The psychology and neurobiology of addiction - College of

Addiction (2000) 95 (Supplement 2) S91ndashS117

ANIMAL MODELS IN CRAVING RESEARCH

The psychology and neurobiology of addictionan incentivendashsensitization view

TERRY E ROBINSON amp KENT C BERRIDGE

Department of Psychology (Biopsychology Program) The University of MichiganAnn Arbor MI USA

AbstractThe question of addiction speci cally concerns (1) the process by which drug-taking behavior in certainindividuals evolves into compulsive patterns of drug-seeking and drug-taking behavior that take place at theexpense of most other activities and (2) the inability to cease drug-taking the problem of relapse In thispaper current biopsychological views of addiction are critically evaluated in light of the ldquoincentive-sensitization theory of addictionrdquo which we rst proposed in 1993 and new developments in research areincorporated We argue that traditional negative reinforcement positive reinforcement and hedonic accountsof addiction are neither necessary nor suf cient to account for compulsive patterns of drug-seeking anddrug-taking behavior Four major tenets of the incentive-sensitization view are discussed These are(1) Potentially addictive drugs share the ability to produce long-lasting adaptations in neural systems(2) The brain systems that are changed include those normally involved in the process of incentive motivationand reward (3) The critical neuroadaptations for addiction render these brain reward systems hypersensitive(ldquosensitizedrdquo) to drugs and drug-associated stimuli (4) The brain systems that are sensitized do not mediatethe pleasurable or euphoric effects of drugs (drug ldquolikingrdquo) but instead they mediate a subcomponent ofreward we have termed incentive salience (drug ldquowantingrdquo) We also discuss the role that mesolimbicdopamine systems play in reward evidence that neural sensitization happens in humans and the implicationsof incentive-sensitization for the development of therapies in the treatment of addiction

IntroductionIn thinking about the problem of addiction andthe development of animal models of addictionit is important to remember that at some timemany people experiment with a variety of poten-tially addictive drugs but most do not becomeaddicted1 In other words mere self-administration of a drug by a human or by anon-human animal is not tantamount to addic-

tion2 Indeed the factors responsible for exper-imental or casual drug use may or may not bedirectly relevant to the problem of addictionDrug-seeking and drug-taking in the addict mayinvolve factors that are qualitatively differentfrom those that motivate drug-taking in the non-addict The question of addiction speci callyconcerns (a) the process by which drug-takingbehavior in certain individuals evolves into

Correspondence to Dr Terry E Robinson Department of Psychology (Biopsychology Program) The Universityof Michigan 525 E University (East Hall) Ann Arbor MI 48109 USA Tel (734) 763 4361 fax (734) 763 7480e-mail terumichedu

Submitted 1st September 1999 initial review completed 16th November 1999 nal version accepted 10th March2000

ISSN 0965ndash2140 printISSN 1360ndash0443 online0008S091ndash27 Oacute Society for the Study of Addiction to Alcohol and Other Drugs

Carfax Publishing Taylor amp Francis Ltd

S92 Terry E Robinson amp Kent C Berridge

compulsive patterns of drug-seeking and drug-taking behavior that take place at the expense ofmost other activities and (b) the inability tocease drug-taking that is the problem of re-lapse2 The purpose of this paper is to exploreone view of the psychological and neurobiologi-cal mechanisms responsible speci cally for thedevelopment of compulsive patterns of drug usethat de ne addiction and to update our earliertreatise on this subject3

Negative and positive reinforcement modelsMost contemporary explanations of addictionsuggest that addicts are motivated to take drugs(crave drugs) for one of two reasons As put byMarkou et al4 ldquoDrug craving is characterized byboth the desire to experience the positive hedo-nic effects of the drug hellip and the desire to avoidaversive withdrawal symptoms helliprdquo (p 176)That is it is generally thought that addicts aremotivated to take drugs either for the pleasuredrugs produce (basically to achieve rememberedpleasure) or to avoid the unpleasant conse-quences of withdrawal Some authors place theweight of explanatory burden on the aversiveconsequences of discontinuing drug use (thewithdrawal syndrome) and thus on the action ofdrugs as negative reinforcers25ndash7 For exampleKoob and colleagues8ndash10 have argued that ldquothemotivation for maintenance of compulsive druguse requires negative reinforcement processes helliprdquo(Koob et al9 p 519 italics added) and thatldquoFrom a motivational perspective addiction canbe equated with the development of a negativeaffectrdquo (Koob11 p 13)

Limitations of negative reinforcement modelsDespite the intuitive appeal of withdrawal avoid-ance models many authors have pointed out theshort-comings of negative reinforcement modelsin general as explanations for addiction312ndash15

For example drugs that do not produce strongwithdrawal syndromes such as psychostimu-lants can be highly addictive Conversely thereare drugs that produce tolerance and withdrawalsyndromes but do not support compulsive pat-terns of use The latter compounds include sometricyclic antidepressants anticholinergics andkappa opioid agonists14 Thus as put by Jaffe14

ldquothere is little correlation between the visibility

or physiological seriousness of withdrawal signsand their motivational forcerdquo (p 9) Anotherproblem for withdrawal-based explanations isthat drug craving is often elicited by drug admin-istration itself in association with euphorigeniceffects at the moments when withdrawal symp-toms should be at their weakest Similarly inanimals trained to self-administer heroin re-instatement of drug-taking behavior followingextinction is more potently elicited by a priminginjection of heroin which elicits a drug-like ef-fect than by the injection of an opioid antago-nist which induces withdrawal signs1617 Forhuman addicts the prolonged cessation of druguse during which time withdrawal symptomsdecay is by no means a guarantee of a cure asrelapse to compulsive use even long after with-drawal is over remains a major problem inaddiction18 In conclusion although there is nodoubt that under some circumstances the desireto avoid withdrawal can be a potent motive fordrug use for these and other reasons manyauthors have suggested that models of addic-tion based on the alleviation of withdrawal symp-toms (whether ldquophysicalrdquo or ldquopsychologicalrdquo) areneither necessary nor suf cient to explain com-pulsive drug-seeking and drug-taking behav-ior31415

Limitations of behaviorist positive reinforcementmodelsIn part because of the shortcomings of negativereinforcement models alternative models haveplaced considerable emphasis on the action ofdrugs as positive reinforcers14 Positive reinforcersare stimuli that have the property of increasingthe probability of behaviors that immediatelyprecede their presentation Like many naturalrewards such as food and water potentiallyaddictive drugs have this property In the drugabuse literature however the Skinnerian con-cept of positive reinforcement is often invokedeither implicitly or explicitly as though it werean explanation of drug-taking behavior and evenas an explanation of why drug-taking behaviorbecomes more and more compulsive in thedevelopment of addiction (Why do people takedrugs Because drugs are positive reinforcers) Butthis is a confusion It is equivalent to sayingthat the reason people take drugs is becausedrugs promote drug-taking behavior the cir-cularity is obvious15 It is important to remem-

An incentivendashsensitization view of addiction S93

ber that positive reinforcement taken as abehaviorist concept is only a description of abehavioral effect not an explanation of the effect(Berridge amp Robinson19 see footnote 3 for de-tailed discussion) In de ning reinforcementSkinner himself20 said ldquoThe only de ningcharacteristic of a reinforcing stimulus is that itreinforcesrdquo and argued that ldquothere is nothingcircular about classifying events in terms of theireffects helliprdquo But he also said ldquoIt would be circu-lar however if we then went on to assert that agiven event strengthens an operant because it isreinforcingrdquo (his italics pp 72ndash3) Or as put sowell by Dews21 ldquohellip many things can reinforceand many things can be maintained by reinforce-ment which is ne of course provided that wedo not come to suppose that in demonstratingthat an event is a reinforcer we have demon-strated something more than that the event is areinforcerrdquo ldquoAny worker studying behavioralphenomena knows that a reinforcer is de nedand recognized through its effects on behaviorthe sole criteria are behavioral But any impartialobserver of the same workers will see that teleol-ogy like hope springs eternal in even a scienti cworkerrsquos breastrdquo (p 77) In other words behav-iorist reinforcement should not be mistaken tobe an explanation of either drug-taking or addic-tion in either a physiological or psychologicalsense The critical question relevant for addic-tion is what explains it That is what effect of adrug is responsible for its positively reinforcingbehavioral property and how does it cause thedevelopment of compulsive drug-seeking anddrug-taking habits

Wise amp Bozarth15 suggested that ldquothe onlyexisting positive reinforcement view of addictionthat can qualify as an explanatory theoryidenti es positive reinforcement with drug eu-phoriardquo (p 474) In this view (hedonia view)drugs are addicting because they produce positiveaffective states that people label with words suchas pleasure or euphoria and these states are whataddicts seek This pleasure-seeking view of ad-diction is the simple common-sense view of ad-diction People want drugs (are motivated toseek and take drugs) because they like drugs(because drugs give pleasure) In this view themotivation to take drugs (drug wanting) is di-rectly attributable to the ability of drugs to pro-duce pleasure ie there is a necessary causalrelationship between wanting drugs and likingdrugs

Limitations of drug pleasure (hedonic reinforcement)modelsIt is probably true that often people are initiallymotivated to take drugs because of the ability ofdrugs to produce positive affective states (andbecause their peers are doing it and for manyother complicated psychosocial reasons) but inthe addict the association between the hedonicconsequences of drug consumption and the abil-ity of drugs and drug-related stimuli to motivatebehavior often become dissociated revealing thatthe relationship between the motivational forceof drugs and their hedonic consequences maynot be a necessary causal relationship As Dews21

cautioned many years ago ldquohellip it was supposedthat the prediction of addiction liability was es-sentially equivalent to prediction of euphorigenicpower As with most self-evident ideas the merematter of there being essentially no evidence infavor of it and much against it had little effecton its acceptancerdquo (p 75)

Perhaps the most compelling evidence againstthe idea that the ability of drugs to promotedrug-taking is directly attributable to their sub-jective pleasurable effects comes from studiesshowing that subjective states are often poorlycorrelated with drug-taking First drug-takingmay increase dramatically over time as an addic-tion develops but the pleasure induced by agiven dose of a drug is not reported to increase(see note 5 in Robinson amp Berridge3 for a dis-cussion of this point) If addicts craved drugs inproportion to their ability to produce pleasurethen craving late in addiction ought not to bestronger then craving after the initial drug ex-periencemdashbut of course that is not the case

Secondly after pharmacological manipula-tions there is often a dissociation between thereported subjective effects of cocaine and co-caine-taking behavior22ndash27 For example Haneyet al26 reported recently that pergolide decreasedcocainersquos cardiovascular effects decreased rat-ings of its subjective effects (ldquohighrdquoldquostimulatedrdquo) increased ratings of ldquoI want co-cainerdquo while having no effect whatsoever oncocaine self-administration behavior SimilarlyHaney et al27 reported ldquothat even a 50 de-crease in certain of cocainersquos subjective effects byABT-431 hellip did not shift cocaine self-adminis-trationrdquo (p 108) Along the same lines Comer etal28 reported that doses of intranasal and intra-venous heroin that maintained the sameldquobreakpointrdquo on a progressive ratio schedule re-


sulted in very different subjective ratings ofldquohighrdquo

Thirdly it has been reported that people willwork for low doses of morphine or cocaine thatproduce no subjective pleasure at all doses thatindeed produce no reported subjective effects ofany kind222429 In summarizing their ndingsLamb et al29 concluded ldquoThe reinforcing effectsof morphine can occur in the absence of self-re-ported subjective effects and thus do not appearto be causally related to drug-liking or euphoriardquo(p 1172) These kinds of data are very import-ant because they establish that the motivation totake drugs (drug wanting) is not always directlyattributable to the subjective pleasurable effectsof drugs (drug liking) and it is possible this isespecially true in addicts That is one mustconsider the possibility that in addicts the sub-jective pleasurable effects and the motivationaleffects of drugs are merely correlated effects Theyoccur together most of the time but they can bedissociated and there is no necessary causalrelationship between them

IncentivendashsensitizationIf compulsive drug-seeking and drug-taking be-havior are often not motivated by either thedesire to obtain pleasure or by the desire torelieve withdrawal then what motivates addic-tive behavior in these instances Why do addictscompulsively seek drugs We have attempted toaddress these questions by proposing the con-cept of ldquoincentivendashsensitizationrdquo330 The basicthesis of the incentivendashsensitization view of ad-diction can be summarized in four points

(1) Potentially addictive drugs share the abilityto produce long-lasting adaptations in neuralsystems (ie addictive drugs change thebrain)

(2) The brain systems that are changed includethose normally involved in the process ofincentive motivation and reward

(3) The critical neuroadaptations for addictionrender these brain reward systems hypersen-sitive (ldquosensitizedrdquo) to drugs and drug-associated stimuli

(4) The brain systems that are sensitized donot mediate the pleasurable or euphoric ef-fects of drugs (drug ldquolikingrdquo) but insteadthey mediate a subcomponent of reward wehave termed incentive salience or

ldquowantingrdquo31930ndash33 It is the psychologicalprocess of incentive salience speci cally thatis responsible for instrumental drug-seekingand drug-taking behavior (drug ldquowantingrdquo)

We have hypothesized that when sensitizedthis incentive salience process produces compul-sive patterns of drug-seeking behavior330

Through associative learning the enhanced in-centive value becomes focused speci cally ondrug-related stimuli leading to more and morecompulsive patterns of drug-seeking and drug-taking behavior Furthermore the persistence ofneural sensitization is hypothesized to leave ad-dicts susceptible to relapse even long after thediscontinuation of drug use In the following wewill review some of the evidence for incentivendash

sensitization and elaborate some of the majorfeatures of this view of addiction

Psychomotor sensitizationMost studies showing that the repeated adminis-tration of drugs of abuse can produce sensitiza-tion (ie an increase in drug effect) involvemeasures of the psychomotor activating effects ofdrugs such as their ability to enhance locomotoractivity rotational behavior or stereotyped motorpatterns334ndash36 The majority of these studies in-volve psychomotor stimulant drugs Studies onthe psychomotor activating effects of drugs arethought to be relevant to addiction because ofthe assumption that the neural substrate thatmediates these effects is either the same as or atleast overlaps with the neural substrate respon-sible for the rewarding effects of drugs15 Thisneural substrate is of course the mesotelen-cephalic dopamine system and especially do-pamine projections to the nucleus accumbensand accumbens-related circuitry (often called themesolimbic or mesocorticolimbic dopaminesystem)

There is now considerable evidence that therepeated intermittent administration of psycho-motor stimulant drugs results in a progressiveincrease in their psychomotor activating effectsand an example of this effect is illustrated in Fig1 Although most studies of psychomotor sensi-tization involve the administration of psychomo-tor stimulants such as amphetamine or cocainepsychomotor sensitization has been reportedwith many other drugs of abuse as well includ-ing methylphenidate fencamfamine morphine


Figure 1 An illustration of three ways of quantifying sensitization of rotational behavior in rats with a unilateral 6-OHDAlesion given repeated ip injections of 30 mgkg of d-amphetamine sulfate (data from Anagnostaras amp Robinson73) Leftpanel mean ( 6 SEM) number of rotations per 5-minute interval over 10 consecutive 90-minute test sessions in animals givenamphetamine (open circles) or saline (closed circles) Test sessions were every 3ndash4 days Sensitization is indicated by theprogressive increase in drug effect seen with repeated amphetamine treatment Middle panel the time course of the behavioralresponse when both saline and amphetamine pretreated animals were given a challenge injection of 15 mgkg ofd-amphetamine The challenge session was 3ndash4 days after the last (10th) pretreatment session Sensitization is indicated bya signi cantly greater behavioral response in amphetamine than in saline pretreated animals Right panel sensitization canalso be quanti ed by measuring the magnitude of the shift to the left in the amphetamine dosendasheffect function in drug versus

saline pretreated animals (see Anagnostaras amp Robinson73)

phencyclidine MDMA nicotine and ethanol(for references see Robinson amp Berridge3)

Most directly relevant to the topic of thisvolume on alcohol abuse is evidence for sensi-tization to ethanol There is relatively little re-search on this topic and it is especially dif cultto study the psychomotor activating effects ofdrugs that also have motor depressant effectssuch as morphine or ethanol With morphine thisproblem has been obviated to some extent byusing direct injections of the drug into the ven-tral tegmental area Nevertheless there is agrowing literature that suggests the repeated ad-ministration of ethanol does indeed induce psy-chomotor sensitization37ndash44 There is alsoevidence for cross-sensitization between ethanoland other drugs of abuse including reports thatpretreatment with ethanol enhances the sub-sequent psychomotor effects of cocaine40 am-phetamine45 and morphine46 and that cocainepretreatment potentiates ethanolrsquos effects40

Cross-sensitization between stress and ethanolhas also been reported44 Especially relevant tothe present discussion is evidence that repeated

treatment with amphetamine increases ethanolintake when rats are tested 3 months after thecessation of amphetamine treatment47 suggest-ing there may be long-lasting sensitization toethanolrsquos rewarding effects4849

Research on the neurobiology of ethanol sensi-tization is in its infancy but there are reportsthat ethanol sensitization is associated with neu-roadaptations in dopamine and accumbens-related circuitry4046 that are reminiscent ofchanges seen with other drugs of abuse Forexample Nestby et al46 have reported that re-peated treatment with cocaine amphetaminemorphine or ethanol all increase the electricallyevoked release of dopamine and acetylcholinefrom striatal slices in vitro The extent to whichdifferent drugs of abuse induce similar neuroad-aptations in brain reward circuitry remains anopen question It is highly likely however thatdifferent drugs will induce different adaptationsespecially at the cellular and molecular level (egWhite et al50) It is possible that the overalloutcome will be similar for the operation ofneural systems that mediate the incentive moti-


vational effects of drugs including ethanol Thisremains an important topic for future investiga-tion

Psychomotor sensitization is a very complexand rich phenomenon with many interesting fea-tures most of which are not well understoodFor example for many drugs sensitization istypically seen only when drugs are administeredintermittently and the most robust sensitizationoccurs when injections are widely spaced intime34 Sensitization is dose-dependent the mostrobust sensitization occurs after treatment withrelatively high doses5152 Sensitization is also of-ten time-dependent53 That is sensitization istypically more evident long after the discontinu-ation of repeated drug treatment than shortlyafter the discontinuation of drug treatment Per-haps the most remarkable feature of sensitizationis its persistence Once they have been sensitizedanimals may remain hypersensitive to the psy-chomotor activating effects of drugs for monthsor years3454 There is relatively little parametricresearch on this aspect of sensitization but itspersistence is probably dependent on complexinteractions among the dose administered theinterval between treatments the number oftreatments the route of administration the en-vironment in which the drug is given the sex andstrain of the animal and of course what drug isadministered3455ndash57 Finally it important to em-phasize that the ability of drugs to induce psy-chomotor sensitization is not a function of thefact that in most animal studies the drug isadministered by the experimenter There arenow a number of reports that drug self-administration experience also promotes psycho-motor sensitization58ndash60

Individual differences in susceptibility to sensitizationThere are two other important features of sensi-tization that deserve mention One is individualvariation There is enormous variation acrossindividuals in susceptibility to sensitization56

Even in animal studies some individuals showrapid and robust sensitization with a given doseof a drug whereas others sensitize very little if atall There are many factors that contribute toindividual variation in the susceptibility to sensi-tization including genetic hormonal and experi-ential factors For example genetic factors havebeen implicated by studies showing that thereare marked strain differences in the susceptibility

to psychomotor sensitization in both rats6162 andmice445663 Gonadal hormones have been impli-cated in studies reporting sex differences in sus-ceptibility to sensitization64ndash66 and these sexdifferences are attenuated by castration of malerats6667 Experiential factors have been impli-cated by studies reporting cross-sensitization be-tween stress and psychostimulant drugs445668

The mechanisms by which these factorsin uence susceptibility to sensitization arelargely unknown although the factors that pre-dispose animals to sensitization appear to bedifferent than those that confer acute sensitivityto drugs566369ndash71 Nevertheless the incentivendash

sensitization theory posits that factors which ren-der people susceptible to sensitization will alsocontribute to individual variation in susceptibil-ity to addiction

Modulation of sensitization by the circumstancessurrounding drug administrationAnother important feature of sensitization wewant to emphasize is that sensitization is not aninevitable consequence of repeated exposure todrugs Instead the ability of drugs to induce orexpress sensitization is powerfully modulated bylearning and the circumstances surrounding drugadministration72 There are at least two ways thatthe circumstances surrounding drug administra-tion modulate sensitization The rst is modu-lation of the expression of neural sensitizationthat has already been induced Perhaps the bestexample of environmental modulation of ex-pression is the phenomenon of context-speci csensitization In studies of this type typically onegroup of animals receives drug injections in aunique test environment and another group re-ceives injections in a different environment (of-ten in its home cage) On the test day all animalsreceive a challenge injection in the same environ-ment (the test environment) Only the animalstreated with drug in the test environment usuallyexpress sensitization The animals treated withdrug in a different environment often fail toexpress sensitization in the test environmentwhere drug has never before been experiencedThus the expression of sensitization is said to beldquocontext-speci crdquo73ndash76 An implication for hu-mans is that the expression of neural sensitiza-tion in addicts can be expected to be strongest inthose contexts in which drugs have often beentaken before


Despite this powerful associative (conditionedstimulus) control over the expression of sensi-tization there are at least two reasons to believethat neural sensitization occurs even in the ani-mals that do not express behavioral sensitizationThe rst is that animals receiving drug treat-ments in an environment other than the testenvironment (eg in a ldquothird worldrdquo) developnormal behavioral sensitization in their drugtreatment environment they simply do not ex-press it in a different environment that has neverbeen paired with drug administration73 Sec-ondly neural sensitization has been describedunder conditions that preclude the in uence ofcontextual stimuli on the neurobiological ex-pression of the drug response For example evi-dence for neural sensitization to a number ofdrugs has been reported using striatal tissueslices in vitro and in anaesthetized animals4677ndash81

It appears therefore that repeated exposure toamphetamine may induce neural sensitizationnon-associatively but whether the consequencesof neural sensitization are expressed at a particu-lar place or time is determined to a large extentby conditional stimuli (especially contextualstimuli) that have been associatively paired withdrug administration73 Furthermore it has beenhypothesized that contextual stimuli may oftenact not only as traditional excitors (ie a CS 1 ) toproduce a conditioned response (CR) but as adifferent class of conditional stimuli known asoccasion-setters which can modulate drug re-sponses without producing a CR73 It may bethat this interaction of neural sensitization withassociative learning is responsible for the focuson drug-associated stimuli in addicts wherebythe acts and objects associated with drug-takingbecome especially powerful incentives them-selves Contextual modulation of the expressionof sensitization may contribute to the critical rolethat context plays in precipitating relapse Thatis an implication for addiction is that the ex-pression of sensitization to the incentive proper-ties of drug-related stimuli may be strongest incontexts that have been also distinctly related todrug-taking in the past The ability of context toact as an occasion-setter and to modulate sensi-tization would interact with the ability of speci cdrug-associated conditioned stimuli to triggercraving as a classically conditioned responsecombining to provide very strong contextualcontrol over both craving and relapse3

The second way that the circumstances sur-

rounding drug administration may modulatesensitization is to in uence whether neural sensi-tization is induced in the rst place (or at leastthe rate and extent of sensitization produced bya given dose of a drug) For example there arenow a number of reports that when low tomoderate doses of amphetamine or cocaine areadministered in the environment where an ani-mal lives (ie at ldquohomerdquo) they are less effectivein inducing psychomotor sensitization than if thesame doses are given in a relatively distinctivetest environment one that is novel to the animaluntil its rst pairing with the drug82ndash84 Indeed ifamphetamine is administered at home using achronically indwelling iv catheter so that drugadministration is completely unsignaled doses of0375ndash10 mgkg (iv) fail to induce sensitiza-tion728586 The same doses do induce sensitiza-tion if drug administration is signaled byplacement of an animal into a distinctly predic-tive test environment A similar effect has alsobeen seen with both cocaine51 and morphine(Badiani et al unpublished studies) Furtherstudies have established that the effect ofunsignaled drug administration is not to com-pletely preclude sensitization but to shift thedosendasheffect curve for the induction of sensitiza-tion When high enough doses of either cocaineor amphetamine are given sensitization is in-duced regardless of environmental condition5152

The ability of environmental context to modu-late the induction of sensitization may be relatedto its ability to modulate the neural circuitryengaged by drugs Badiani and colleagues87 re-cently reported for example that the ability ofamphetamine to induce c-fos mRNA in the stria-tum is powerfully modulated by the environmen-tal context in which amphetamine isadministered Indeed it appears that that en-vironmental context can modulate which cellpopulations in the striatum are engaged by am-phetamine When given at home amphetamineinduced c-fos only in striatal neurons also posi-tive for dopamine D1 receptor mRNA (not incells positive for D2 receptor mRNA) but whengiven in association with environmental noveltyamphetamine induced c-fos in both D1 and D2mRNA-positive neurons88

In summary sensitization is not an inevitableconsequence of exposure to potentially addictivedrugs That is it is not a simple pharmacologicalphenomenon but both the expression and theinduction of sensitization can be powerfully


modulated by non-pharmacological factors in-cluding environmental (and presumably psycho-logical) factors associated with drugadministration The in uence of environmentalfactors on sensitization has important implica-tions not only for understanding the phenom-enon but for thinking about therapeuticapproaches in treating addiction (see below)

Sensitization and drug rewardThe studies reviewed above on sensitization tothe psychomotor activating effects of drugs indi-cate that addictive drugs induce neural sensitiza-tion However by themselves they provide onlyindirect evidence that sensitization occurs to theincentive motivational or rewarding effects ofdrugs15 More direct evidence that the neuralsubstrate that is sensitized is involved in mediat-ing drug reward comes from two other sourcesThe rst are studies showing that not only do thepsychomotor stimulant effects of drugs sensitizebut so do their rewarding effects89 There area number of reports that prior exposure toa variety of potentially addictive drugs enhan-ces the later acquisition of both a drug self-administration habit90ndash97 or a conditioned placepreference98ndash102 Prior sensitization to am-phetamine also increases the ldquobreakpointrdquo foramphetamine self-administration when rats aretested using a progressive ratio schedule103104

and the enhanced responding for a conditionedreward produced by intra-accumbens am-phetamine is potentiated by cocaine sensitiza-tion105 Furthermore in recent studies Derocheet al106 have found that experience with self-administered cocaine later enhances the motiv-ation to seek cocaine in for example a runwayapparatus and De Vries and colleagues in theNetherlands have reported that the ability ofdifferent drugs to reinstate (prime) drug-seekingbehavior is positively related to whether they alsoshow cross-psychomotor sensitization107ndash110 In-deed these latter researchers have reported ldquoallof the agonists that elicited sensitized locomotorresponses in morphine- or amphetamine-pre-treated rats hellip appeared to cause reinstatementof previously extinguished heroin or cocaine-seeking behavior respectively Taken togetherthese studies suggest a marked relationship be-tween drug-seeking behavior and drug sensitiza-tionrdquo (Vanderschuren et al110 p 251)Similarly Deroche et al106 concluded on the

basis of their experiments that ldquothe progressiveshift from cocaine use to dependence and thevery high frequency of relapse of abstinentabusers probably originate from a sensitizationphenomenonrdquo

The ability of sensitization to enhance respon-siveness to rewards does not appear to becon ned to drug rewards but also applies toother aspects of incentive motivation Repeatedtreatment with either morphine111 or am-phetamine112 for example later facilitates theappetitive or anticipatory phase of a sexual en-counter Male rats sensitized to amphetaminelater exhibit facilitated sexual behavior towardsan estrus female ldquoas indicated by shorter laten-cies to mount and intromit and a greater per-centage of rats copulatingrdquo (Fiorino ampPhillips112 p 200) This sensitization-related fa-cilitation of sexual motivation is accompanied byaugmented dopamine ef ux in the nucleus ac-cumbens in response to presentation of a recep-tive female113 In discussing their ndingsFiorino amp Phillips112 (p 206) raised the relatedand very interesting clinical observation that ldquoAsmany as 70 of patients admitted to a NewYork cocaine addiction treatment program werealso reported to suffer from compulsive sexu-alityrdquo114 Sensitization may also facilitate re-sponding to learned properties of rewards (eventhough mesostriatal dopamine systems are notessential for reward learning19) This suggestionis consistent with recent reports that sensitizationto amphetamine can facilitate the acquisition ofboth excitatory115116 and inhibitory117 Pavlovianassociations in a task using food (sucrose) re-ward Harmer amp Phillips117118 point out that theability of amphetamine sensitization to facilitatebehavior guided by Pavlovian learning may berelated to its ability to enhance amphetamine-stimulated dopamine ef ux in both the nucleusaccumbens115119 and amygdala115116 The rela-tive roles of the amygdala versus the accumbensin this associative facilitation are as yet un-clear120

The second line of evidence that the neuralsubstrate sensitized by drugs of abuse is involvedin mediating drug reward comes from studies onthe neurobiology of sensitization There is notspace here to review this large literature butsuf ce it to say there is now considerable evi-dence that behavioral sensitization is associatedwith neuroadaptations in dopamineaccumbenssystems33436121 ndash124 This is important because it


is well established that these neural systems playan important role in mediating the rewardingeffects of drugs and other incentives15125126

Thus if sensitization-related neuroadaptationsare found in this mesocorticolimbic circuitry thisis strong evidence that at least one neural systemknown to be critical for mediating drug rewardundergoes ldquoneural sensitizationrdquo

Both pre- and post-synaptic neuroplasticadaptations have been described in the do-pamineaccumbens system of sensitized animalsAn example of a presynaptic adaptation is apersistent increase in the ability of a variety ofdrugs to increase the over ow of dopamine inthe nucleus accumbens and striatum of sensi-tized animals in vitro and in vivo3344679ndash81121122

Examples of postsynaptic adaptations include anincrease in the sensitivity of dopamine D1 recep-tors78123 and a decrease in the sensitivity ofglutamate receptors127 in the nucleus accumbensof sensitized animals (see Wolf124 for a review ofthe role of excitatory amino acids in sensitiza-tion) More recently it has been reported thatboth amphetamine and cocaine sensitization arealso accompanied by persistent structuralmodi cations in the morphology of output neu-rons in both the nucleus accumbens and prefron-tal cortex128129 Repeated treatment withamphetamine or cocaine increases the length ofdendrites on medium spiny neurons in the nu-cleus accumbens and on pyramidal neurons inthe prefrontal cortex This is accompanied by anincrease in spine density on the distal dendritesof these cells On medium spiny neurons there isan especially large increase in the number ofbranched spines that is spines with multipleheads These structural data suggest that sensi-tization may involve more than a simple up- ordownregulation of biochemical processes but itmay involve changes in patterns of synaptic con-nectivity in brain reward systems changes thatmay be similar to those seen in other neuralsystems in association with other forms of experi-ence-dependent plasticity128129 These observa-tions are consistent with increasing evidenceimplicating neurotrophic factors in sensitiza-tion130ndash132

To reiterate the basic thesis of the incentivendash

sensitization view of addiction it was originallyproposed3 that addictive drugs share the abilityto produce persistent neuroadaptations in brainregions involved in the process of incentive mo-tivation and reward adaptations that render

these regions hypersensitive (ldquosensitizedrdquo) Itshould be clear from the above that there is nowa wealth of evidence to support this claim Theincentivendashsensitization view also posits that it islargely because of sensitization of a neural sub-strate that mediates drug reward that with re-peated drug use drugs gradually become moreand more attractive (ie they acquire greater andgreater incentive value) and become increasinglyable to control behavior Studies on sensitizationof drug reward support this claim Furthermorewe have suggested it is the persistence of neuralsensitization that leaves addicts susceptible torelapse even long after the discontinuation ofdrug use Studies on the relationship betweensensitization and reinstatement in animal modelssupport this claim as well Of course these latterhypotheses are more speculative and are predi-cated on the assumption that repeated exposureto drugs of abuse can induce neural sensitizationin humans It is one thing to demonstrate incen-tivendashsensitization in animals models butmdashascritics of our theory occasionally point outmdashquite another to demonstrate its occurrence inaddicts

Sensitization in humansAs might be expected from the dif culty instudying this issue in humans there has beenvery little research on the topic of whether sensi-tization actually occurs in the brains of humanaddicts It could be argued that the enormousincrease in the incentive value of drugs in thedevelopment of addiction is de facto evidence forsensitization of a neural substrate that mediatesthis function in humans but unfortunately forus many will consider this argument insuf cientUntil recently the only direct evidence that re-peated exposure to psychostimulant drugs canproduce sensitization in humans came fromstudies on the phenomenology of amphetamineand cocaine psychosis65133ndash136 There is a con-siderable clinical literature that suggests repeatedexposure to amphetamine or cocaine results in aprogressive increase in their psychotomimetic ef-fects133 and that this enhanced sensitivity maypersist long after the discontinuation of druguse134135137 Related effects have been describedin non-human primates138

More direct evidence for sensitization to thepsychomotor effects of amphetamine in humanshas been lacking until only very recently but


there are now three reports of psychomotor sen-sitization in humans Strakowski et al139 rstreported the results of a double-blind placebo-controlled study in drug naive volunteers giventwo treatments (48 hours apart) with 025 mgkgd-amphetamine They found that the secondtreatment with amphetamine elicited asigni cantly greater increase than the rst in fourbehavioral measures activityenergy mood rateand amount of speech and eyeblink rate In asecond study Strakowski amp Sax140 replicated andextended these ndings to see if three treatmentswith amphetamine would produce a progressiveincrease in drug effect as is usually seen inanimal experiments Two measures increasedprogressively with repeated amphetamine treat-ment activityenergy and eyeblink rate Indeedfor eyeblink rate there was no effect of the rsttreatment with amphetamine relative to placebobut an increase in eyeblink rate emerged withsubsequent drug treatments even though thedose was the same Interestingly subjective rat-ings of drug liking did not increase with threedrug treatments which is consistent with ourhypothesis that sensitization applies to ldquowantingrdquodrugs but not to ldquolikingrdquo drugs (see below)These two studies involved within-subjects as-sessments of sensitization More recentlyStrakowski et al141 reported evidence forsigni cant psychomotor sensitization in humansusing a between-subjects design There has alsobeen one report which failed to nd evidence forcocaine sensitization in humans142 but there areat least two reasons that this may be the caseFirst as indicated by these authors in a letter tothe editor of Biological Psychiatry experiencedcocaine users were used in this latter study andtherefore ldquobecause of their extensive cocaineexposure prior to research participation [thesesubjects] may have already undergone the maxi-mum sensitization process hellip leaving no roomfor the relatively short-term low-dose researchexposure to demonstrate further sensitizationrdquo(Gorelick amp Rothman143 p 230) Secondly aspointed out by Strakowski et al144 in their re-sponse ldquoRothman et al concentrated on physio-logic responses hellip [which] from animalstudies hellip would not be expected to exhibit sen-sitization hellip and indeed we also did not observesensitization in vital signs measurementsrdquo(p 230) Finally additional evidence supportingthe concept of incentivendashsensitization in humansrelevant speci cally to drug taking comes from

the interesting tentative observation of Bartlett etal145 that cocaine users who developed sensitiza-tion to the psychotomimetic effects of the drughave an elevated incidence of relapse as indi-cated by more frequent rehospitalizations

Human imaging studiesNeuroimaging studies of human addicts are alsorelevant to the incentive sensitization hypothesisof addiction3 Especially germane for exampleis a study by Breiter and colleagues146 who usedfunctional MRI to monitor signals related toblood ow in the brain of human cocaine addictsas they received intravenous cocaine or a vehicleAs expected on the basis of animal studies theyfound that cocaine produced a rapid signal in-crease in many structures including the nucleusaccumbens the neostriatum (caudateputamen)many neocortical regions ventral tegmentumand a variety of other brain areas Signal de-creases were seen in the amygdala temporal poleand the medial frontal cortex All these transientchanges correlated with the cocaine rush or eu-phoric effects reported by the addicts Most in-terestingly from the point of view of cravinghowever were more sustained changes in cer-ebral blood ow that outlasted the euphoricrush and that correlated best with subjectivecraving reports for more cocaine Craving-correlated signal increases were found in thenucleus accumbens region parahippocampalcortex and parts of the lateral prefrontal cor-tex146 A craving-correlated decrease in signalwas reported in the amygdala Interestingly oneregion to show bilateral activation during a salineretest was the nucleus accumbens which theauthors speculate could be related to expectancyfor cocaine Activation of this circuitry by stimulithat predict cocaine as has been reported inanimals studies (Berridge amp Robinson19 for re-view) is certainly compatible with the incentivendash

sensitization hypothesisA slightly different pattern of brain changes

was found in a PET study by Childress et al147

who showed former cocaine addicts and normalsubjects videotapes with themes of drug-takingdesigned to pique an addictrsquos craving for co-caine Childress et al147 did not distinguishanatomically between the nucleus accumbensand other parts of the neostriatum but had onlya single ldquocaudaterdquo category The two brain re-gions that in addicts that showed the greatest


change in cerebral blood- ow in response toviewing drug-related stimuli were the amygdalaand the caudate Blood ow increasedsigni cantly in the amygdala and decreasedsigni cantly in the caudate and lenticular nu-cleus Non-addict normal subjects did not showany signi cant changes in blood ow in responseto drug-related stimuli In a related study Grantet al148 found that increases in glucose metab-olism were correlated with self-reports of cravingprovoked by drug-associated stimuli only in theprefrontal cortex amygdala and cerebellum (seealso Mass et al149) whereas Wang et al150 re-ported changes in metabolism only in the or-bitofrontal cortex left insular cortex andcerebellum

Recently PET has also been used to quantifychanges in blood ow in heroin addicts giveneither an injection of heroin or exposed toheroin-related cues151 In this study both heroinand heroin-related cues activated the same struc-tures especially a region of the midbrain cen-tered on the periaqueductal grey (PAG) andventral tegmental area (VTA) The PAG hasprojections to the VTA and of course the VTAis the origin of ascending dopamine projectionsto the nucleus accumbens and neocortex Fur-thermore these authors reported that ldquomidbrainactivations predict responses to salient [drug-related] cues in cortical and subcortical regionsimplicated in reward-related behaviorrdquo includ-ing the anterior cingulate amygdala and dorso-lateral prefrontal cortex (Sell et al151 p 1042)

It is dif cult to draw strong conclusions giventhe small number of studies so far the limita-tions of imaging techniques and the apparentdiscrepancies in results It is interesting from thepoint of view of the incentive-sensitization hy-pothesis that in two studies of addicts thestrongest craving-correlated signal changes wereseen in the nucleus accumbens or caudate aswell as amygdala146147 These studies disagree inthe direction of the accumbenscaudate signalchange one suggesting an increase in blood owduring craving and the other suggesting a de-crease The interpretation of this difference indirection is complicated by the different scales ofanatomical and temporal resolution used in thesestudies by reports that cocaine itself can pro-duce cerebral vasoconstriction in humans152 andby the possibility that the neural signal conveyedby dopamine may under some conditions beinhibitory (hyperpolarizing) and in other condi-

tions excitatory153154 Nevertheless there arenow a reasonable number of imaging studiesshowing that the mesocorticolimbic projectionsystems are engaged when addicts are givendrugs or when they are exposed to drug-associated stimuli and that in some cases thisis associated with reports of craving Such dataare entirely consistent with the incentivendash

sensitization theory of addictionIn summary although there is little research in

humans and it is fraught with technical limita-tions the available evidence suggests that (a)repeated exposure to psychostimulant drugs cansensitize some drug effects in humans and (b)the same mesocorticolimbic circuitry that in ani-mals is known to mediate drug-seeking and toshow neural sensitization is also powerfully en-gaged in humans upon exposure to drugs ordrug-associated stimuli Further studies on be-havioral sensitization in humans will be critical intesting the notion of incentivendashsensitization butit is worth injecting a note of caution in inter-preting negative behavioral studies It is not ob-vious a priori which behavioral measures inhumans will provide the most sensitive indicatorsof a sensitization process This is even a dif cultissue in animal studies For example it is oftendif cult to quantify behavioral sensitization usingmeasures of locomotor activity unless just theright dose and treatment conditions are used85

Also in rats some behaviors show robust sensi-tization such as rotational behavior repetitivesnif ng and repetitive head movements whereasother seemingly related stereotyped behaviors donot such as oral movements3485 Furthermorethe doses used in studies with humans are lowerthan those typically used in animal studies anddrugs are often given orally These conditionsmay produce only marginal sensitization even inanimals5152

Finally one needs to keep in mind that for themost part indices of behavioral sensitization areimportant only as secondary measures becausethey provide indicators of underlying neuroadap-tive processes (neural sensitization) and it isneural sensitization that is critical or primary forincentivendashsensitization predictions regarding ad-diction Even in animal studies the fact that abehavior like rotational behavior sensitizes is ofinterest only because the change in behaviorprovides an indicator of an underlying neuroad-aptive process and because we know a great dealabout the neural systems that mediate this be-


havior and thus have some clues as to whatneural systems might be effected The incentivendash

sensitization hypothesis makes strong predictionsregarding neural sensitization in human addictsbut not necessarily about what which speci cbehaviors might best re ect neural sensitization(even though inferences can be drawn from ani-mal studies) The critical prediction made by theincentive-sensitization view of addiction is thisthe brains of human addicts who compulsivelycrave drugs will contain a neural substrate thathas been rendered sensitized by drugs A role ofthat neural substrate will be to mediate the in-centive salience of drug rewards Further indi-viduals will differ in their susceptibility forsensitization of that neural substrate and thosewho sensitize most readily will be most at risk foraddiction These predictions are testable and sothe incentive sensitization theory of addictioncan be con rmed or disproved on the basis ofempirical evidence

A better understanding of the nature of neuralsensitization based on animal studies will becrucial to developing proper tests of the theory inhuman addicts Once we understand the neuralbasis of sensitization in non-human animals weshould be able to determine if the same neuroad-aptions exist in the brains of addicts If they donot the incentivendashsensitization theory is provedwrong Of course this proof rst requires thatwe understand which neurobiological adapta-tions produced by repeated treatment with drugsare causally related to the development of sensi-tization which we do not as yet Secondly itwill require that adequate technological tools bedeveloped to quantify the relevant neuroadapta-tions in the relevant brain regions in humanswhich given the rapid advances in this eldshould appear in the future Thus future re-search on neuroadaptations engendered by druguse in humans derived from an understandingof the development of neural sensitization inanimal models will eventually provide a nal testof the notion of incentivendashsensitization

ldquoWantingrdquo versus ldquolikingrdquoThe nal crucial issue we would like to addressconcerns the nature of the psychological processthat is mediated by the neural substrate thatundergoes sensitization To the extent this is thedopamineaccumbens system it concerns the na-ture of the incentive and reward function medi-

ated by this system This leads us to the topic ofwhat we have termed ldquowantingrdquo versusldquolikingrdquo319303233155

It is often assumed that the primary role of thedopamineaccumbens systems in reward is tomediate the subjective pleasurable or hedonicaspects of reward (ldquolikingrdquo) This view wasstated most explicitly in Wisersquos156 anhedonia hy-pothesis of dopamine function (also Gardner ampLowinson157) Wise156 argued that after disrup-tion of dopamine neurotransmission by treat-ment with dopamine antagonists ldquoall of lifersquospleasuresmdashthe pleasures of primary reinforce-ment and the pleasures of their associated stim-ulimdashlose their ability to arouse the animalrdquo(p 52) Although this view is no longer held byWise158 dopamine is typically associated withpleasure in popular media accounts159160 andthis view is implicit or explicit in many scienti cdiscussions of dopamine and reward19 For ex-ample it is often argued that a suppression indopamine neurotransmission mediates anhedo-nia during drug withdrawal5161ndash164 a view that isa direct extension of Wisersquos anhedonia hypoth-esis of neuroleptic action

The idea that drug pleasure is mediated bydopamine systems continues to be endorsed by anumber of neuroscientists who study addictionIn their own words for example Gardner ampLowinson157 (p 360) stated ldquoa subportion ofthe mesolimbic dopamine neurons originating inthe ventral tegmental area hellip and synapsing intothe nucleus accumbens and adjacent ar-eas hellip appears highly specialized for carryingneural messages encoding hedonic tonerdquo [our ital-ics] Thus suppression of the dopamine systemis often held as by Wise originally to producedysphoria or anhedonia In an explicit statementof this hypothesis Dackis amp Gold5 graphicallyillustrated in their Fig 4 the opinion that ldquoSinceincreased dopamine neurotransmission can pro-duce euphoric states dopamine depletion aftercocaine use may lead to cocaine urges and dys-phoriardquo (p 473) This view was more recentlyreiterated by Markou Kosten amp Koob165 whoposit that ldquoBased on the ample evidence for arole of mesocorticolimbic dopamine neurotrans-mission in reward and incentivemotivationalprocesses and that abnormalities in these two pro-cesses (ie inability to experience pleasure and lossof motivation) constitute core symptoms of de-pression a dysfunction in the mesocorticolimbic do-paminergic system may be mediating these


symptomsrdquo (p 150 italics added) Similarly DiChiara amp Tanda166 (p 353) posit that the ca-pacity for pleasure is so closely linked to do-pamine that a physiological measure ofdopamine neurotransmission should be able toindex psychological pleasure proposing that ldquoasa biochemical test for anhedoniahellip [one maymeasure] the blunting of DA neurotransmissionin the Nac lsquoshellrsquo rdquo Most investigators do notmake that inferential leap but many appear topresume that measures of neural activity in themesolimbic dopamine projection system re ectthe hedonic impact of an event For exampleChildress and colleagues147 (pp 11ndash12) hypo-thesize that ldquobrain structures activated duringcocaine craving may be among those activatedby cocaine itself including the dopamine-innervated limbic regions implicated in cocainersquospleasurable effectsrdquo (italics added) Indeed on thebasis of PET studies with cocaine Volkow etal167 reported ldquoThe magnitude of the self-reported high was correlated with the degree ofdopamine transporter occupancyrdquo (p 827)

If a depression in dopamine neurotransmissionleads to anhedonia it follows according to thehedonia hypothesis that enhanced dopamineneurotransmission should lead to enhanced plea-sure If that were true then sensitized humanaddicts should gain more pleasure than usualfrom their drugs Indeed Koob amp Le Moal10

(p 52) in a discussion of drug abuse and hedo-nic dysregulation note rst that ldquothe facilitationof dopamine neurotransmission in the meso-corticolimbic dopamine system appears to becritical for the acute reinforcing actionsrdquo of drugsof abuse and go on to equate the positive rein-forcing effects of drugs with hedonic euphoriaThey then explicitly incorporate sensitizationinto their explanation of addiction by graphicallydescribing sensitization as producing a 10ndash20increase in a drugrsquos positive effect along a hedo-nic scale (see their Fig 4B p 56) In otherwords they postulate that repeated drug use maysensitize or increase an addictrsquos experience of thehedonic effect of a drug enhanced drug ldquolikingrdquoas well as drug ldquowantingrdquo (in contrast to ourview that sensitization applies to drug ldquowantingrdquobut not to drug ldquolikingrdquo see Fig 2 below)

On the other hand in different accounts Kooband colleagues have hypothesized instead thataddiction is not driven primarily by an increasein the hedonic impact of drugs themselves butrather driven by the negative hedonic conse-

Figure 2 A schematic illustration of the hypotheticalrelationship between changes in the incentive value of drugs(drug ldquowantingrdquo) and changes in the ability of drugs toproduce subjective pleasurable effects (drug ldquolikingrdquo) duringthe development of addiction The top panel indicates therelationship posited by the Robinson amp Berridge3 incentivendash

sensitization view Robinson amp Berridge3 argued that in thedevelopment of addiction sensitization leads to enhancedldquowantingrdquo due to sensitization of the neural substrateresponsible for incentive salience while at the same time thereis either no change or a small decrease in the hedonic effectsof drugs (see Robinson amp Berridge3 for a full discussion) Thebottom panel indicates the relationship posited by Koob amp LeMoal10 in their Fig 4B They indicate that sensitization ischaracterized by an increase in the intensity of the primarydrug effect along a hedonic scale That is in the developmentof addiction they suggest there is not only an increase in theincentive value of drugs (ldquowantingrdquo in our terms) but also an

increase in hedonic effect (ldquolikingrdquo in our terms)

quences of discontinuing drug use8ndash10165 Theyargue for example that suppression of do-pamine neurotransmission in withdrawal pro-


duces ldquohedonic homeostatic dysregulationrdquo ordysphoria and suggest addicts seek drugs tore-establish ldquohedonic homeostasisrdquo by takingmore drugs to restore dopamine neurotransmis-sion to normal levels10 In yet another accountKoob and colleagues168 have posited that addic-tion is characterized by an increase in a ldquohedonicset pointrdquo whereby drug intake is escalated theysay because individuals ldquoare trying to reach andthen to maintain a higher state of intoxicationrdquo(p 300) Thus in this latter formulation there isno sensitization to the hedonic impact of thedrug itself but only ldquoa change in the hedonic setpointrdquo (p 299) It is unclear whether a set pointfor pleasure actually exists as the set point con-cept implies that organisms should choose toincrease pleasure only to the level of their setpoint and not beyond that level The only evi-dence for a hedonic set point seems to be thatindividuals achieve stable levels of drug self-administration Stable self-administration mightbe explained by several factors so one hopes thata clearer explanation will be forthcoming by theauthors of what such a set point entails

Despite their inconsistencies all these hypoth-eses share in common the idea that hedonic stateis what regulates compulsive patterns of drug-seeking and drug-taking behavior in the addictand that changes in dopamine neurotransmissionmove an individual up and down along an hedo-nic scale Many authors do not link dopamineneurotransmission with drug pleasure so ex-plicitly as do Koob and colleagues but many doposit essentially the same point implicitly bysubstituting terms such as ldquoreinforcementrdquo forthe function mediated by dopamine neurotrans-mission in ways that are dif cult to distinguishfrom hedonic impact (eg Volkow et al167 seefootnote 3 in Berridge amp Robinson19 for a dis-cussion of this point) Thus it seems clear thatthe dopamine hedonia hypothesis is not onlyfound in popular media accounts of dopaminersquosfunction in reward but it still lives in the sci-enti c literature Although it is possible in prin-ciple that dopamine systems mediate hedonicprocesses and that drug pleasure might showsensitization as Koob amp Le Moal10 have pro-posed we must emphasize that this view differsin at least two ways from our concept of in-centivendashsensitization First the incentivendash

sensitization theory holds that drugs can activatepositive core processes of motivation in the ab-sence of conscious awareness so that positive

effects may not be indicated on any scale ofsubjective affective intensity31930155 For exam-ple as discussed above drugs that activate do-pamine systems may promote drug-takingbehavior in the absence of any subjective hedo-nic effects222429 which is not consistent with thenotion that the positive reinforcing effects ofdrugs can be equated with their hedonic impactSecondly the incentivendashsensitization theory ex-plicitly posits that hedonic affect either as sub-jective pleasure or its underlying core process(ldquolikingrdquo) is not the component of drug rewardthat is sensitized in addiction and is not thepsychological process that is mediated by do-pamine systems31933 Instead we have hypothe-sized that dopamine systems are crucial to theldquowantingrdquo component of incentive motiv-ation31933 Indeed there is convincing evidenceto support the view that mesoaccumbens do-pamine systems do not mediate hedonic pro-cesses but rather mediate a separable ldquowantingrdquocomponent namely incentive salience in motiv-ation and reward31931ndash33169

The evidence that dopamine systems to notmediate hedonic processes has been reviewedrecently by us19 and so the main points aresummarized only brie y here First there is nowevidence from studies using neurochemical le-sions dopamine agonists or antagonists andother manipulations which shows that alterationsin dopamine neurotransmission have no effecton the ability of rats to make judgements aboutthe hedonic properties of taste stimuli19 (for re-views see Berridge33) For example experimentswith rats that have complete striatal dopaminedepletions have established that caudate and ac-cumbens dopamine is not necessary for reward-ing taste stimuli to elicit normal hedonicreactions193133170 Secondly there is an largeliterature showing that dopamine and accum-bens neurons often discharge in anticipation ofrewards not during actual commerce with anexpected reward when the most pleasure is pre-sumably experienced171172 Thirdly it is wellestablished that dopamine systems are activatednot only by positive stimuli but by aversivepainful and stressful stimuli and events (for ref-erences see Berridge amp Robinson19 and Salam-one et al173) Fourthly there is a growingliterature indicating that even in humans do-pamine antagonists such as pimozide or halope-ridol fail to reduce amphetamine-inducedratings of pleasure or euphoriamdasheven when the


same antagonists reduce ratings of how muchamphetamine is wanted ie a subjective likingwanting dissociation (for review see Berridge ampRobinson19 Berger et al174 Brauer amp De-Wit175176 and Ohuoha et al177) Fifthly enhanc-ing dopamine neurotransmission is not suf cientto produce pleasurable subjective effects in hu-mans (for review see Rothman amp Glowa178) Forexample Volkow et al179 (p 14) state ldquoblockadeof striatal dopamine transporters by intravenousmethylphenidate [in humans] is not suf cient toinduce self-reports of lsquohighrsquo rdquo Thus points 4and 5 together suggest that in humans increaseddopamine neurotransmission is neither necessarynor suf cient for psychostimulants to producesubjective pleasurable effects

In summary despite correlational evidence fora relationship between dopamine activation andsubjective pleasure in some instances (for exam-ple Volkow et al167) a more thorough examin-ation of the evidence does not support thehypothesis that this represents a necessary causalrelationship or that dopamine mediates plea-sure19173 Given that the role of the dopamineaccumbens system in reward is not related to thehedonic aspects of reward what is its contribu-tion What is the nature of the psychologicalprocess that is ldquosensitizedrdquo in the addict

We have interpreted the role of the dopamineaccumbens system in reward and the role ofsensitization of this substrate in addiction in thecontext of a view of incentive motivation devel-oped from studies on the neural systems respon-sible for taste hedonics This view is an extensionof traditional psychological models of incentivemotivation developed by theorists such asBindra180 and Toates181 In these traditionalmodels of incentive motivation which coincidewith the common view expressed in much of theliterature it was hypothesized that a single pro-cess mediates both incentive value (how muchan incentive is ldquowantedrdquo) and hedonic value(how much it is ldquolikedrdquo) Incentives were hy-pothesized to have incentive value because oftheir ability to produce pleasuremdashldquowantingrdquo andldquolikingrdquo were therefore necessarily connectedand treated as explanations for positive re-inforcement (in a non-circular sense) In ourextension of these earlier models however wehave hypothesized that the psychological processand neural substrate responsible for motivatingbehavior for determining incentive value(ldquowantingrdquo) is separable from the psychological

process and neural substrate that mediates hedo-nics (ldquolikingrdquo3193233) Manipulations of mesote-lencephalic dopamine systems alter ldquowantingrdquomore directly and powerfully than they alterldquolikingrdquo19

It is further hypothesized that the psychologi-cal process that leads to ldquowantingrdquo involves theattribution of attractive salience to stimuli andtheir representations a process we call incentivesalience attribution We have suggested it is theprocess of incentive salience attribution thattransforms the sensory features of ordinary stim-uli or more accurately the neural and psycho-logical representations of stimuli so that theybecome especially salient stimuli stimuli thatldquograb the attentionrdquo that become especially at-tractive and wanted thus eliciting approach andguiding behavior to the goal31933 It is incentivesalience that determines the value of incentivesand that controls seeking and instrumental be-havior regarding them19

The major feature of our view of incentivemotivation that distinguishes it from earlier mod-els is that it posits there are at least two distinctpsychological processes involved in reward (a)subjective pleasure (ldquolikingrdquo) and (b) incentivesalience attribution (ldquowantingrdquo) These two psy-chological processes are mediated by differentneural systems Furthermore it is suggested thatthe neural systems that are sensitized by addictivedrugs are those involved speci cally in incentivesalience attribution3 The neural systems thatmediate the subjective pleasurable (hedonic) ef-fects of drugs do not appear to sensitize Thismay be why addiction is characterized by anincreasing dissociation between the incentivevalue of drugs (how much they are wanted) andtheir subjective pleasurable effects (how muchthey are liked) With the development of anaddiction drugs become pathologically wanted(ldquocravedrdquo) and this can occur even if drugs areliked less and less The distinction between theRobinson amp Berridge3 ldquoincentive salience sensi-tizationrdquo view and the Koob amp Le Moal10

ldquohedonic sensitizationrdquo view is illustrated graphi-cally in Fig 2

Finally it is interesting to consider that theneural system responsible for incentive salienceattribution can sometimes produce goal-directedbehavior (ldquowantingrdquo) not only in the absence ofsubjective pleasure as discussed above29 but inthe absence of conscious awareness of ldquowantingrdquoitself3033155 Activation of this system may con-


stitute an implicit rather than explicit psycholog-ical process similar to implicit memory or toimplicit perceptual processes182183 and can actsometimes as an unconscious motivational pro-cess330155 We become aware of its activationonly by engaging interpretive cognitive processesneeded to translate implicit activation into ex-plicit subjective feelings19184ndash186 It may be be-cause these psychological processes often operateoutside of conscious awareness that addicts haveso little insight into why they want drugs somuch Addicts may report they are miserabletheir life is in ruins and that even the drug is notthat great anymore They are themselves bewil-dered by the intensity of their own compulsivebehavior Indeed addicts probably have no moreinsight into what motivates their daily behaviorthan do the rest of us which is arguably notmuch186ndash188 (for additional discussion and refer-ences see Berridge amp Robinson30 andBerridge155)

The incentivendashsensitization view of addictionhas focused on drug-induced alterations in ac-cumbens-related circuitry and associatedchanges in motivational processes and howthese may enhance associative learning We mustemphasize however that incentivendashsensitizationis just one contributor to addiction and thatdrugs of abuse produce persistent alterations inmany neural systems altering many other psy-chological processes Some of these may contrib-ute directly to the development andormanifestation of sensitized incentive salienceand others may contribute to addiction via alter-nate mechanisms For example in addition todrug hedonic processes withdrawal-related pro-cesses and incentive salience processes Phillipsand his colleagues115ndash118 have described sensitiza-tion-related changes in dopaminergic activity inthe amygdala that may directly facilitate Pavlo-vian learning Sarter amp Bruno189 recently re-viewed evidence that sensitization also increasesthe activity of basal forebrain cholinergic neu-rons leading to enhanced cortical acetylcholine-mediated activity They hypothesized that thismay lead to alterations in attentional processesin particular cognitive or hyperattentional statesthat may contribute to the pathological levels ofincentive salience attributed to drug-relatedstimuli Finally a number of researchers havesuggested that repeated exposure to psychostim-ulant drugs may result in frontocortical dysfunc-tion and associated cognitive de cits including

impairments in decision-making and judge-ment190 Indeed there is increasing evidence thatcocaine addicts show both neuropsychologi-cal191192 and neurobiological191193ndash195 signs offrontal dysfunction Resulting impairments ofcognitive strategies to avoid drug use196 or tocontrol impulsivity190 might interact with theincreased motivation to seek and take drugs viathe process of incentivendashsensitization describedhere Thus in the addict drugs may becomeincreasingly ldquowantedrdquo while at the same time theability to make reasoned judgements about thefuture consequences of continued drug use be-comes increasingly impaired How these drug-induced alterations in motivational attentionaland cognitive processes interact to produce thecompulsive patterns of drug-seeking and drug-taking behavior that characterizes addiction re-mains an important challenge for futureresearch

Implications for therapyIn closing we would like to point out that theincentivendashsensitization view of addiction has anumber of implications for therapy First it sug-gests that pharmacotherapeutic approacheswhich fail to address the neuroadaptive processesthat lead to addiction in the rst place willprobably provide only symptomatic relief and inthe long term will probably be of limited ef cacyFor example the treatment of withdrawal symp-toms by themselves has proven to have littleeffect in the long-term18 We suggest that this isbecause avoidance of withdrawal is not the fun-damental motivating force in addiction Thusthe incentivendashsensitization view of addiction pre-dicts that the most ef cacious medications willeither (a) reverse the neuroadaptations that un-derlie incentivendashsensitization andor (b) preventthe expression of neural sensitization in behaviorie inhibit the output of a sensitized ldquowantingrdquosystem

There are of course many potential limita-tions of drugs with such effects For example itis not clear whether it is possible to develop anagent that could reverse speci cally drug-experi-ence dependent plasticity without effectingother forms of experience-dependent plasticitythat are probably very similar at the cell andmolecular level Also most human addicts arepolysubstance abusers and it is not obviouswhether any single agent would be effective if


different drugs of abuse induce different sensi-tization-related neuroadaptations Furthermorethese pharmacotherapeutic approaches are notlikely to have long-term ef cacy in the absence ofpsychotherapeutic and social supports that alterlife style For example a medication that re-versed sensitization-related neuroadaptationswould not be effective if after treatment a personresumed drug-taking and reinitiated the sensi-tization process Nevertheless the classes ofmedications currently in use probably do notdirectly attack the problem of reversing incen-tivendashsensitization

Substitution approachesOpiate addicts can be maintained for long peri-ods of time by substitution of heroin or mor-phine with long-acting mu opiate receptoragonists such as methadone or levo-alpha acetylmethadyl (LAAM) and more recently by partialagonists such as buprenorphine This approachhas prompted interest in developing analogouslong-lasting substitutes for cocaine Althoughsubstitution therapies might be effective in man-aging addictive disorders it must be acknowl-edged that they do not eliminate the addictionThey simply substitute one addictive drug foranother that has more benign pharmacologicalproperties These substitutes are themselveschronically self-administered and may promotethe same neuroadaptive processes as the orig-inally abused agent thus maintaining thestrength of an addiction There is certainly noevidence that they can reverse neuroadaptiveprocesses such as neural sensitization that mayhave produced addictive behavior in the rstplace

AntagonistsAntagonist therapies such as naltrexone havedifferent implications regarding the incentivendash

sensitization theory Antagonists that block opi-oid receptors may suppress a component ofreinforcement involving ldquolikingrdquo as well asldquowantingrdquo333 Presumably they might be effec-tive in preventing the development of an addic-tion and may possibly also prevent there-boosting of incentive salience attributions thatwould otherwise strengthen the addiction further(for discussion of re-boosting and incentivesalience see Berridge amp Robinson19) However

there is no reason to believe that opioid antago-nists are capable of permanently reversing any ofthe neuroadaptations in an addict that lead toincentive sensitization and so an individual maystill remain at risk to relapse

AntidepressantsA variety of antidepressants have been used overthe years in the treatment of addiction based inpart on the assumption they will reduce symp-toms of depression (eg anhedonia) in with-drawal and that by itself should be useful intreating addiction For example there were ini-tially enthusiastic reports on using tricyclic an-tidepressants such as desipramine in treatingcocaine dependence197 However later studiessuggested that the initial enthusiasm was notwarranted197ndash199 Indeed there have been reportsthat tricyclics may in some instances actuallypromote relapse200 This may be because suchagents promote catecholamine neurotransmis-sion and this can ldquoprimerdquo drug responding (pro-moting drug ldquowantingrdquo from our point of view)Indeed repeated treatment with desipramine hasbeen reported to induce sensitization of do-pamine neurotransmission201 Obviously froman incentivendashsensitization view this would bedisadvantageous

More recently a different antidepressantbupropion (Wellbutrin) has been reported toincrease abstinence from cigarettes for smok-ers202203 Bupropion is a monoamine uptakeblocker and modulates both norepinephrine anddopamine activity204ndash206 However bupropionalso increases the level of mRNA expression forthe dopamine transporter within the ventral teg-mental area and substantia nigra205 Increasednumbers of the transporter molecules after thisdrug could facilitate re-uptake and so exert asuppressive effect on dopamine neurotransmis-sion that would oppose the original re-uptakeblocking action207208 (Dr KY Little personalcommunication) If bupropion acts on cravingspeci cally rather than on general aspects ofdepression that contribute to smoking behaviorthen suppression of dopamine neurotransmissionwould be expected to be more useful than facili-tation from our point of view

Since smokers take the drug chronically andcraving is affected over months the long-termeffects of taking the drug are likely to be mostimportant to its therapeutic action As with most


antidepressants the long-term effects of thisdrug are least understood However as withdesipramine there is evidence that repeatedtreatment with bupropion can itself induce be-havioral sensitization and ldquobupropion-inducedbehavioral sensitization is accompanied by aselective potentiation of the effects of this com-pound on interstitial dopamine concentrations inthe nucleus accumbensrdquo209 (p 7) If neural sen-sitization occurs after therapeutic doses ofbupropion then the incentivendashsensitization the-ory must certainly regard it as a less than idealdrug for treating addiction

AcamprosateAcamprosate has been described as a ldquopartialco-agonistrdquo for NMDA glutamate receptorsalthough its effects on NMDA transmissionappear to be complex and possibly state-dependent210211 Called an ldquoanti-cravingrdquo drugit has been reported to increase the proportion ofalcoholics who successfully abstain from alcoholfor several months (although possibly not be-yond212) and reduces some of the acute psycho-logical and physiological consequences of alcoholand morphine withdrawal213214 It is possiblethat acamprosate might act in part by modulat-ing the sensitized incentive salience of drug-related stimuli If acamprosate acts primarily onNMDA receptors if the location of thoseNMDA receptors were in the mesoaccumbenssystem or its major connections and if NMDAreceptors are important mediators of the ex-pression of neural sensitization124 (124) then itmight conceivably interfere with an NMDAmechanism involved in the expression of sensi-tization Clearly however this hinges on a num-ber of assumptions and so the relation betweenacamprosate and the incentivendashsalience hypoth-esis must remain unclear for the time being

ImmunotherapiesFinally there recently has been interest in devel-oping immunotherapies for cocaine abuse18

which involve treatment with primary antibodiesor catalytic antibodies to cocaine These treat-ments effectively reduce the amount of cocainethat reaches the brain Of course this approachalso fails to reverse the neuroadaptive processesresponsible for addiction even though it mayimpede their further growth Because of this

failure to address persisting neural sensitizationcocaine addicts treated with such vaccines maystill crave the drug They might satisfy theirdesire by either taking enough cocaine to over-come the antibody or by taking a different psy-chostimulant such as amphetamine which isnot targeted by the vaccine Indeed one mightfear that such vaccines could exacerbate some ofthe social problems associated with cocaineabuse such as spurring some individuals to com-mit more crimes because recidivist addictswould require more money to obtain the addi-tional cocaine needed to overcome the antibody

Future pharmacotherapiesThe ability of existing drugs to treat addiction(other than perhaps substitution therapy) is farfrom impressive Success for anti-craving drugsis typically measured as a modest increase in thepercentage of addicts who give up their drugs fora few months or even just a few weeks Forseveral therapeutic drugs such as some antide-pressants even this goal is often not reachedClearly current drugs provide no magic bulletdrug therapy for addiction So what are theprospects for better drugs in the future

The incentive sensitization theory does notrule out the possibility of more effective drugtherapies but it highlights that a pharmacologi-cal ldquocurerdquo for addiction is a dif cult task Usingdrugs to block the development of sensitizationshould be effective and in animals studies manysuch dopaminergic and glutaminergic agentshave been identi ed124 However it is unlikelythat people would be willing to take such agentsbefore they become addicts and so these are notlikely to be useful therapeutic tools The optimalapproach presumably would be to reverse theneural changes underlying sensitization in ad-dicts Given that sensitization appears to involvecomplex changes in patterns of synaptic connec-tivity in regions such as the nucleus accumbensand prefrontal cortex and multiple biochemicaladaptations in monoamine and excitatory aminoacid neurotransmitter systems122ndash124128129 itseems unlikely that a pharmacological agentcould reverse all these neuroadaptationsmdashandpossibly moremdashwithout disrupting other neuralprocesses necessary for normal brain functionAlso as mentioned above it is not clear whethera single agent could target the multiple neuroad-aptations likely to be associated with the poly-


substance abuse typical of addicts Howeverthese are empirical questions that will only beanswered by future research

It might be more reasonable to hope to modu-late the expression of neural sensitization even ifone could not reverse it A drug therapy thatacted to block the attribution of sensitized incen-tive salience to drug-related stimuli and associ-ated representations might well reduce addictivecraving and compulsive drug taking Therapeuticdrugs that target the neural mechanisms involvedin the expression of sensitized incentive saliencemay offer the best hope of pharmacotherapies foraddiction from the point of view of the incen-tivendashsensitization theory124125 It is even possiblethat some current drugs to the degree that theytarget craving at all might interact with neuralmechanisms that express sensitization Futuretherapeutic drugs might be developed to do thisbetter especially when the mechanisms that ex-press sensitized incentive salience are more fullyunderstood

However in developing such compounds theincentivendashsensitization theory posits that theirneural target must be the neural substrate re-sponsible speci cally for sensitized incentivesalience and it is not well established that thissubstrate is the same as that responsible forpsychomotor sensitization216217 There may bemultiple neural systems sensitized by repeatedexposure to drugs of abuse that mediate differentbehaviors but according to incentivendash

sensitzation theory only the neural substrate re-sponsible for incentive salience (ldquowantingrdquo) iscrucial in addiction In developing preclinicalmodels it will be important to determine therelationship between the sensitization of differentbehaviors (eg locomotion different stereo-typies self-administration post-stereotypy hy-peractivity rotational behavior etc) and thesensitization of different neural substrates It willalso be important to identify which of thesesubstrates is most predictive of the sensitizationof incentive salience relevant to addiction

PsychotherapiesTo end on a positive note the incentivendashsensi-tization theory suggests that in the absence ofeffective pharmacotherapeutics and despite thepersistence of neural sensitization properly ap-plied psychotherapeutic (including behavioral)approaches may be effective in treating addic-

tion They may offer the best hope for addictstoday This is because environmental (and pre-sumably psychological) factors can powerfullymodulate the expression and development ofsensitization as discussed above7273 This sug-gests that behavioralcognitive mechanisms maybe employed to gate the output of the sensitizedneural systems mediating core motivational pro-cesses thus preventing their expression in behav-ior Sadly the persistence of neural sensitizationmay mean to paraphrase Alcoholics Anony-mous that in a neurobiological sense once anaddict always an addict But by developing effec-tive long-term behavioral cognitive and psycho-social support structures one should be able tomanage more effectively the urges arising fromdrug sensitized neural systems that mediate thebasic motivational processes discussed here

References1 INSTITUTE OF MEDICINE COMMITTEE ON

OPPORTUNITIES IN DRUG ABUSE RESEARCH

(1996) Pathways of Addiction (Washington DCNational Academy Press)

2 EDWARDS G (1981) Nomenclature andclassi cation of drug- and alcohol-related prob-lems a WHO memorandum Bulletin of the WorldHealth Organization 59 225ndash242

3 ROBINSON T E amp BERRIDGE K C (1993) Theneural basis of drug craving an incentivendash

sensitization theory of addiction Brain ResearchReviews 18 247ndash291

4 MARKOU A WEISS F GOLD L H CAINE SB SCHULTEIS G amp KOOB G K (1993) Animalmodels of drug craving Psychopharmacology 112163ndash182

5 DACKIS C A amp GOLD M S (1985) New con-cepts in cocaine addiction the dopamine deple-tion hypothesis Neuroscience BiobehavioralReviews 9 469ndash477

6 JAFFE J H (1990) Drug addiction and drugabuse in GILMAN A G RALL T W NIES AS amp TAYLOR P (Eds) The Pharmacological Basisof Therapeutics pp 522ndash573 (New York Perga-mon Press)

7 WIKLER A (1948) Recent progress in researchon the neurophysiological basis of morphine ad-diction American Journal of Psychiatry 105 329ndash

3388 KOOB G F STINUS L LE MOAL M amp BLOOM

F E (1989) Opponent process theory of motiv-ation neurobiological evidence from studies ofopiate dependence Neuroscience BiobehavioralReviews 13 135ndash140

9 KOOB G F CAINE S B PARSONS LMARKOU A amp WEISS F (1997) Opponent pro-cess model and psychostimulant addiction Phar-macology Biochemistry and Behavior 57513ndash521


10 KOOB G F amp LE MOAL M (1997) Drug abusehedonic homeostatic dysregulation Science 27852ndash58

11 KOOB G F (1997) Neurochemical explanationsfor addiction Hospital Practice April 12ndash14

12 GOUDIE A J amp DEMELLWEEK C (1986)Conditioning factors in drug tolerance inGOLDBERG S R amp STOLERMAN I P (Eds)Behavioral Analysis of Drug Dependence pp 225ndash

285 (New York Academic Press)13 GOUDIE A J (1990) Conditioned opponent

processes in the development of tolerance topsychoactive drugs Progress in Neuro-Psychopharmacology and Biological Psychiatry 14675ndash688

14 JAFFE J H (1992) Current concepts of addic-tion in OrsquoBRIEN C P amp JAFFE J H (Eds)Addictive States pp 1ndash21 (New York RavenPress)

15 WISE R A amp BOZARTH M A (1987) A psycho-motor stimulant theory of addiction PsychologicalReview 94 469ndash492

16 SHAHAM Y RAJABI H amp STEWART J (1996)Relapse to heroin-seeking in rats under opioidmaintenance the effects of stress heroin primingand withdrawal Journal of Neuroscience 161957ndash1963

17 STEWART J amp WISE R A (1992) Reinstatementof heroin self-administration habits morphineprompts and naltrexone discourages renewed re-sponding after extinction Psychopharmacology108 79ndash84

18 OrsquoBRIEN C P (1997) A range of research-basedpharmacotherapies for addiction Science 27866ndash70

19 BERRIDGE K C amp ROBINSON T E (1998) Whatis the role of dopamine in reward hedonic im-pact reward learning or incentive salienceBrain Research Reviews 28 309ndash369

20 SKINNER B F (1953) Science and HumanBehavior (New York The Free Press)

21 DEWS P (1977) Remarks in THOMPSON T ampUNNA K R (Eds) Predicting Dependence Liabilityof Stimulant and Depressant Drugs pp 75ndash79(Baltimore University Park Press)

22 FISCHMAN M W (1989) Relationship betweenself-reported drug effects and their reinforcingeffects studies with stimulant drugs NIDAResearch Monographs 92 211ndash230

23 FISCHMAN M W FOLTIN R W NESTADT Gamp PEARLSON G D (1990) Effects of desipraminemaintenance on cocaine self-administration byhumans Journal of Pharmacology and Experimen-tal Therapeutics 253 760ndash770

24 FISCHMAN M W amp FOLTIN R W (1992) Self-administration of cocaine by humans a labora-tory perspective in BOCK G R amp WHELAN J(Eds) Cocaine scienti c and social dimensionsCIBA Foundation Symposium No 166pp 165ndash180 (Chichester UK Wiley)

25 FOLTIN R W amp FISCHMAN M W (1991) As-sessment of abuse liability of stimulant drugs inhumans a methodological survey Drug andAlcohol Dependence 28 3ndash48

26 HANEY M FOLTIN R W amp FISCHMAN M W(1998) Effects of pergolide on intravenous co-caine self-administration in men and womenPsychopharmacology 137 15ndash24

27 HANEY M COLLINS E D WARD A SFOLTIN R W amp FISCHMAN M W (1999)Effect of a selective dopamine D1 agonist (ABT-431) on smoked cocaine self-administration inhumans Psychopharmacology 143 102ndash110

28 COMER S D COLLINS E D MACARTHERR B amp FISCHMAN M W (1999) Comparisonof intravenous and intranasal heroin self-administration by morphine-maintained humansPsychopharmacology 143 327ndash338

29 LAMB R J PRESTON K L SCHINDLER C WMEISCH R A DAVIS F KATZ J L HENNING-

FIELD J E amp GOLDBERG S R (1991) The rein-forcing and subjective effects of morphine inpost-addicts a dosendashresponse study Journal ofPharmacology and Experimental Therapeutics 2591165ndash1173

30 BERRIDGE K C amp ROBINSON T E (1995) Themind of an addicted brain neural sensitizationof wanting versus liking Current Directions inPsychological Science 4 71ndash76

31 BERRIDGE K C VENIER I L amp ROBINSON T E(1989) Taste reactivity analysis of 6-hydroxydo-pamine-induced aphagia implications for arousaland anhedonia hypotheses of dopamine functionBehavioral Neuroscience 103 36ndash45

32 BERRIDGE K C amp VALENSTEIN E S (1991)What psychological process mediates feedingevoked by electrical stimulation of the lateralhypothalamus Behavioral Neuroscience 105 3ndash

1433 BERRIDGE K C (1996) Food reward brain

substrates of wanting and liking NeuroscienceBiobehavioral Reviews 20 1ndash25

34 ROBINSON T E amp BECKER J B (1986) Endur-ing changes in brain and behavior produced bychronic amphetamine administration a reviewand evaluation of animal models of amphetaminepsychosis Brain Research Reviews 11 157ndash198

35 SEGAL D S GEYER M A amp SCHUCKIT M A(1981) Stimulant-induced psychosis an evalu-ation of animal models Essays in Neurochemistryand Neuropharmacology 5 95ndash129

36 STEWART J amp BADIANI A (1993) Tolerance andsensitization to the behavioral effects of drugsBehavioral Pharmacology 4 289ndash312

37 BROADBENT J amp HARLESS W E (1999) Differ-ential effects of GABA(A) and GABA(B) ago-nists on sensitization to the locomotor stimu-lant effects of ethanol in DBA2 J micePsychopharmacology 141 197ndash205

38 CRABBE J C JOHNSON N A GRAY D KKOSOBUD A amp YOUNG E R (1982) Biphasiceffects of ethanol on open- eld activity sensi-tivity and tolerance in C57BL6N and DBA2Nmice Journal of Comparative and PhysiologicalPsychology 96 440ndash451

39 CUNNINGHAM C L amp NOBLE D (1992) Con-ditioned activation induced by ethanol role insensitization and conditioned place preference


Pharmacology Biochemistry and Behavior 43 307ndash

31340 ITZHAK Y amp MARTIN J L (1999) Effects of

cocaine nicotine dizocipline and alcohol onmice locomotor activity cocaine-alcohol cross-sensitization involves upregulation of striatal do-pamine transporter binding sites Brain Research818 204ndash211

41 LESSOV C N amp PHILLIPS T J (1998) Durationof sensitization to the locomotor stimulant effectsof ethanol in mice Psychopharmacology 135374ndash382

42 MASUR J amp BOERNGEN R (1980) The excita-tory component of ethanol in mice a chronicstudy Pharmacology Biochemistry and Behavior13 777ndash780

43 MASUR J OLIVEIRA DE SOUZA M L ampZWICKER A P (1986) The excitatory effect ofethanol absence in rats no tolerance andincreased sensitivity in mice PharmacologyBiochemistry and Behavior 24 1225ndash1228

44 PHILLIPS T J ROBERTS A J amp LESSOV C N(1997) Behavioral sensitization to ethanol gen-etics and the effects of stress PharmacologyBiochemistry and Behavior 57 487ndash493

45 MANLEY S J amp LITTLE H J (1997) Enhance-ment of amphetamine- and cocaine-induced lo-comotor activity after chronic ethanoladministration Journal of Pharmacology andExperimental Therapeutics 281 1330ndash1339

46 NESTBY P VANDERSCHUREN L J DE VRIES TJ HOGENBOOM F WARDEH G MULDER A Hamp SCHOFFELMEER A N (1997) Ethanol likepsychostimulants and morphine causes long-lasting hyperreactivity of dopamine and acetyl-choline neurons of rat nucleus accumbenspossible role in behavioural sensitizationPsychopharmacology 133 69ndash76

47 FAHLKE C HANSEN S ENGEL J A amp HARD E(1994) Effects of ventral striatal 6-OHDA lesionsor amphetamine sensitization on ethanol con-sumption in the rat Pharmacology Biochemistryand Behavior 47 345ndash349

48 HUNT W A amp LANDS W E (1992) A role forbehavioral sensitization in uncontrolled ethanolintake Alcohol 9 327ndash328

49 NEWLIN D B amp THOMSON J B (1991) Chronictolerance and sensitization to alcohol in sons ofalcoholics Alcohol Clinical and Experimental Re-search 15 399ndash405

50 WHITE F J AMIT J KOELTZOW T E amp HUX-T (1998) Dopamine receptor antagonists failto prevent induction of cocaine sensitizationNeuropsychopharmacology 18 26ndash40

51 BROWMAN K E BADIANI A amp ROBINSON T E(1998) The in uence of environment on theinduction of sensitization to the psychomotoractivating effects of intravenous cocaine in rats isdose-dependent Psychopharmacology 137 90ndash

9852 BROWMAN K E BADIANI A amp ROBINSON T E

(1998) Modulatory effect of environmental stim-uli on the susceptibility to amphetamine sensi-tization a dose-effect study in rats Journal of

Pharmacology and Experimental Therapeutics 2871007ndash1014

53 ANTELMAN S (1988) Time-dependent sensitiza-tion as the cornerstone for a new approach topharmacotherapy drugs as foreignstressful stim-uli Drug Development Research 14 1ndash30

54 PAULSON P E CAMP D M amp ROBINSON T E(1991) The time course of transient behavioraldepression and persistent behavioral sensitizationin relation to regional brain monoamine concen-trations during amphetamine withdrawal in ratsPsychopharmacology 103 480ndash492

55 HENRY D J amp WHITE F J (1995) The persist-ence of behavioral sensitization to cocaine paral-lels enhanced inhibition of nucleus accumbensneurons Journal of Neuroscience 15 6287ndash6299

56 ROBINSON T E (1988) Stimulant drugs andstress factors in uencing individual differencesin the susceptibility to sensitization in KALIVASP W amp BARNES C (Eds) Sensitization of theNervous System pp 145ndash173 (Caldwell NJTelford Press)

57 WHITE F J amp WOLF M E (1991) Psychomotorstimulants in PRATT J (Ed) The BiologicalBases of Drug Tolerance and Dependence pp 153ndash

197 (New York Academic Press)58 HOOKS M S DUFFY P STRIPLIN C amp

KALIVAS P W (1994) Behavioral and neuro-chemical sensitization following cocaine self-administration Psychopharmacology 115 265ndash

27259 MARINELLI M LE MOAL M amp PIAZZA P V

(1998) Sensitization to the motor effects of con-tingent infusions of heroin but not of kappaagonist RU 51599 Psychopharmacology 139281ndash285

60 PHILLIPS A G amp DI CIANO P (1996) Behavioralsensitization is induced by intravenous self-administration of cocaine by rats Psychopharma-cology 124 279ndash281

61 GLICK S D SHAPIRO R M DREW K LHINDS P A amp CARLSON J N (1986) Differ-ences in spontaneous and amphetamine-inducedrotational behavior and in sensitization to am-phetamine among SpraguendashDawley derived ratsfrom different sources Physiology and Behavior38 67ndash70

62 LEITH N J amp KUCZENSKI R (1982) Two disso-ciable components of behavioral sensitization fol-lowing repeated amphetamine administrationPsychopharmacology 76 310ndash315

63 SHUSTER L YU G amp BATES A (1977) Sen-sitization to cocaine stimulation in micePsychopharmacology 52 185ndash190

64 GLICK S D amp HINDS P A (1984) Sex differ-ences in sensitization to cocaine-induced ro-tation European Journal of Pharmacology 99119ndash121

65 POST R M amp CONTEL N R (1983) Humanand animal studies of cocaine implications fordevelopment of behavioral pathology inCREESE I (Ed) Stimulants neurochemical behav-ioral and clinical perspectives pp 169ndash203 (NewYork Raven Press)


66 ROBINSON T E (1984) Behavioral sensitizationcharacterization of enduring changes in rotationalbehavior produced by intermittent injections ofamphetamine in male and female rats Psycho-pharmacology 84 466ndash475

67 CAMP D M amp ROBINSON T E (1988) Suscepti-bility to sensitization II The in uence of go-nadal hormones on enduring changes in brainmonoamines and behavior produced by the re-peated administration of D-amphetamine or re-straint stress Behavioural Brain Research 3069ndash88

68 ANTELMAN S M EICHLER A J BLACK C A ampKOCAN D (1980) Interchangeability of stressand amphetamine in sensitization Science 207329ndash331

69 CUNNINGHAM C L (1995) Localization of genesin uencing ethanol-induced conditioned placepreference and locomotor activity in BXD re-combinant inbred mice Psychopharmacology120 28ndash41

70 PHILLIPS T J HUSON M GWIAZDON CBURKHART-KASCH S amp SHEN E H (1995) Ef-fects of acute and repeated ethanol exposures onthe locomotor activity of BXD recombinant in-bred mice Alcohol Clinical Experimental Research19 269ndash278

71 TOLLIVER B K BELKNAP J K WOODS W Eamp CARNEY J M (1994) Genetic analysis of sen-sitization and tolerance to cocaine Journal ofPharmacology and Experimental Therapeutics 2701230ndash1238

72 ROBINSON T E BROWMAN K E CROMBAG HS amp BADIANI A (1998) Modulation of the in-duction or expression of psychostimulant sen-sitization by the circumstances surroundingdrug administration Neuroscience BiobehavioralReviews 22 347ndash354

73 ANAGNOSTARAS S G amp ROBINSON T E (1996)Sensitization to the psychomotor stimulant ef-fects of amphetamine modulation by associativelearning Behavioral Neuroscience 110 1397ndash

141474 PERT A POST R amp WEISS S R (1990) Con-

ditioning as a critical determinant of sensitizationinduced by psychomotor stimulants NIDAResearch Monograph 97 208ndash241

75 POST R M LOCKFELD A SQUILLACE K M ampCONTEL N R (1981) Drug-environment inter-action context dependency of cocaine-inducedbehavioral sensitization Life Sciences 28 755ndash

76076 TERELLI E amp TERRY P (1999) Amphetamine-

induced conditioned activity and sensitizationthe role of habituation to the test context and theinvolvement of Pavlovian processes BehavioralPharmacology 9 409ndash419

77 CASTANEDA E BECKER J B amp ROBINSON T E(1988) The long-term effects of repeated am-phetamine treatment in vivo on amphetamineKCl and electrical stimulation evoked striataldopamine release in vitro Life Sciences 42 2447ndash

245678 HENRY D J amp WHITE F J (1991) Repeated

cocaine administration causes persistent en-hancement of D1 dopamine receptor sensitivitywithin the rat nucleus accumbens Journal ofPharmacology and Experimental Therapeutics 258882ndash890

79 KANTOR L HEWLETT G H amp GNEGY M E(1999) Enhanced amphetamine- and K 1 -medi-ated dopamine release in rat striatum after re-peated amphetamine differential requirementsfor Ca2 1 - and calmodulin-dependent phos-phorylation and synaptic vesicles Journal ofNeuroscience 19 3801ndash3808

80 ROBINSON T E amp BECKER J B (1982) Behav-ioral sensitization is accompanied by an enhance-ment in amphetamine-stimulated dopaminerelease from striatal tissue in vitro EuropeanJournal of Pharmacology 85 253ndash254

81 VANDERSCHUREN L J WARDEH G DE VRIEST J MULDER A H amp SCHOFFELMEER A N(1999) Opposing role of dopamine D1 andD2 receptors in modulation of rat nucleusaccumbens noradrenaline release Journal ofNeuroscience 19 4123ndash4131

82 BADIANI A ANAGNOSTARAS S G amp ROBINSONT E (1995) The development of sensitization tothe psychomotor stimulant effects of am-phetamine is enhanced in a novel environmentPsychopharmacology 117 443ndash452

83 BADIANI A BROWMAN K E amp ROBINSON T E(1995) In uence of novel versus home environ-ments on sensitization to the psychomotor stimu-lant effects of cocaine and amphetamine BrainResearch 674 291ndash298

84 BADIANI A CAMP D M amp ROBINSON T E(1997) Enduring enhancement of amphetaminesensitization by drug-associated environmentalstimuli Journal of Pharmacology and ExperimentalTherapeutics 282 787ndash794

85 CROMBAG H C MUELLER H BROWMAN KE BADIANI A amp ROBINSON T E (1999) Acomparison of two behavioral measures of psy-chomotor activation following intravenousamphetamine or cocaine dose- and sensitization-dependent changes Behavioural Pharmacology10 205ndash213

86 FRAIOLI S CROMBAG H S BADIANI A ampROBINSON T E (1999) Susceptibility to am-phetamine-induced locomotor sensitization ismodulated by environmental stimuli Neuro-psychopharmacology 20 533ndash541

87 BADIANI A OATES M M DAY H E WWATSON S J AKIL H amp ROBINSON T E(1998) Amphetamine-induced behavior do-pamine release and c-fos mRNA expressionmodulation by environmental novelty Journal ofNeuroscience 18 10579ndash10593

88 BADIANI A OATES M M DAY H E WWATSON S J AKIL H amp ROBINSON T E(1999) Environmental modulation of am-phetamine-induced c-fos expression in D1 versusD2 striatal neurons Behavioural Brain Research103 203ndash209

89 SCHENK S amp PARTRIDGE B (1997) Sensitiza-tion and tolerance in psychostimulant self-


administration PharmacologyBiochememistry andBehavior 57 543ndash550

90 HORGER B A SHELTON K amp SCHENK S(1990) Preexposure sensitizes rats to the reward-ing effects of cocaine Pharmacology Biochemistryand Behavior 37 707ndash711

91 HORGER B A GILES M K amp SCHENK S(1992) Preexposure to amphetamine and nic-otine predisposes rats to self-administer a lowdose of cocaine Psychopharmacology 107 271ndash

27692 PIAZZA P V DEMINIERE J M LE MOAL M amp

SIMON H (1989) Factors that predict individualvulnerability to amphetamine self-administrationScience 245 1511ndash1513

93 PIAZZA P V DEMINIERE J M LE MOAL M ampSIMON H (1990) Stress- and pharmacologically-induced behavioral sensitization increases vul-nerability to acquisition of amphetamineself-administration Brain Research 514 22ndash26

94 PIERRE P J amp VEZINA P (1997) Predispositionto self-administer amphetamine the contributionof response to novelty and prior exposure to thedrug Psychopharmacology (Berlin) 129 277ndash

28495 PIERRE P J amp VEZINA P (1998) D1 dopamine

receptor blockade prevents the facilitation of am-phetamine self-administration induced by priorexposure to the drug Psychopharmacology 138159ndash166

96 VALADEZ A amp SCHENK S (1994) Persistence ofthe ability of amphetamine preexposure to facili-tate acquisition of cocaine self-administrationPharmacology Biochemistry and Behavior 47203ndash205

97 WOOLVERTON W L GOLDBERG L I amp GINOSJ Z (1984) Intravenous self-administration ofdopamine receptor agonists by rhesus monkeysJournal of Pharmacology and Experimental Thera-peutics 230 678ndash683

98 GAIARDI M BARTOLETTI M BACCHI AGUBELLINI C COSTA M amp BABBINI M (1991)Role of repeated exposure to morphine in deter-mining its affective properties place and tasteconditioning studies in rats Psychopharmacology103 183ndash186

99 LETT B T (1989) Repeated exposures intensifyrather than diminish the rewarding effects ofamphetamine morphine and cocaine Psy-chopharmacology 98 357ndash362

100 SHIPPENBERG T S amp HEIDBREDER C (1995)Sensitization to the conditioned rewarding effectsof cocaine pharmacological and temporal char-acteristics Journal of Pharmacology and Exper-imental Therapeutics 273 808ndash815

101 SHIPPENBERG T S HEIDBREDER C ampLEFEVOUR A (1996) Sensitization to the con-ditioned rewarding effects of morphine pharma-cology and temporal characteristics EuropeanJournal of Pharmacology 299 33ndash39

102 SHIPPENBERG T S LEFEVOUR A ampHEIDBREDER C (1996) k-opioid receptor ago-nists prevent sensitization to the conditionedrewarding effects of cocaine Journal of Pharma-

cology and Experimental Therapeutics 276 545ndash

554103 LORRAIN D S ARNOLD G M amp VEZINA P

(2000) Previous exposure to amphetamine in-creases incentive to obtain the drug long-lastingeffects revealed by the progressive ratio scheduleBehavioural Brain Research 107 9ndash19

104 MENDREK A BLAHA C D amp PHILLIPS A G(1998) Pre-exposure of rats to amphetamine sen-sitizes self-administration of this drug under aprogressive ratio schedule Psychopharmacology135 416ndash422

105 TAYLOR J R amp HORGER B A (1999) Enhancedresponding for conditioned reward produced byintra-accumbens amphetamine is potentiated af-ter cocaine sensitization Psychopharmacology142 31ndash40

106 DEROCHE V LE MOAL M amp PIAZZA P V(1999) Cocaine self-administration increases theincentive motivational properties of the drug inrats European Journal of Neuroscience 11 2731ndash

2736107 DE VRIES T J SCHOFFELMEER A N M

MULDER A H amp VANDERSCHUREN L J M J(1997) Reinstatement of drug-seeking behaviorfollowing long-term extinction of cocaine andheroin self-administration possible role of behav-ioral sensitization Society for NeuroscienceAbstracts 23 2147

108 DE VRIES T J SCHOFFELMEER A NBINNEKADE R MULDER A H amp VANDER-

SCHUREN L J (1998) Drug-induced reinstate-ment of heroin- and cocaine-seeking behaviourfollowing long-term extinction is associated withexpression of behavioural sensitization EuropeanJournal of Neuroscience 10 3565ndash3571

109 DE VRIES T J SCHOFFELMEER A N MBINNEKADE R amp VANDERSCHUREN L J M J(1999) Dopaminergic mechanisms mediating theincentive to seek cocaine and heroin followinglong-term withdrawal of IV drug self-administration Psychopharmacology 143 254ndash

260110 VANDERSCHUREN L J M J SCHOFFELMEER A

N M MULDER A H amp DE VRIES T J (1999)Dopaminergic mechanisms mediating the long-term expression of locomotor sensitizationfollowing pre-exposure to morphine oramphetamine Psychopharmacology 143 244ndash

253111 MITCHELL J B amp STEWART J (1990) Facilita-

tion of sexual behaviors in the male rat associatedwith intra-VTA injections of opiates Pharma-cology Biochemistry and Behavior 35 643ndash650

112 FIORINO D F amp PHILLIPS A G (1999) Facilita-tion of sexual behavior in male rats followingd-amphetamine-induced behavioral sensitizationPsychopharmacology 142 200ndash208

113 FIORINO D F amp PHILLIPS A G (1999) Facilita-tion of sexual behavior and enhanced dopamineef ux in the nucleus accumbens of male rats afterD-amphetamine-induced behavioral sensitiza-tion Journal of Neuroscience 19 456ndash463

114 WASHTON A M amp STONE-WASHTON N (1993)


Outpatient treatment of cocaine and crackaddiction a clinical perspective NIDA ResearchMonographs 135 15ndash30

115 HARMER C J HITCHCOTT P K MORUTTO SL amp PHILLIPS G D (1997) Repeated d-amphetamine enhances stimulated meso-amygdaloid dopamine transmission Psychophar-macology 132 247ndash254

116 HARMER C J amp PHILLIPS G D (1999) En-hanced dopamine ef ux in the amygdala by apredictive but not a non- predictive stimulusfacilitation by prior repeated D-amphetamineNeuroscience 90 119ndash130

117 HARMER C J amp PHILLIPS G D (1999) En-hanced conditioned inhibition following repeatedpretreatment with d-amphetamine Psychophar-macology 142 120ndash131

118 HARMER C J amp PHILLIPS G D (1998) En-hanced appetitive conditioning following repeatedpretreatment with d-amphetamine BehavioralPharmacology 9 299ndash308

119 ROBINSON T E JURSON P A BENNETT J A ampBENTGEN K M (1988) Persistent sensitization ofdopamine neurotransmission in ventral striatum(nucleus accumbens) produced by past experi-ence with ( 1 )-amphetamine a microdialysisstudy in freely moving rats Brain Research 462211ndash222

120 ROBBINS T W amp EVERITT B J (1996) Neurobe-havioural mechanisms of reward and motivationCurrent Opinions in Neurobiology 6 228ndash236

121 KALIVAS P W amp STEWART J (1991) Dopaminetransmission in the initiation and expression ofdrug- and stress-induced sensitization of motoractivity Brain Research Reviews 16 223ndash244

122 PIERCE R C amp KALIVAS P W (1997) A circuitrymodel of the expression of behavioral sensitizationto amphetamine-like psychostimulants BrainResearch Reviews 25 192ndash216

123 WHITE F J amp KALIVAS P W (1998) Neuro-adaptations involved in amphetamine and cocaineaddiction Drug and Alcohol Dependence 51 141ndash

153124 WOLF M E (1998) The role of excitatory amino

acids in behavioral sensitization to psychomotorstimulants Progress in Neurobiology 54 679ndash720

125 SMITH G P (1995) Dopamine and food rewardin MORRISON A M amp FLUHARTY S J (Eds)Progress in Psychobiology and Physiological Psy-chology pp 83ndash144 (New York)

126 WISE R A amp ROMPRE P-P (1989) Brain do-pamine and reward Annual Review of Psychology40 191ndash225

127 WHITE F J HU X T ZHANG X F amp WOLFM E (1995) Repeated administration of cocaineor amphetamine alters neuronal responses to glu-tamate in the mesoaccumbens dopamine systemJournal of Pharmacology and Experimental Thera-peutics 273 445ndash454

128 ROBINSON T E amp KOLB B (1997) Persistentstructural modi cations in nucleus accumbensand prefrontal cortex neurons produced by pre-vious experience with amphetamine Journal ofNeuroscience 17 8491ndash8497

129 ROBINSON T E amp KOLB B (1999) Alterations inthe morphology of dendrites and dendritic spinesin the nucleus accumbens and prefrontal cortexfollowing repeated treatment with amphetamineor cocaine European Journal of Neuroscience 111598ndash1604

130 FLORES C RODAROS D amp STEWART J (1998)Long-lasting induction of astrocytic basic broblast growth factor by repeated injections ofamphetamine blockade by concurrent treatmentwith a glutamate antagonist Journal of Neuro-science 18 9547ndash9555

131 FLORES C SAMAHA A-N amp STEWART J S(2000) Requirement of endogenous basic broblast growth factor for sensitization to am-phetamine Journal of Neuroscience 20 RC55 1ndash5

132 HORGER B A IYASERE C A BERHOW M T etal (1999) Enhancement of locomotor activity andconditioned reward to cocaine by brain-derived neurotrophic factor Journal of Neuro-science 19 4110ndash4122

133 ANGRIST B (1994) Amphetamine psychosisclinical variations of the syndrome in CHO A Kamp SEGAL D S (Eds) Amphetamine and its Analogspsychopharmacology toxicology and abuse pp 387ndash

414 (New York Academic Press)134 SATO M CHEN C C AKIYAMA K amp OTSUKI

S (1983) Acute exacerbation of paranoid psy-chotic state after long-term abstinence in patientswith previous methamphetamine psychosisBiological Psychiatry 18 429ndash440

135 SATO M (1986) Acute exacerbation of metham-phetamine psychosis and lasting dopaminergicupersensitivitymdasha clinical survey Psychopharma-cology Bulletin 22 751ndash756

136 SEGAL D S amp SCHUCKIT M A (1983) Animalmodels of stimulant-induced psychosis inCREESE I (Ed) Stimulants Neurochemical Be-havioral and Clinical Perspectives pp 131ndash167(New York Raven Press)

137 UTENA H (1966) Behavioral aberrations inmethamphetamine-intoxicated animals andchemical correlates in the brain in TOKIZANE Tamp SCHADE J P (Eds) Progress in Brain ResearchVol 21B Coerrelative neurosciences clinical studies pp 192ndash207 (Amsterdam Elsevier)

138 CASTNER S A amp GOLDMAN-RAKIC P S (1999)Long-lasting psychotomimetic consequences ofrepeated low-dose amphetamine exposure in rhe-sus monkeys Neuropsychopharmacology 20 10ndash

28139 STRAKOWSKI S M SAX K W SETTERS M J amp

KECK P E JR (1996) Enhanced response torepeated d-amphetamine challenge evidence forbehavioral sensitization in humans Biological Psy-chiatry 40 872ndash880

140 STRAKOWSKI S M amp SAX K W (1998) Pro-gressive behavioral response to repeated d-amphetamine challenge further evidence for sen-sitization in humans Biological Psychiatry 441171ndash1177

141 STRAKOWSKI S M ROSENBERG H L DEL-

BELLO M P amp SAX K W (1999) Behavioralsensitization in humans results of a parallel-


group double-blind study Abstracts AmericanCollege of Neuropsychopharmacology 38 86

142 ROTHMAN R B GORELICK D A BAUMANNM H GUO X Y HERNING R I PICKWORTHW B GENDRON T M KOEPPL B THOMSONL E amp HENNINGFIELD J E (1994) Lack ofevidence for context-dependent cocaine-inducedsensitization in humans preliminary studiesPharmacology Biochemistry and Behavior 49583ndash588

143 GORELICK D A amp ROTHMAN R B (1997)Stimulant sensitization in humans Biological Psy-chiatry 42 230ndash231

144 STRAKOWSKI S M SAX K W SETTERS M Jamp KECK P E JR (1997) Stimulant sensitizationin humansmdashresponse Biological Psychiatry 42230ndash231

145 BARTLETT E HALLIN A CHAPMAN B ampANGRIST B (1997) Selective sensitization to thepsychosis-inducing effects of cocaine a possiblemarker for addiction relapse vulnerabilityNeuropsychopharmacology 16 77ndash82

146 BREITER H C GOLLUB R L WEISSKOFF RM KENNEDY D N MAKRIS N BERKE J DGOODMAN J M KANTOR H L GASTFRIENDD R RIORDEN J P MATHEW R T ROSEN BR amp HYMAN S E (1997) Acute effects ofcocaine on human brain activity and emotionNeuron 19 591ndash611

147 CHILDRESS A R MOZLEY P D MCELGIN WFITZGERALD J REIVICH M amp OrsquoBRIEN C P(1999) Limbic activation during cue-induced co-caine craving American Journal of Psychiatry156 11ndash18

148 GRANT S LONDON E D NEWLIN D BVILLEMAGNE V L LIU X CONTOREGGI CPHILLIPS R L KIMES A S amp MARGOLIN A(1996) Activation of memory circuits duringcue-elicited cocaine craving Proceedings of theNational Academy Sciences USA 93 12040ndash

12045149 MAAS L C LUKAS S E KAUFMAN M J

WEISS R D DANIELS S L ROGERS V WKUKES T J amp RENSHAW P F (1998) Func-tional magnetic resonance imaging of humanbrain activation during cue-induced cocaine crav-ing American Journal of Psychiatry 155 124ndash

126150 WANG G J VOLKOW N D FOWLER J S

CERVANY P HITZEMANN R J PAPPAS N RWONG C T amp FELDER C (1999) Regionalbrain metabolic activation during craving elicitedby recall of previous drug experiences LifeSciences 64 775ndash784

151 SELL L A MORRIS J BEARN J FRACKOWIAKR S FRISTON K J amp DOLAN R J (1999) Acti-vation of reward circuitry in human opiate ad-dicts European Journal of Neuroscience 111042ndash1048

152 KAUFMAN M J LEVIN J M MAAS L CROSE S L LUKAS S E MENDELSON J HCOHEN B M amp RENSHAW P F (1998) Cocainedecreases relative cerebral blood volume in hu-mans a dynamic susceptibility contrast magnetic

resonance imaging study Psychopharmacology138 76ndash81

153 GONON F amp SUNDSTROM L (1996) Excitatoryeffects of dopamine released by impulse ow inthe rat nucleus accumbens in vivo Neuroscience75 13ndash18

154 GONON F (1997) Prolonged and extrasynapticexcitatory action of dopamine mediated by D1receptors in the rat striatum in vivo Journal ofNeuroscience 17 5972ndash5978

155 BERRIDGE K C (1999) Pleasure pain desireand dread hidden core processes of emotion inKAHNEMAN D DIENER E amp SCHWARZ N(Eds) Well Being the foundations of hedonic psy-chology pp 527ndash559 (New York Russell SageFoundation)

156 WISE R A (1982) Neuroleptics and operantbehavior the anhedonia hypothesis Behavioraland Brain Sciences 5 39ndash87

157 GARDNER E L amp LOWINSON J H (1993) Drugcraving and positivenegative hedonic brain sub-strates activated by addicting drugs Seminars inNeuroscience 5 359ndash368

158 WISE R A (1994) A brief history of the anhedo-nia hypothesis in LEGG C R amp BOOTH D(Eds) Appetite neural and behavioral basespp 140ndash319 (New York Oxford UniversityPress)

159 NASH M J (1997) Addicted why do people gethooked Mounting evidence points to a powerfulbrain chemical called dopamine Time May 568ndash76

160 WICKELGREN I (1997) Getting the brainrsquos atten-tion Science 278 35ndash37

161 MARKOU A amp KOOB G F (1991) Postcocaineanhedonia an animal model of cocaine with-drawal Neuropsychopharmacology 4 17ndash26

162 ROSSETTI Z L HMAIDAN Y amp GESSA G L(1992) Marked inhibition of mesolimbic do-pamine release a common feature of ethanolmorphine cocaine and amphetamine abstinencein rats European Journal of Pharmacology 221227ndash234

163 VOLKOW N D WANG G J FOWLER J SLOGAN J GATLEY S J HITZEMANN R CHENA D DEWEY S L amp PAPPAS N (1997) De-creased striatal dopaminergic responsiveness indetoxi ed cocaine-dependent subjects Nature386 830ndash833

164 WEISS F MARKOU A LORANG M T amp KOOBG F (1992) Basal extracellular dopamine levelsin the nucleus accumbens are decreased duringcocaine withdrawal after unlimited-access self-administration Brain Research 593 314ndash318

165 MARKOU A KOSTEN T R amp KOOB G R(1998) Neurobiological similarities in depressionand drug dependence a self-medication hypoth-esis Neuropsychopharmacology 135ndash174

166 DI CHIARA G amp TANDA G (1997) Blunting ofreactivity of dopamine transmission to palatablefood a biochemical marker of anhedonia in theCMS model Psychopharmacology 134 351ndash353discussion 371ndash377

167 VOLKOW N D WANG G J FISCHMAN M W


FOLTIN R W FOWLER J S ABUMRAD N NVITKUN S LOGAN J GATLEY S J PAPPAS NHITZEMANN R amp SHEA C E (1997) Relation-ship between subjective effects of cocaine anddopamine transporter occupancy Nature 386827ndash830

168 AHMED S H amp KOOB G F (1998) Transitionfrom moderate to excessive drug intake changein hedonic set point Science 282 298ndash300

169 BLACKBURN J R PFAUS J G amp PHILLIPS A G(1992) Dopamine functions in appetitive anddefensive behaviours Progress in Neurobiology 39247ndash279

170 PECINA S BERRIDGE K C amp PARKER L A(1997) Pimozide does not shift palatability sep-aration of anhedonia from sensorimotor sup-pression by taste reactivity PharmacologyBiochemistry and Behavior 58 801ndash811

171 SCHULTZ W (1992) Activity of dopamine neu-rons in the behaving primate Seminars in Neuro-science 4 129ndash138

172 SCHULTZ W (1998) Predictive reward signal ofdopamine neurons Journal of Neurophysiology80 1ndash27

173 SALAMONE J D COUSINS M S amp SNYDER B J(1997) Behavioral functions of nucleus accum-bens dopamine empirical and conceptual prob-lems with the anhedonia hypothesis NeuroscienceBiobehavioral Reviews 21 341ndash359

174 BERGER S P HALL S MICKALIAN J D REIDM S CRAWFORD C A DELUCCHI K CARRK amp HALL S (1996) Haloperidol antagonism ofcue-elicited cocaine craving Lancet 347 504ndash

508175 BRAUER L H amp DEWIT H (1996) Subjective

responses to d-amphetamine alone and after pi-mozide pretreatment in normal healthy volun-teers Biological Psychiatry 39 26ndash32

176 BRAUER L H amp DEWIT H (1997) High dosepimozide does not block amphetamine-inducedeuphoria in normal volunteers PharmacologyBiochemistry and Behavior 56 265ndash272

177 OHUOHA D C MAXWELL J A THOMSON LE III CADET J L amp ROTHMAN R B (1997)Effect of dopamine receptor antagonists on co-caine subjective effects a naturalistic case studyJournal of Substance Abuse Treatment 14 249ndash

258178 ROTHMAN R B amp GLOWA J R (1995) A review

of the effects of dopaminergic agents on humansanimals and drug-seeking behavior and itsimplications for medication development Focuson GBR 12909 Molecular Neurobiology 11 1ndash

19179 VOLKOW N D WANG G J FOWLER J S

GATLEY S J LOGAN J DING Y S DEWEY SL HITZEMANN R GIFFORD A N amp PAPPAS NR (1999) Blockade of striatal dopamine trans-porters by intravenous methylphenidate is notsuf cient to induce self-reports of ldquohighrdquo Journalof Pharmacology and Experimental Therapeutics288 14ndash20

180 BINDRA D (1978) How adaptive behavior isproduced a perceptualndashmotivation alternative to

response reinforcement Behavioral and BrainSciences 1 41ndash91

181 TOATES F (1986) Motivational Systems (Cam-bridge Cambridge University Press)

182 TIFFANY S T (1990) A cognitive model of drugurges and drug-use behavior role of automaticand nonautomatic processes PsychologicalReview 97 147ndash168

183 WEISKRANTZ L (1997) Consciousness Lost andFound a neuropsychological exploration (NewYork Oxford University Press)

184 HILGARD E R (1986) Divided Consciousnessmultiple controls in human thought and action (NewYork John Wiley and Sons)

185 LEDOUX J (1996) The Emotional Brain the mys-terious underpinnings of emotional life (New YorkSimon and Schuster)

186 NISBETT R E amp WILSON T D (1977) Tellingmore than we can know verbal reports on mentalprocesses Psychological Review 84 231ndash259

187 KAHNEMAN D (1994) New challenges to therationality assumption Journal of Institutional andTheoretical Economics 150 18ndash36

188 LOEWENSTEIN G (1999) A visceral account ofaddiction in ELSTER J amp SKOG J (Eds) GettingHooked rationality and addiction pp 235ndash264(Cambridge Cambridge University Press)

189 SARTER M amp BRUNO J P (1999) Abnormalregulation of corticopetal cholinergic neuronsand impaired information processing in neu-ropsychiatric disorders Trends in Neuroscience22 67ndash74

190 JENTSCH J D amp TAYLOR J R (1999) Impulsiv-ity resulting from frontostriatal dysfunction indrug abuse implications for the control of behav-ior by reward-related stimuli Psychopharma-cology 146 373ndash390

191 BOLLA K I CADET J L amp LONDON E D(1998) The neuropsychiatry of chronic cocaineabuse Journal of Neuropsychiatry and ClinicalNeuroscience 10 280ndash289

192 ROGERS R D EVERITT B J BALDACCHINO ABLACKSHAW A J SWAINSON R WYNNE KBAKER N B HUNTER J CARTHY T BOOKERE LONDON M DEAKIN J F SAHAKIAN B J ampROBBINS T W (1999) Dissociable de cits in thedecision-making cognition of chronic am-phetamine abusers opiate abusers patients withfocal damage to prefrontal cortex and tryp-tophan-depleted normal volunteers evidence formonoaminergic mechanisms Neuropsycho-pharmacology 20 322ndash339

193 BIGGINS C A MACKAY S CLARK W amp FEING (1997) Event-related potential evidence forfrontal cortex effects of chronic cocaine depen-dence Biological Psychiatry 42 472ndash485

194 VOLKOW N D FOWLER J S WOLF A PHITZEMANN R DEWEY S BENDRIEM BALPERT R amp HOFF A (1991) Changes in brainglucose metabolism in cocaine dependence andwithdrawal American Journal of Psychiatry 148621ndash626

195 VOLKOW N D HITZEMANN R WANG G JFOWLER J S WOLF A P DEWEY S L amp


HANDLESMAN L (1992) Long-term frontal brainmetabolic changes in cocaine abusers Synapse11 184ndash190

196 STEELE C M amp JOSEPHS R A (1990) Alcoholmyopia American Psychologist 45 921ndash933

197 MEYER R E (1992) New pharmacotherapies forcocaine dependence hellip revisited [published erra-tum appears in Archives of General Psychiatry1993 50(1)16] Archives of General Psychiatry49 900ndash904

198 GALLOWAY G P NEWMEYER J KNAPP TSTALCUP S A amp SMITH D (1996) A controlledtrial of imipramine for the treatment of metham-phetamine dependence Journal of SubstanceAbuse Treatment 13 493ndash497

199 NUNES E V MCGRATH P J QUITKIN F MOCEPEK-WELIKSON K STEWART J W KOENIGT WAGER S amp KLEIN D F (1995) Imipraminetreatment of cocaine abuse possible boundariesof ef cacy Drug and Alcohol Dependence 39185ndash195

200 WEISS R D (1988) Relapse to cocaine abuseafter initiating desipramine treatment Journal ofthe American Medical Association 260 2545ndash

2546201 NOMIKOS G G DAMSMA G WENKSTERN D

amp FIBIGER H C (1991) Chronic desipramineenhances amphetamine-induced increases in in-terstitial concentrations of dopamine in the nu-cleus accumbens European Journal ofPharmacology 195 63ndash73

202 GOLDSTEIN M G (1998) Bupropion sustainedrelease and smoking cessation Journal of ClinicalPsychiatry 59 66ndash72

203 JORENBY D E LEISCHOW S J NIDES M ARENNARD S I JOHNSTON J A HUGHES A RSMITH S S MURAMOTO M L DAUGHTON DM DOAN K FIORE M C amp BAKER T B(1999) A controlled trial of sustained-releasebupropion a nicotine patch or both for smokingcessation New England Journal of Medicine 340685ndash691

204 COOPER B R WANG C M COX R FNORTON R SHEA V amp FERRIS R M (1994)Evidence that the acute behavioral and electro-physiological effects of bupropion (Wellbutrin)are mediated by a noradrenergic mechanismNeuropsychopharmacology 11 133ndash141

205 PETRIE E C VEITH R C amp SZOT P (1998)Bupropion and desipramine increase dopaminetransporter mRNA expression in the ventral teg-mental areasubstantia nigra of rat brain Progressin Neuropsychopharmacology and BiologicalPsychiatry 22 845ndash856

206 TELLA S R LADENHEIM B amp CADET J L(1997) Differential regulation of dopamine trans-porter after chronic self- administration of bupro-pion and nomifensine Journal of Pharmacologyand Experimental Therapeutics 281 508ndash513

207 LITTLE K Y ZHANG L DESMOND T FREYK A DALACK G W amp CASSIN B J (1999)Striatal dopaminergic abnormalities in humancocaine users American Journal of Psychiatry156 238ndash245

208 ZHANG L ELMER L W amp LITTLE K Y (1998)Expression and regulation of the human do-pamine transporter in a neuronal cell line [pub-lished erratum appears in 1998 Dec 10 63(1)205] Molecular Brain Research 59 66ndash73

209 NOMIKOS G G DAMSMA G WENKSTERN Damp FIBIGER H C (1992) Effects of chronicbupropion on interstitial concentrations of do-pamine in rat nucleus accumbens and striatumNeuropsychopharmacology 7 7ndash14

210 AL QATARI M BOUCHENAFA O amp LITTLETON J(1998) Mechanism of action of acamprosatePart II Ethanol dependence modi es effects ofacamprosate on NMDA receptor binding inmembranes from rat cerebral cortex AlcoholClinical and Experimental Research 22 810ndash814

211 NAASSILA M HAMMOUMI S LEGRAND EDURBIN P amp DAOUST M (1998) Mechanism ofaction of acamprosate Part I Characterization ofspermidine-sensitive acamprosate binding site inrat brain Alcohol Clinical and ExperimentalResearch 22 802ndash809

212 BESSON J AEBY F KASAS A LEHERT P ampPOTGIETER A (1998) Combined ef cacy ofacamprosate and disul ram in the treatment ofalcoholism a controlled study Alcohol Clinicaland Experimental Research 22 573ndash579

213 KRATZER U amp SCHMIDT W J (1998) The anti-craving drug acamprosate inhibits the con-ditioned place aversion induced bynaloxone-precipitated morphine withdrawal inrats Neuroscience Letters 252 53ndash56

214 PUTZKE J SPANAGEL R TOLLE T R ampZIEGLGANSBERGER W (1996) The anti-cravingdrug acamprosate reduces c-fos expression in ratsundergoing ethanol withdrawal European Journalof Pharmacology 317 39ndash48

215 BLACKBURN J R amp SZUMLINSKI K K (1997)Ibogaine effects on sweet preference and am-phetamine induced locomotion implications fordrug addiction Behavioural Brain Research 8999ndash106

216 JACKSON A MEAD A N ROCHA B A ampSTEPHENS D N (1998) AMPA receptors andmotivation for drug effect of the selective antag-onist NBQX on behavioural sensitization and onself-administration in mice Behavioral Pharma-cology 9 457ndash467

217 MEAD A N amp STEPHENS D N (1998) AMPA-receptors are involved in the expression of am-phetamine-induced behavioural sensitisation butnot in the expression of amphetamine- inducedconditioned activity in mice Neuropharmacology37 1131ndash1138


compulsive patterns of drug-seeking and drug-taking behavior that take place at the expense ofmost other activities and (b) the inability tocease drug-taking that is the problem of re-lapse2 The purpose of this paper is to exploreone view of the psychological and neurobiologi-cal mechanisms responsible speci cally for thedevelopment of compulsive patterns of drug usethat de ne addiction and to update our earliertreatise on this subject3

Negative and positive reinforcement modelsMost contemporary explanations of addictionsuggest that addicts are motivated to take drugs(crave drugs) for one of two reasons As put byMarkou et al4 ldquoDrug craving is characterized byboth the desire to experience the positive hedo-nic effects of the drug hellip and the desire to avoidaversive withdrawal symptoms helliprdquo (p 176)That is it is generally thought that addicts aremotivated to take drugs either for the pleasuredrugs produce (basically to achieve rememberedpleasure) or to avoid the unpleasant conse-quences of withdrawal Some authors place theweight of explanatory burden on the aversiveconsequences of discontinuing drug use (thewithdrawal syndrome) and thus on the action ofdrugs as negative reinforcers25ndash7 For exampleKoob and colleagues8ndash10 have argued that ldquothemotivation for maintenance of compulsive druguse requires negative reinforcement processes helliprdquo(Koob et al9 p 519 italics added) and thatldquoFrom a motivational perspective addiction canbe equated with the development of a negativeaffectrdquo (Koob11 p 13)

Limitations of negative reinforcement modelsDespite the intuitive appeal of withdrawal avoid-ance models many authors have pointed out theshort-comings of negative reinforcement modelsin general as explanations for addiction312ndash15

For example drugs that do not produce strongwithdrawal syndromes such as psychostimu-lants can be highly addictive Conversely thereare drugs that produce tolerance and withdrawalsyndromes but do not support compulsive pat-terns of use The latter compounds include sometricyclic antidepressants anticholinergics andkappa opioid agonists14 Thus as put by Jaffe14

ldquothere is little correlation between the visibility

or physiological seriousness of withdrawal signsand their motivational forcerdquo (p 9) Anotherproblem for withdrawal-based explanations isthat drug craving is often elicited by drug admin-istration itself in association with euphorigeniceffects at the moments when withdrawal symp-toms should be at their weakest Similarly inanimals trained to self-administer heroin re-instatement of drug-taking behavior followingextinction is more potently elicited by a priminginjection of heroin which elicits a drug-like ef-fect than by the injection of an opioid antago-nist which induces withdrawal signs1617 Forhuman addicts the prolonged cessation of druguse during which time withdrawal symptomsdecay is by no means a guarantee of a cure asrelapse to compulsive use even long after with-drawal is over remains a major problem inaddiction18 In conclusion although there is nodoubt that under some circumstances the desireto avoid withdrawal can be a potent motive fordrug use for these and other reasons manyauthors have suggested that models of addic-tion based on the alleviation of withdrawal symp-toms (whether ldquophysicalrdquo or ldquopsychologicalrdquo) areneither necessary nor suf cient to explain com-pulsive drug-seeking and drug-taking behav-ior31415

Limitations of behaviorist positive reinforcementmodelsIn part because of the shortcomings of negativereinforcement models alternative models haveplaced considerable emphasis on the action ofdrugs as positive reinforcers14 Positive reinforcersare stimuli that have the property of increasingthe probability of behaviors that immediatelyprecede their presentation Like many naturalrewards such as food and water potentiallyaddictive drugs have this property In the drugabuse literature however the Skinnerian con-cept of positive reinforcement is often invokedeither implicitly or explicitly as though it werean explanation of drug-taking behavior and evenas an explanation of why drug-taking behaviorbecomes more and more compulsive in thedevelopment of addiction (Why do people takedrugs Because drugs are positive reinforcers) Butthis is a confusion It is equivalent to sayingthat the reason people take drugs is becausedrugs promote drug-taking behavior the cir-cularity is obvious15 It is important to remem-

































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































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The psychology and neurobiology of addiction - College of

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