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.