Negative Reinforcement Theories of Addiction

•  Sub-TypesofNegativeReinforcementModels•  Self-MedicationHypothesis

•  Drugsareusedtoself-medicate,i.e.,relievesymptomsthatoccurindependentofdruguse(e.g.,pain,anxiety)

•  PhysicalDependenceHypothesis•  DistressSyndromeReductionTheories,withdrawalavoidance•  Withthedevelopmentoftoleranceandphysicaldependencedruguseissustainedinordertoavoidtheunpleasantconsequencesassociatedwithwithdrawal

•  peoplecontinuetotakedrugstoease“distresssyndrome”(physicaland/orpsychological)associatedwiththecessationofdruguse

•  perhapsduetoadaptationsinbrainrewardsystems(compensatoryreboundidea),oropponentprocess

BrainDysregulationinAddiction(CNSactivity,mood,behavior)

Koob&LeMoal,NeurobiologyofAddiction,2006

Normal

Addicted

Problems

•  Peopleandanimalsself-administerdrugsatdosesthataretoolowtoproducephysicaldependence

•  Thereisahightendencytorelapseevenafteranextendedperiodofabstinence,longafterwithdrawal

Conclusion: physical dependence and withdrawal are neither necessary nor sufficient conditions for addiction

•  •“Physicaldependenceiscurrentlyviewednotsomuchasadirectcauseofdrugdependencebutasoneofseveralfactorsthatcontributetoitsdevelopment”

•  (J.H.Jaffe,inA.Gilmanetal.(eds.),ThePharmacologicalBasisofTherapeutics,1990)

•  “Forratsandmonkeysphysicaldependenceisneitheranecessarynorsufficientconditionforopiatestoactasreinforcers”

•  (C.Schuster,inG.Edwardsetal.(eds.),TheNatureofDrugDependence,1990)

•  “Theroleofphysicaldependenceinaddictionissuggestedtovaryfromdrugtodrugandtobeofsecondaryimportanceintheunderstandingofcompulsivedrugself-administration

•  (R.A.Wise&M.A.Bozarth,PsychologicalReview,1987)

•  Toleranceandwithdrawalarestillwidelystudied– Ethanolinhalation– Withdrawal-inducedseizures– Antinociceptivetolerance(hot-platetest)

Positive reinforcement theory of addiction

• Drugtakingismaintainedbecausedrugsactaspositivereinforcers:•  thusincreasetheprobabilityofprecedingbehavior(drug-taking)•  positivereinforcementmodelsgenerallyequatepositivereinforcementwithpleasure•  (“pleasure-seeking”model)

Positive reinforcement

•  “Theonlyexistingpositivereinforcementviewofaddictionthatmightqualifyasanexplanatorytheoryidentifiespositivereinforcementwithdrugeuphoria”.• Primarymotivationalforcedrivingdrugseekinganddrug-takingbehaviorintheaddictisthedesiretoobtainpleasure

(R.A.Wise&M.A.Bozarth,PsychologicalReview,1987,94:469)

Problems: “euphoria” models

•  “...itwassupposedthatthepredictionofaddictionliabilitywasessentiallyequivalenttopredictionofeuphorigenicpower.Aswithmostself-evidentideas,themerematteroftherebeingessentiallynoevidenceinfavorofit,andmuchagainstit,hadlittleeffectonitsacceptance.”(Dews,1977)

Problems: “euphoria” models

•  Theincentivevalueofdrugsisdissociablefromtheirsubjectivepleasurableeffects•  “Wanting”drugs(motivationtotakedrugs)isdissociablefromtheirsubjectivepleasurableeffects(“liking”drugs)

• Howcanweassestheabusepotentialofdifferentdrugs,andstudythemechanismsbywhichdrugsproducerewardingeffectsanddependence• Canexaminethestimuluspropertiesofdrug

•  (“whatdoesitfeellike?”)• Canexaminethereinforcing/incentivepropertiesofdrugs

•  (“willyouworkforit?”;”doyou‘want’it?”).• Withameasureofthesedrugeffects,wecanassesse.g.ifaparticularneurotransmitterisinvolvedindrugreward

People “want” drugs that they don’t “like”

NeuronVolume76,Issue32012470-485

KeyPoint:Dopaminemediates“wanting”or“drug-seeking”or“incentivemotivation”

Incentivetotakedrugincreasesduringaddiction

IncentiveSensitizationTheory:RobinsonandBerridge,(1993)

Drug-induceddopamineincreasesasafunctionofwithdrawal

i.e.,opioidreceptorsmediatepleasure,butdopaminemediatestheincentive/addictiveproperties

dopamine

opioids

Incentivemotivation“wanting”

Subjectivepleasure“liking”

Drugs

Phases of SA

Incubation of craving during drug self-administration

•  Twogroups:•  Shortaccess(1hour/day)•  Longaccess(6hours/day)

Withdrawal-induced escalation apparent in LgA rats.

Face validity to the extreme: addicted rats

• Ratsself-administeredintravenouscocaineforthreemonths•  TheDSMcriteriaevaluated:

•  Thesubjecthasdifficultystoppingdruguseorlimitingdrugintake•  Thesubjecthasanextremelyhighmotivationtotakethedrug,withactivitiesfocusedonitsprocurementandconsumption

•  Substanceuseiscontinueddespiteitsharmfulconsequences.

•  (AtoD)Addiction-likebehaviorsinratspositiveforthepresenceofzero,one,two,orthreeaddiction-likecriteria.

•  Anindividualwasconsideredpositiveforanaddiction-likecriterionwhenitsscoreforoneofthethreeaddiction-likebehaviorswasinthe66thto99thpercentileofthedistribution.•  (A)Persistenceindrugseeking,asmeasuredbynumberofnose-pokesinthe

cocaine-associateddeviceduringtheno-drugperiodofthe54thSAsession.•  (B)Resistancetopunishment,asmeasuredbychangeinthenumberofcocaine

self-infusions(expressedaspercentageofbaselineSA)whencocainedeliverywasassociatedwithanelectricshockbetweenthe72ndand74thSAsessions.

•  (C)Motivationforthedrug,asmeasuredbythebreakingpointduringaprogressive-ratioscheduleperformedbetweenthe52ndand60thSAsessions.

•  (D)Percentageofthetotalpopulation(n=58)ofratspositiveforzero,one,two,orthreeaddiction-likecriteria.

•  ratsshowinghigh(blackcircles,HRein)orlow(opencircles,LRein)cocaine-inducedreinstatementafter30daysofwithdrawal

30days

•  Developmentofaddiction-likebehaviorsoversubsequentcocaineSAsessionsinratsshowinghigh(blackcircles,HRein)orlow(opencircles,LRein)cocaine-inducedreinstatementafter5daysofwithdrawal.

•  (A)Persistenceindrugseeking,asmeasuredbynumberofnose-pokesinthecocaine-associateddeviceduringtheno-drugperiod.

•  (B)Resistancetopunishment,asmeasuredbychangeinthenumberofcocaineself-infusions(expressedaspercentageofbaselineSA)whencocainedeliverywasassociatedwithanelectricshock.

•  (C)Motivationforthedrug,asmeasuredbythebreakingpointduringaprogressive-ratioschedule.

•  (D)Drug-inducedreinstatement,asmeasuredbynumberofnose-pokesinthedrug-associateddeviceasafunctionoftheprimingdoseofcocaine.LReinandHReincontainedtherats(n=7pergroup)withthelowestandhighestreinstatement,respectively,inducedbycocaineinfusionat1.6mg/kg.