudiesofEEGactivity.• IncreasedhighfrequencyEEGoccursinalcoholicsandtheiroffspring.
• Alcoholicsandtheiroffspringalsoshowareductioninthenormal“dip”intheP300wave,whichisacomponentoftheevokedpotentialelicitedbyanenvironmentalstimulus.
• TheseEEGabnormalitiesarenotspecifictoalcoholism.• Theyoftenoccurindisorderscharacterizedbybehavioraldisinhibition,suchasconductdisorder,antisocialbehavior,andothertypesofdrugabuse.
TheRoleofGenesinAddictionFigure5.17:EvokedPotentialsinHigh&LowRiskChildren
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TheRoleofGenesinAddiction
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• Addictionresearchhasbroadimplicationsforunderstandingvulnerabilityandbehavioralinheritance:• Behaviorresultsfromaninterplaybetweenenvironmentandgenetics.
• Thesetwoforcesoperatedifferentlyindifferentsubgroupsandcultures.
• Itisnotenoughtoassignrelativerolestoenvironmentandheredity;wemustthenunderstandthemechanisms—theneurotransmitters,receptors,pathways,enzymes,ansoon.
• Inaddictionandallkindsofbehaviorwemustlookbeyondappealstowillpowerasexplanation.