Validation crisis in animal models of drug addiction: Beyond non-disordered drug use toward drug addiction

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  • Neuroscience and Biobehavioral Reviews 35 (2010) 172184

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    Validatdrug us

    Serge H.a Universit Bob Universit Bo

    a r t i c l

    Key-words:ChoiceSelf-controlRationalitySelf-medicatioDecision-makAbstinenceResilienceVoucher-based treatment

    administration in the rat as a paradigm example. Overall, available evidence shows that when a valuablebehavioral option, even abiologically or physiologically inessential one, ismade available during access tococaine self-administration, most rats readily abstain from cocaine use in favor of the alternative rewardregardless of the amount of past cocaine use. Only a small minority of rats continue to self-administerthe drug despite the opportunity of making a different choice. This pattern of results (i.e., abstinence in


    1. Labeli1.

    2. Decon2.1.2.2.

    3. Havin3.

    4. Choic4.1.4.2.

    CorresponTel.: +33 557

    E-mail add

    0149-7634/$ doi:10.1016/j.most rats; cocaine preference in few rats) maps well onto what is currently known about the epidemiol-ogy of human cocaine addiction. It is thus possible that the minority of cocaine-preferring rats would behomologous to the minority of human cocaine users with a diagnosis of addiction while the remainingmajority of abstinent rats would be resilient to cocaine addiction. Choice could represent an objectivemethod of selection of addicted animals for future research on the neurobiological dysfunctions thatare hypothesized to underlie cocaine addiction. Other competing interpretations of the same pattern ofresults are also discussed at the end of this review.

    2010 Elsevier Ltd. All rights reserved.

    ng, dening and modeling cocaine addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173Dependence or addiction: words of choice and choice of words . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173Rates of cocaine use and addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173Cocaine addiction from a rational choice perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173Modeling cocaine addiction in experimental animals: doubts and pitfalls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173struction of animal models of cocaine addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174A brief history of experimental research on animal drug self-administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174Cocaine self-administration in animals: compulsion or expectable response to lack of choice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

    g the choice during access to cocaine self-administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175Introducing choice during access to cocaine: a methodological prolegomenon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176Most animals stop cocaine use when given a choice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176Animals abstain from cocaine use no matter how heavy was past drug use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178Only a minority of animals continue to take cocaine despite choice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

    e as a sieve for cocaine addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179Disease- versus choice-based conceptions of cocaine addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179Resilience and vulnerability to cocaine addiction in animals and humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

    dence address: Universit Victor-Segalen Bordeaux 2, CNRS, Mouvement Adaptation Cognition, UMR 5227, 146 rue Lo-Saignat, 33076 Bordeaux, France.571 566; fax: +33 556 900 278.ress:

    see front matter 2010 Elsevier Ltd. All rights reserved.neubiorev.2010.04.005ion crisis in animal models of drug addiction: Beyond non-disorderede toward drug addiction


    rdeaux 2, CNRS, Mouvement Adaptation Cognition, UMR 5227, Francerdeaux 1, CNRS, Mouvement Adaptation Cognition, UMR 5227, France

    e i n f o


    a b s t r a c t

    In standard drug self-administration settings, animals have no choice than drug use. As a result, seriousdoubt exists about the interpretation of drug use in experimental animals. Is it symptomatic of an under-lying addiction state or merely an expectable response to lack of choice? This incertitude in turn castsa shadow over many behavioral and neurobiological changes that have been well documented in ani-mals following extended drug self-administration. Do they reect pathological dysfunctions or normalneurobiological adaptations? Here I address these questions by focusing on intravenous cocaine self-

  • S.H. Ahmed / Neuroscience and Biobehavioral Reviews 35 (2010) 172184 173

    4.3. Cocaine abstinence in animals and behavioral treatment for cocaine addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1814.4. Current indeterminacy in the interpretation of cocaine abstinence in animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1814.5. Future preclinical research on choice and drug addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182Refer . . . . .

    The goaexperimentanimals. Thadministratanimal specbelow) buto other druspecies. Ovdrug self-adselect drugmerely bybased approis strongly athat dependother types

    1. Labeling

    1.1. Dependwords

    In curreof the AmeManual [DSferred to the(see Sectioncalled for afollowed inHolden, 201of the termmistakewconsequencMaddux anreplacemenAccording tlonger justisuggests a btion is lessother formsfavor of thetoday no rition) and agiven to thein the end othat addictiwith compe

    1.2. Rates o

    CocaineEuropean U2009). Abouleast once incocaine in tof cocaine upast 10 yeaeventually qoccupations

    eir dron. Ievel

    s of ud totrapoonee in tboth



    mosperst theRedise at teria 4ewarter che dike cIn coors isultss; mte abcos

    e. Evtionneurrobiation


    anon-rs invitofrl reg(Voer, bbrainstuds remo usegnosr sciecal bl expasivences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    l of this review is to provide a novel perspective onal modeling of human drug addiction in laboratorye review mainly focuses on intravenous cocaine self-ion in the rat which is by far the most frequently usedies in experimental addiction research (see Section 2.1t itsmain conclusions should also hopefully be relevantgs of abuse, routes of self-administration and animal

    erall I propose that offering a choice during access toministration could uniquely allow one to identify and

    -addicted rats among those that self-administer drugsdefault of other options. Though the use of a choice-ach in future experimental research on drug addictiondvocated here, it must nevertheless be acknowledgeding on the research question, there is ample room forof self-administration approaches.

    , dening and modeling cocaine addiction

    ence or addiction: words of choice and choice of

    nt ofcial diagnostic nomenclatures (e.g., 4th versionrican Psychiatric Association Diagnostic and StatisticalM] of Mental Disorders), the term dependence is pre-word addiction to label the samebehavioral disorder1.3 below). However, several authors have recently

    reversal of preferencea call that will be apparentlythe forthcoming 5th version of the DSM (Miller and0). As put bluntly by OBrien et al. (2006), the choicedependence over the term addiction was a serioushich caused confusion among clinicianswith negativees to the patients. Using a more historical approach,d Desmond (2000) have also cogently argued for thet of the term dependence by the term addiction.o them, the preference for the term dependence is noed for three main reasons: (1) addiction more clearlyehavioral disorder than does dependence; (2) addic-likely to be confused with physical dependence andof dependence; and nally, (3) the original reason inuse of dependence is no longer valid, that is, there is

    sk of confusion between habituation (or accommoda-ddiction. In this review, preference is also exclusivelyword addiction. However, as will be explained laterf this review, one of the disadvantages of this choice ison is widely used across different scientic disciplinesting, even opposite, meanings (see Section 4.1 below).

    f cocaine use and addiction

    is currently the second most used illegal drug in thenion, after cannabis, and its use is increasing (EMCDDA,t 13 millions adults aged 1564 have used cocaine attheir life. It is further estimated that 4.5 millions used

    he last year. In France, for instance, lifetime prevalence

    late thaddictiusers d2 yearresponThe exaboutcocaintion inrepres

    1.3. Co

    Thechoiceagains2007;cocainIV critmore rThe latciple, twho ta2008).behavially rejob losmotivaof suchcocainfree, rafor theing neumake r

    1.4. Mand pit

    Humaddictiregionthe orbcorticaordersHowevtion ofhumanchangehope tsis, proFurthebiologiparallemit invse among schooled adolescents has increased over thers (EMCDDA, 2009). Fortunately, most cocaine usersuit cocaine use to engage in other,more socially valuedand activities. Only a minority of cocaine users esca-

    Paradoxicalconceptualresearch onin a contex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

    ug consumption and eventually transition to a state ofn the US, it is estimated that less than 10% of cocaineop a DSM-based diagnosis of cocaine addiction withinse (Reboussin and Anthony, 2006) which roughly cor-an annual incidence of 0.5 million addicted individuals.lation of this rate of addiction to Europe predicts that

    additional million Europeans will become addicted tohe near future. The relatively high rate of cocaine addic-the US and in Europe probably explains why it now

    one of the paragons of addiction.

    e addiction from a rational choice perspective

    t perplexing aspect of cocaine addiction from a rationalpective is that addicted individuals apparently behaveir best interests and judgments (Bechara, 2005; Paulus,h et al., 2008; Heyman, 2009). They seek and take morehe expense of other activities or occupations (i.e., DSM-, 5 and 6) that are generally, though not necessarily,ding in the long-termand that are otherwise accessible.ondition is signicant because it allows, at least in prin-stinction of addicted individuals from other drug usersocaine by default of other valuable choices (Alexander,caine addiction, the progressive neglect of alternative

    n favor of drug procurement and consumption eventu-in important opportunity costs (e.g., poor education;

    arital dissolution; legal sanction) that should normallystinence from cocaine use. However, even in the facets, many cocaine addicts continue to seek and to takeerything happens as if they had lost the ability to makeal and voluntary choice. One of the critical challengesoscience of cocaine addiction is to identify the underly-ological dysfunctions of this apparent loss of ability toal and voluntary choices (Koob and Le Moal, 2006).

    ng cocaine addiction in experimental animals: doubts

    brain imaging studies have consistently found cocaineelated metabolic changes in several cortical brainolved in normal choice-making processes, notably inontal cortexa phylogenetically conserved prefrontalion that is also dysfunctional in other compulsive dis-lkow et al., 1991, 2005; Volkow and Fowler, 2000).ecause of limitations in the spatial and temporal resolu-imaging technologies and in the correlational design ofies, the origin, nature and causal effect of these corticalain poorly understood. As a result, there is still littlethis neurobiological knowledge to inform the diagno-is and/or treatment of drug addiction (Hyman, 2007a).ntic advancement in our understanding of the neuro-asis of cocaine addiction will thus continue to requireerimental research on laboratory animals which per-

    e neurobiological investigations not feasible in humans.

    ly, however, though cocaine addiction has long beenized in reference to rational choice, littleneurobiologicalanimals has so far examined drug self-administration

    t of choice (Ahmed, 2005). As will be shown below, in

  • 174 S.H. Ahmed / Neuroscience and Biobehavioral Reviews 35 (2010) 172184

    standard experimental settings, animals have free access to cocaineself-administration with no or little valuable alternative actions oractivities (Ahmed, 2005). As a result, serious doubt exists aboutthe interpretation of cocaine use in animals. Is it symptomatic ofan underlyithe lack ofmany behavumented inreect pathtations to rethe past 20is by itselfprocess hto the mole2000; Hym2008). Howsensitizatiolarly, escalaof extinctiophenomenainterpretatirelevant anthese behabehavioralmeasure ofturn will leare conceiv

    As it turoratory foua nondrugsurvival ansaccharin),(Lenoir etcocaine selfdrug use anheavy wasity of animaself-adminivaluable chepidemioloand is consshowing thcocaine usethan non-ait is possibbe homolococaine addresilient todrug addic1983; ZinbeDalgarno, 2establishedtively for dhumans. Cothe resilienthe neuroblie cocaineresults exisreview.

    2. Deconst

    The goalof scienticexperimenttive or rep

    researchers who have founded the eld of animal drug self-administration and to reveal that since its birth, this eld hasregrettably largely neglected the role of choice in studying andanalyzing cocaine addiction in experimental animals.


    ut 5(196Upjarti

    escrions ied toine intoe th

    phin. At aed simally rmentine bly, thhumg, 19as n


    for reson,on, 1ta, 1Wood,Decaquly (pt unl stuviduaf abshednsidetancelf-adke]se senteredividrugsmans, 19anata, 19erlins anLyncisto

    minaer an, shos a leer inng addiction state or merely an expectable response tochoice? This incertitude in turn casts a shadow overioral and neurobiological changes that have been doc-animals following cocaine self-administration. Do theyological dysfunctions or normal neurobiological adap-warding experiences and behaviors? For instance, overyears, the neurobiology of drug sensitization whicha fascinating drug-induced long-lasting neuroplasticas been intensely studied from the circuit level downcular intracellular levels (Vanderschuren and Kalivas,an et al., 2006; Hyman, 2007b; Robinson and Berridge,ever, there is still little certitude about the role of drugn in the pathophysiology of cocaine addiction. Simi-tion of drug use and its reinstatement after a periodn or incubation are now well-documented behavioral(Epstein et al., 2006; Ahmed, in press). However, their

    on as behavioral signs of addiction in animals, thoughd plausible, remains nevertheless uncertain becauseviors occur in experimental settings devoid of otheroptions than drug use. It is predicted that taking fullthis situation could lead to a validation crisis that inad to a change in the way animal models of addictioned and validated.ns out, a recent series of experiments from our lab-nd that when offered a choice between cocaine andalternative that is otherwise inessential for growth,d reproduction (i.e., drinking water sweetened withthe large majority of rats readily stop taking cocaineal., 2007; Cantin et al., 2009). This abstinence from-administrationwas observed even following extendedd escalation of consumption. In fact, no matter howpast cocaine self-administration, only a small minor-ls (i.e., about 10%, see Section 3.4 below) continued toster cocaine despite the opportunity of making anotheroice. This pattern of results maps well onto the knowngy of human cocaine addiction, as summarized above,istent with a very recent laboratory study in humansat when given a choice between money and cocaine,rs with a diagnosis of addiction choose more cocaineddicted long-term users (Walsh et al., 2010). Thus,le that the minority of cocaine-preferring rats wouldgous to the minority of humans with a diagnosis ofiction while the majority of abstinent rats would becocaine addiction (Cantin et al., 2009). Resilience totion has long been suspected in humans (Harding,rg, 1984; Shiffman, 1989; Robins, 1993; Shewan and005; Warburton et al., 2005) but could not be rmly, mostly because it is difcult to control retrospec-ifferences in drug self-exposure and/or availability inmparing the minority of cocaine-preferring rats witht majority could thus bring unprecedented insights intoiological dysfunctions that are hypothesized to under-addiction. Other possible interpretations of the samet, however, and will be also discussed at the end of this

    ruction of animal models of cocaine addiction

    of this section is to present a brief historical overviewresearch on intravenous drug self-administration in

    al animals. This overview is not intended to be exhaus-resentative. Its goal is 2-fold: to praise the earlier

    2.1. Aself-ad

    AboWeeksing at2-pagetion dinjectireportmorphlar veinrst timof morintakereportphysicexperimorphsumabunlike(Spragphine wanima

    Thephine ashownmals [ThompJohansYanagi1981;theelsus masevereto exisseminaof indidrugs oestablican coFor insdrug se[in intaAll thesome iand inmost dnonhuPickenSpealmYanagiand HRobert2000;

    Of hthe seSchustScienceto prescathethistory of experimental research on animal drugtration

    0 years ago, back into the twentieth century, James2) an American experimental pharmacologist work-ohn Company, Kalamazoo, Michigan published acle in Science entitled Experimental morphine addic-bing, in hiswords, a method for automatic intravenousn unrestrained rats. Adult female, albino rats werelearn a novel, lever-press response to self-administerthrough a polyethylene cannula passed down the jugu-the right heart (p. 143). This work established for the

    at the rate of self-injection varied inversely with dosee (p. 143), suggesting that rats were regulating opiatebout the same time, Thompson and Schuster (1964)ilar ndings in adult, male rhesus monkeys that were

    estrained. Interestingly, in those two seminal series ofs, animals were rst made physically dependent onefore being allowed to self-administer the drug. Pre-e rationale for doing this was that at the time, animals,ans,werenot expected to spontaneously takemorphine40; Coppock et al., 1956). Or, putmore technically, mor-ot expected to act as a positive reinforcer in nonhuman

    sequent history is well known. Few years later, mor-ther drugs of abuse, including cocaine,were denitivelypossess genuine positive reinforcing effects in ani-views contemporary to this period, see (Schuster and1969; Thompson and Pickens, 1970; Goldberg, 1976;978; Pickens et al., 1978; Spealman andGoldberg, 1978;978, 1980; Grifths et al., 1980; Schuster and Johanson,ds, 1983)]. In one of the most enduring contribution toneau et al. (1969) reported that initially drug-nave rhe-es self-administered those drugs which man abuses. 46). As formulated by the authors, animals preferredder the inuence of the drugs effects (p. 46). Thisdy also showed the existence of a signicant degreel variation in the propensity to self-administer certain

    use that could be reduced by drug pre-exposure. It alsothat the day-to-day pattern of drug self-administrationrably vary as a function of the self-administered drug.,morphinemaintained a stable, nycthemeral pattern ofministrationwhile cocaine induced an erratic increaseculminating in convulsions and death within 30 days.minal ndings have been reproduced many times, withsting variation across species, strains, sexes, age groupsual animals. It is now almost a platitude to state thatabused by humans can act as positive reinforcers in

    animals (Schuster and Thompson, 1969; Thompson and70;Goldberg, 1976; Johanson, 1978; Pickens et al., 1978;ndGoldberg, 1978;Yanagita, 1978;Grifths et al., 1980;80; Schuster and Johanson, 1981; Woods, 1983; Young

    g, 1986; Wise, 1987; Yokel, 1987; Katz, 1989, 1990;d Goeders, 1989; Brady, 1991; Campbell and Carroll,h and Carroll, 2001).rical note, it is intriguing to mention that 1 year beforel publication of James Weeks, Robert Clark, Charlesd JosephBrady (1961) published a 2-page article, also inwing thatwater-deprived rhesusmonkeys readily learnver to drink saline through an intravenous indwellingthe internal jugular vein. Importantly, monkeys readily

  • S.H. Ahmed / Neuroscience and Biobehavioral Reviews 35 (2010) 172184 175

    Fig. 1. Scienti n of jthe abstract or -admiself-infus. (b t/s, mosubjects fordr Cdata(Her), amphet es inprimary journ

    stopped toad libitumofor saline wtioned, andthis articlepublicationtheless proself-adminiinitial operaof an addict

    The discself-adminiern researcpublicationincreasing e350 in 2008ducted in rPubMed Celished reseexperimentmonkeys andrug is, by40% of pubThus, overaaddiction wexplains thereview.

    Over theadministratreinstatemeat a behavimost of thelength of exbeen recentAhmed, inthat followiare more li1998), to wmore risk tEveritt, 200ability of cobehavioralthe past 102002; Epste

    tensiandAltonfored dce to

    creast is u

    nwd ab

    cainble r

    malbestace, pse inextene phe seminis whorturtz,t setc research output on animal drug self-administration. (a) Annual rate of publicatiothe title words that begin with the following root terms: self-administ (e.g., self

    ) Frequency (in percent of total) of journal articles in the PMC database that used raug self-administration. (c) Frequency (inpercentof total) of journal articles in thePMamine/methamphetamine (Am) or nicotine (Nic) for self-administration. All searchal articles. Review articles were excluded.

    lever-press for intravenous saline when provided withralwater. As summarized by the authors, lever-pressingas shown to be conditioned, extinguished, recondi-brought under stimulus control (p. 1829). Though

    has fallen into almost complete oblivion soon after its(it has been cited only 4 times since 1961), it never-

    vided an initial, valid demonstration that intravenousstration of a substance (i.e., rate of responding abovent level) is not, in itself, sufcient evidence for inferenceion state.overy that most drugs of abuse can be spontaneouslystered by laboratory animals marked the birth of mod-h on drug addiction. Since then, the annual rate ofof research on animal drug self-administrationhas keptxponentially, from 1 publication in 1962 to more than(Fig. 1a). By far, most of this research has been con-

    ats, as estimated from primary journal articles in thentral database (Fig. 1b). Specically, about 66% of pub-arch on animal drug self-administration used rats asal subjects, compared to about 14% and 10% that usedd mice, respectively. Furthermore, the most studied

    a large margin, cocaine which accounts for more thanlished research on drug self-administration (Fig. 1c).ll,most experimental researchonanimalmodels ofdrugas done in rats self-administering cocaine which partlyfocus on rat cocaine self-administration in the present

    ing exAhmed2007).the reiextendreferenthis incally, ithe dowover an

    2.2. Coexpecta

    Aniof thegood fdrug uwhichtion. Osince tself-adtunitieor opp(Schwaoperanpast 20 years, the different stages of cocaine self-ion, including acquisition, maintenance, escalation andnt after extinction, have been studied extensively bothoral and neurobiological level. Of particular interest,se stages were recently shown to be inuenced by theposure to cocaine self-administration. This researchhasly reviewed exhaustively elsewhere (Koob et al., 2004;press). Overall, there is now good evidence showingng extended access to cocaine self-administration, ratskely to escalate drug consumption (Ahmed and Koob,ork harder (Paterson and Markou, 2003) and to takeo seek and/or to obtain cocaine (Vanderschuren and4). In addition, there is now strong evidence that thecaine to reinstate cocaine seeking after extinction aphenomenon that has been considerably studied overyears as a model of relapse or craving (Shalev et al.,in et al., 2006; Kalivas, 2009) is increased follow-

    either littlewith no pro(e.g., sleepiin a conneIn other woimental anrestricted. Fwonder whself-adminiimental addthat self-adered addictmerely by d

    3. Havingself-admin

    Previousa natural reournal articles in the PubMed Central (PMC) database that contain innistration, self-administering, self-administered) OR self-inject ORnkey/s (Mo), mouse/mice (Mi) or other (Ot) animals as experimental

    base that tested cocaine (Coc), alcohol/ethanol (Eth), heroin/morphinethe PMC database were limited to research on animals published in

    ve cocaine self-administration (Mantsch et al., 2004;Cador, 2006;Kippinet al., 2006;Knackstedt andKalivas,gether, these behavioral effects strongly suggest thatcing and/or incentive value of cocaine increases withrug use. However, as will be discussed later, without aother rewarding activities, the relative magnitude of

    e in cocaine value remains poorly understood. Speci-nknown whether it would be sufcient to set in motionard spiral of cocaine addiction, with increasing drug useove other nondrug-related activities.

    e self-administration in animals: compulsion oresponse to lack of choice

    cocaine self-administration is often presented as oneanimal model in psychiatry. No doubt this model hasredictive and constructive validities for non-addictivehumans. The key issue, however, is whether and to

    nt one can extend these validities to cocaine addic-otential obstacle to this extension of validity is thatminal work by Weeks, rats have been tested for drugstration in experimental settings devoid of other oppor-ich sharply contrast with the richness of possibilitiesnities open to human drug users in the real world2004; Alexander, 2008). More specically, in standardtings, alternative options to drug use exist but have

    intrinsic value (e.g., pressing an inactive lever, an actiongrammed effect) or are contextually weakly motivatedng during the active period; grooming or explorationd, bare and familiar environment) (Herrnstein, 1970).rds, though non-null, the degree of freedom of exper-imals during drug access is nevertheless abnormallyacing such a low degree of freedom, it is perhaps noy most rats self-administer most drugs that humansster, including cocaine. The major challenge for exper-iction research, however, is to determine among ratsminister cocaine which and how many can be consid-ed to cocaine and which and how many take cocaineefault of other valuable options.

    the choice during access to cocaineistration

    research in rats has shown that concurrent access towarding activity during access to cocaine can indeed

  • 176 S.H. Ahmed / Neuroscience and Biobehavioral Reviews 35 (2010) 172184

    inuence cocaine self-administration (Campbell and Carroll, 2000;Ahmed, 2005). For instance, in a seminal series of experiments,Marilyn Carroll and colleagues showed that concurrent access towater sweetened with saccharin and glucose reduces the propor-tion of ratscan also deafter acquisilarly, overchoosing beof the best ein drug sel1977; AignElsmore et1991; Paronin one partiallowed to cnumber of fof a total ofmal dose ofresearch isstandard exmerely by dthis seminaerality and(Lenoir and2009). The

    3.1. Introdumethodolog

    We rstcedure in dpreferencesin rats follolation of cowere allowbetween twto obtain o0.75mg/kg)saccharin (0crete trialsphases, sampling, eachrats to sepacic conseqaction comtrial. Durinwere preseeither leveraction selecnext trial. Ative rewardchoice wastunity costsloss of oppo

    Several aitly statedmisinterpreexperimenthas been eand Koob, 1will be desalso obtaina rewardinotherwise iand Sclafan

    modulated, but does not require, any prior food or uid restric-tion (Collier and Novell, 1967; Berridge, 1996; Chandrashekar etal., 2006; de Araujo et al., 2008). Importantly, consistent with pre-vious research (Smith and Sclafani, 2002), we recently found that

    givenar oproc). ThlarlyLenor waanduto f

    ect oElsma clooth

    Collielwae accsly plster relale, ra10m

    ost a

    ve rawardringnditirrespher lditiosponr addonly, ratsn-represereinfus rele, re ofprefee tharew

    etatiion.pedmostconsto c93).desp2007ose c( t

    es adf cocen oof cook cthat eventually acquire cocaine self-administration andcrease the maintenance of cocaine self-administrationition (Carroll et al., 1989; Carroll and Lac, 1993). Sim-the past 30 years, research in nonhuman primatestween food and cocaine (or heroin) has provided somevidence for the powerful role of alternative reinforcers

    f-administration (Grifths et al., 1975; Wurster et al.,er and Balster, 1978; Woolverton and Balster, 1979;al., 1980; Grifths et al., 1981; Nader and Woolverton,is et al., 2002;Negus, 2003;Gasior et al., 2004).Notably,cularly signicant study, food-restricted monkeys werehoose between different doses of cocaine and differentood pellets. It was found that most monkeys (i.e., 3 out4) preferred the highest amount of food to the maxi-cocaine (Nader and Woolverton, 1991). This previous

    clearly consistent with the view advanced here that inperimental settings, some animals may take cocaineefault of other rewarding activities. By following up onl research, we were recently able to increase its gen-validity across a wide range of factors and conditionsAhmed, 2007, 2008; Lenoir et al., 2007; Cantin et al.,

    next section summarizes this more recent research.

    cing choice during access to cocaine: aical prolegomenon

    developed and validated a discrete-trials choice pro-rug-nave animals to assess the distribution of initial(Lenoir et al., 2007). This procedure was then testedwing extended cocaine self-administration and esca-nsumption (Sections 3.3 and 3.4 below). Briey, ratsed to choose during several consecutive daily sessionso alternative actions: pressing on one of two leversne intravenous bolus of cocaine (0.25mg or aboutor on the other lever to drink water sweetened with.2%). Each daily choice session consisted of several dis-

    , spaced by 10min, and divided into two successivepling and choice (Lenoir et al., 2007). During sam-lever was presented alternatively, thereby allowingrately perform each action and thus to learn its spe-uence before making their choice. Immediately uponpletion, the lever retracted until the next samplingg choice, the cocaine- and saccharin-associated leversnted simultaneously and rats were free to respond onto obtain the corresponding reward. Immediately upontion, the two levers retracted simultaneously until thes a result, selecting one reward excluded the alterna-, thereby allowing rats to express their preference (i.e.,mutually exclusive or either/or). Or in terms of oppor-, the cost of selecting one reward corresponded to thertunity of obtaining the other reward.dditional features of this procedure need to be explic-at the outset to avoid subsequent confusion and/ortation. First, the dose of cocaine tested in the series ofs summarized below is a moderate to high dose thatxtensively used in previous research in rats (Ahmed998; Ahmed et al., 2002; Ahmed and Cador, 2006). Ascribed below, however, similar choice outcomes wereed with higher doses of cocaine. Second, saccharin isg articial sweetener in both rats and humans that isnessential for growth, survival and reproduction (Smithi, 2002). The rewarding efcacy of sweet taste can be

    whenral sugchoiceresultsparticusized (food oexplanlimiteding effvalue (able inhad no1980;intervacocainobviouand Baof ratsavailabvals of2007).

    3.2. M

    Natwo remeasutrol cothe cothe ottal conand rerin (fowhencharinthe nowhentivelyprevioavailabthe ratstablecocainformerinterprconditdeveloand althat isaccessLac, 19sistedet al.,to chowaterrelatedprovidvalue o

    Whbolusrats toa choice, rats largely prefer sucrose (520%) a natu-ver the highest concentration of saccharin tested in theedure (0.2%) (EricAugier andSergeAhmed,unpublishedus, saccharin should not be considered necessarily as ahigh reward, contrary to what we initially hypothe-

    ir et al., 2007). Third, during choice, rats were neitherter-deprived. Thus, hunger or thirst is not a signicantm in this specic procedure. Fourth, choice trials wereew per day (i.e., 8) to prevent the eventual confound-f differential reward satiation on assessment of rewardore et al., 1980). Fifth, each type of reward was avail-sed economy, meaning that except during testing, ratser opportunity to access either type of reward (Hursh,r and Johnson, 1997). Finally, the minimum inter-trial

    s set at 10min to reduce the direct anorexigenic effect ofumulation on ingestive behavioran effect that wouldromote cocaine choice, as suggested previously (Aigner, 1978). Note that trial spacing in itself is not the causetive lack of interest in cocaine; when no other choice ists self-administer cocainewith forced inter-dose inter-in or even longer (Fitch and Roberts, 1993; Lenoir et al.,

    nimals stop cocaine use when given a choice

    ts were trained under 3 reward conditions. The rstconditionswere control conditions aimed at separatelythe effectiveness of each type of reward. In those con-ons, only responding on one lever was rewarded byonding reward (cocaine or saccharin); responding onever remained unrewarded. In the third, experimen-n, responding on one lever was rewarded by cocaineding on the alternate lever was rewarded by saccha-itional details, see (Lenoir et al., 2007)). As expected,one response was rewarded by either cocaine or sac-developed a signicant preference for it and ignored

    warded lever (Fig. 2a). This result demonstrates thatnted alone, each type of reward effectively and selec-orced and maintained responding. This result conrmssearch showing that when no other valuable choice isats do self-administer cocaine. Surprisingly, however,preference acquisition (i.e., number of days to reach arence) was slower when behavior was rewarded withn with sweetened water (Fig. 2b), suggesting that theard is probably less efcacious than the latter. Thison is conrmed by the outcome of the experimentalWhen responding on either lever was rewarded, ratsa rapid and marked preference for sweetened watercompletely ignored cocaine (Fig. 2a and b), a ndingistent with previous research in rats with concurrentocaine and saccharin (Carroll et al., 1989; Carroll andInterestingly, this preference was acquired and per-ite near maximal sampling of the cocaine lever (Lenoir). Finally, after stabilization of preference, the latencyocaine was greater than the latency to choose sweet2c). Since the latency to respond is generally inverselyhe magnitude of the upcoming reward, this outcomeditional, independent conrmation that the rewardaine is weaker than that of sweetened water in rats.ffered a choice between either taking an intravenouscaine or drinking water sweetened with saccharin,

    ocaine almost exclusively during the sampling period

  • S.H. Ahmed / Neuroscience and Biobehavioral Reviews 35 (2010) 172184 177

    Fig. 2. The effects of choice on cocaine self-administration. (a) Choice (mean SEM) between the saccharin-associated lever (S) and the cocaine-associated lever (C) acrossreward conditions (S+/C: only responses on lever S are rewarded; S/C+: only responses on lever C are rewarded; S+/C+: responses on both levers are rewarded). Preferencescores were normalized as described previously (Lenoir et al., 2007). The horizontal dotted line at 0 indicates the indifference level. Scores above 0 indicate a preference forsweet water while values below 0 indicate a preference for cocaine. *Different from the indifference level (P

  • 178 S.H. Ahmed / Neuroscience and Biobehavioral Reviews 35 (2010) 172184

    Fig. 4. Sweet had rst 3 days (3 corresfrom Lenoir et to staa continuous r om Ca

    rst trainedeither cocaof reinforcesession to esponding resaccharin seprocedure.retarded, thIn fact, ratsas early aspreferenceduring FR1value to thecess that dpreference.were traineperiod wasa FR1 scheallowed to stia played aexpect thatthe cocaineever, rats sehour) durintheir respo2007). Thisfrom cocaintence of swThus, the sais availablewhen offere

    Overall,reward valutaste sweetto cocaine sof this diffeaddress thito earn swcocaine untpoint of indquantitativwould experats progres2009). At thvirtually all2009). Impo

    swee009)h lowf intrinenceine,e andsaccchartrati

    en cotratiint oe lowragencendatattomsistee ref intense

    imaug us

    ferene-naminipreference is not due to behavioral inertia. (a) Reversal of preference in rats whichto 1) correspond to baseline choice under the S/C+ condition. The next 10 daysal. (2007). (b) Immediate expression of sweet preference in rats previously trainedeinforcement schedule. *Different from the indifference level (P

  • S.H. Ahmed / Neuroscience and Biobehavioral Reviews 35 (2010) 172184 179

    Fig. 5. Sweet ine se(0.75mg per i re. *Dsweet water (m P50%d trials). Importantly, preference for cocaine was notto a mere lack of interest in or aversion to sweetenedduring sampling trials, cocaine-preferring rats earnedcesses to sweetened water and drank as much as theother rats (Cantin et al., 2009). To assess the impact ofe use on the frequency of cocaine-preferring individu-al amount of self-administered cocaine before choice

    calculated for each individual. This amount ranged86mg and dened 5 levels of severity (Cantin et al.,risingly, the frequency of cocaine-preferring individu-d stable around about 10%. Thus, nomatter how intenseel of past cocaine use, cocaine preference remains rareional in rats with alternative possibilities during drugimportant to note that the heaviest level of past cocainered here was clearly shown in previous research tofunction compared to lower levels of past cocaine use

    ily absregardCantintinue ta diffeenvisiointerprceptionbrief o

    4.1. Diaddicti

    Broing scichoicetion, dother c(Jelline2007bthat rochoicetion wdrug ution ofover bdrug ation Diof mention isal., 2002, 2003, 2005; Ferrario et al., 2005; Edwards; Madayag et al., 2007; Briand et al., 2008a,b; George; Ben-Shahar et al., 2009; Orio et al., 2009). However,biological changes were apparently not sufcient tomaking in favor of cocaine use, at least in the majority

    s a sieve for cocaine addiction

    e seminal work by Weeks, ample research has estab-hennovaluable options to druguse are available,mostlearn to self-administer cocaine and escalate cocainewing extended drug use (Ahmed, in press). In con-own here, when a valuable behavioral option, even aor physiologically inessential one (i.e., for survival orn), ismadeavailable duringdrug access,most rats read-

    some undean expectabet al., 2008associated blatter criternosis validet al., 2002diagnosis obereavemeuals who mwho are expto the deatthis generaas an expethus be excself-medicalf-administration during extended access to a high dose of cocaineifferent from the rst day (P

  • 180 S.H. Ahmed / Neuroscience and Biobehavioral Reviews 35 (2010) 172184

    Alternatively, there are a set of other scientic views thatdene drug addiction as a voluntary choice (Schelling, 1980; Thalerand Shefrin, 1981; Herrnstein and Prelec, 1991; Heyman, 1996,2009; Ainslie, 2000), though not in the sense of a rational life-time decisiand Murphuser does naddict. Theand unwanchoice-makchoice of thterm optioncan underdrug availa2009). In thloss of contability to mthe downwkeep his/hebe able to qcircumstanas a voluntaof spontaneefcacy of pfor instance

    It mayalmost a cecommunityof drug addstill co-exisargumentsof establishogy in humone concepeach concepextensive cgiven the ocontinues t

    4.2. Resilienand humans

    Accordintern of resuvulnerabilittings, resilioptions. Thto an abnorwould not nfunction. Abrain of thdence for acould indeeand uniqueresilient rattake cocain(Lenoir et aframeworkrats could bwho eventudrug use (Fity of resilithe neurobicocaine addprocedure daddiction:

    enng ratse use

    n circlcaineusers

    iallyiditystude andion chocainet ainte

    abilitiolopartty ofed toy, 2

    to bece fonowandporteho hint od hety ofe wortue lie wiereactivis inuse and evidence of physical dependence, so many veterans0%) permanently quitted heroin use upon return to home.despite chronic, heavy heroin consumption, most soldiersed resistant to heroin addiction. I am not aware of equiva-idence for resilience to cocaineaddictionafter chronic, heavye use in humans. However, there is evidence for resilienceiction-like behavior to chronic dopaminergic medication insondisease (Evans andLees, 2004;Voonet al., 2009). To com-e for the irreversible loss of midbrain dopamine neuronsneurodegeneration, Parkinsonian patients receive chronicine replacement therapies, including the dopamine pre-levodopa and direct dopamine agonists. In the course ofronic treatment, some of these patients eventually developive dopaminergic medication use, despite severe motor andotor side effects (Voon et al., 2009). This syndrome is oftenthe dopamine dysregulation syndrome and is currentlyon as in certain theories of rational addiction (Beckery, 1988; Schaler, 2000; Dalrymple, 2006). The drugot choose rationally and in advance to become a drugtransition to drug addiction happens as an unexpectedted consequence of suboptimal, though normal, dailying. For instance, though impulsive choice-making (i.e.,e best immediate optionswithout regard to better long-s) is very prevalent in both young and adult humans, itsome circumstances lead to addiction (e.g., increasedbility combined with lack of opportunity) (Heyman,is general conception, there would be no pathologicalrol and no brain dysfunction that rob the individualsake voluntary, free choices. Even at the very bottom ofard spiral of drug addiction, the drug addict would stillr ability to exert control over drug use and would evenuit, with or without professional help, under propitiousces (Heyman, 2009). The conception of drug addictionry though irrational, choice is supported by high ratesous recovery from addiction and is consistent with thesychosocial interventions for cocaine addiction such as,, voucher-based treatment (Heyman, 2009).seem shocking, perhaps even scandalous, that afterntury of debate and research on addiction, the scienticas a whole did not reach yet a consensus on the natureiction and that two general conceptions of addictiont and compete with each other. However, the scienticon both sides are solid and coherent and, in the absenceed evidence for drug addiction-related neuropathol-ans, there is currently no scientic basis for choosingtion over the other. In the following, I will show howtion of addiction can differently interpret why despiteocaine use most rats abstain from cocaine use whenpportunity to make a different choice while a minorityo take the drug.

    ce and vulnerability to cocaine addiction in animals

    g to the brain disease conception of addiction, this pat-lts could be interpreted as evidence for resilience andy to cocaine addiction. In standard experimental set-ent rats would take cocaine merely by default of othereir behavior would be merely an expectable reactionmal situation (i.e., lack of choice or opportunity) andecessarily reect an underlying addiction-related dys-

    s a result, neuroadaptive changes documented in theese rats should not be necessarily interpreted as evi-ddiction-specic pathological changes. These changesd also reect normal neuroplastic adaptations to novelbehavioral experiences. In contrast to the majority ofs, a small minority of rats (i.e., about 10%) continue toe despite the opportunity of making a different choicel., 2007; Cantin et al., 2009). Within the brain diseaseof drug addiction, this minority of cocaine-preferringe homologous to the minority of human cocaine usersally become addicted to cocaine following extended

    ig. 6). Comparing this minority of rats with the major-ent rats could thus bring unprecedented insights intoological dysfunctions that are hypothesized to underlieiction. From a methodological standpoint, the choiceescribed here could serve as a sort of sieve for cocaine

    it would weed out resilient rats and only retain rats

    Fig. 6. Vpreferrinof cocainThe opefrom cococaine

    potentthe valratorycocainaddictterm c(Walsh

    Thevulnerepidemtion inminoriaddictAnthonlikelyevidenfrom aRobinsvey re90%) wthe postoppeminoriafter thtle oppto makto copdiers woutletuse. Thheroin(i.e., 9Thus,remainlent evcocainto addParkinpensatdue todopamcursorthis chexcessnon-mcalleddiagrams illustrating the hypothesis that the minority of cocaine-(closed circles in the left set) would be homologous to the minority

    rswith a diagnosis of cocaine addiction (closed circles in the right set).es on the left and right set represent the majority of rats that abstainself-administration when given a choice or the majority of humanwho do not become addicted to cocaine.

    addicted to cocaine (Cantin et al., 2009). In support ofof this choice-based method of selection, a recent labo-y in humans showed that when given a choice betweenmoney, cocaine users with a DSM-based diagnosis ofoose cocaine more frequently than non-addicted long-e users, regardless of the amount of money availablel., 2010).rpretation of our choice data in terms of resilience andy to addiction maps well with what we know about thegy of drug addiction in general and of cocaine addic-icular. As mentioned earlier in the Introduction, only acocaine users (i.e., less than 10%) eventually becomecocaine following extended drug use (Reboussin and

    006), suggesting that about 90% of cocaine users areresistant to cocaine addiction. One of the most directr human resilience to drug addiction, however, comesold, though still valid, epidemiological survey by Lee

    co-workers (Robins et al., 1974; Robins, 1993). This sur-d that the large majority of Vietnam veterans (aboutad used heroin on a chronic basis in Vietnam, even tof becoming physically dependent, readily and durablyroin use upon return from war (Robins, 1993). Only aindividuals (i.e., about 10%) continued to use heroin

    ar. For soldiers during the Vietnams war, there was lit-nity and heroin use was a cheap, easily available wayfe in service bearable, enjoyable and also probablyth the stress of war (Robins, 1993). As a result, sol-probably using heroin by default of other rewarding orities, and not because they lost power to control drugterpretation explains why despite chronic and heavy

  • S.H. Ahmed / Neuroscience and Biobehavioral Reviews 35 (2010) 172184 181

    hypothesized to be akin to a state of drug addiction (Evans and Lees,2004). It is currently estimated that this syndrome appears onlyin a small minority of patients chronically treated with dopaminereplacement therapies (i.e., less than 10%), suggesting thus that theremainingmyears of dop

    The hypof cocaineextensive dusing a diffet al., 2008this approais based onarbitrarily trats with anselection cothat is a minshould therof resilienctrast, the chset arbitrariquency of coattain 100%much lowerthan presupindividuals

    4.3. Cocaincocaine add

    Accordinabstinencesarily rule ostrong precaddiction (C2008; Lesagthough subinterventiotherapy, a ncocaine absand an alteand OnkenSpecicallyvouchers thactivities. Tthe choice saddicts facand other ralternative15 dollars acounseling,cial intervenin cocainethough mostreatment,indeed reinadministrataddiction, bmanagementheminorittunity to maof human ctherapy. Fintreatment peffective ovwho enroll

    the majority of cocaine addicts. Thus, more research remains to bedone in this area.

    4.4. Current indeterminacy in the interpretation of cocainence i

    s takant dd abtionts abate. I-induats, tn envtermof abmenand

    Berghenats sue (Dmeninterin thuld rmenst, ind cocnot

    t, it sintened

    ve themmorldse fogencform



    there re

    l drue ty

    , food. It woralal inectsminient oviden drad Kr

    or thtualto s

    ce dued towermini008ajority is likely to be resilient to this syndrome despiteaminergic medication use.othesis that in rats, like in humans, only a minorityusers would become addicted to cocaine, even afterrug use, was previously reached by other researcherserent approach (Deroche-Gamonet et al., 2004; Belin). Though innovative and interesting, the validity ofch should nevertheless be considered with caution. Ita circular statistical method that limits a priori ando less than 33% the maximum possible frequency ofaddiction-like behavior. Obviously, such a method of

    uld only nd what it was designed at the outset to nd,ority of potentially addicted individuals. This outcomeefore not be considered as an objective demonstratione or vulnerability to cocaine addiction in rats. In con-oice-basedmethodof selectionadvocatedheredoesnotly and in advance a limit to the maximum possible fre-caine-preferring rats. In principle, this frequency could. The fact that the observed maximum frequency was(i.e., about 10%) could objectively demonstrate, ratherpose, that cocaine addiction only affects a minority ofamong a sea of resilient ones.

    e abstinence in animals and behavioral treatment foriction

    g to the choice-based conception of addiction, cocainein rats offered a nondrug alternative would not neces-ut cocaine addiction. It could even be reinterpreted aslinical support for voucher-based treatment for cocainearroll and Lac, 1993; Ahmed, 2005; Lenoir and Ahmed,e, 2009). In this view cocaine addiction is a normal,optimal, voluntary choice that could be reversed byns on environmental contingencies. In voucher-basedovel reinforcement contingency is established betweentinence in cocaine users with a diagnosis of addictionrnative reinforcer (Higgins et al., 1991, 1994; Carroll, 2005; Lussier et al., 2006; Stitzer and Petry, 2006)., cocaine abstinence is encouraged by rewarding it withat could be exchanged for other desirable goods oro phrase it in a way that emphasizes similarity withtudies in rats, during voucher-based treatment, cocainee a mutually exclusive choice between cocaine useewarding activities. Though the money value of theseactivities are relatively low (i.e., generally less thanday), voucher-based therapy, together with standardhas proven to be one of the most effective psychoso-tions for promoting abstinence and preventing relapse

    addiction (Dutra et al., 2008). As expected, however,t cocaine addicts respond positively to voucher-basedsome do not. In light of these clinical ndings, one canterpret choice-induced abstinence from cocaine self-ion inmost rats, not as evidence for resilience to cocaineut as a preclinical model of the efcacy of contingencyt therapy for cocaineaddiction. In this reinterpretation,

    y of rats that continue to take cocainedespite the oppor-ke a different choice would correspond to the minorityocaine addicts who fail to respond positively to thisally, it is important to note that though voucher-basedrograms are successful, they do not always remainer extended periods of time. In addition, individualsin such programs are not necessarily representative of


    Letsignicinduceconcepwhile ition stchoicemost rtions oof indeformspunish(Grove1977;that wmost rcontinPunishferentAgainior wopunishcontrainducethoughpresening onementioeffectithis dilreal wa diseacontinuntarycontin

    4.5. Fu

    Anoincreasanimaonly onthat iswater)behavior socithe effself-adstatemgood etion caPing antions fof habineededof choiextendeffectsself-adet al., 2n animals

    e stock of what we have achieved so far. There exists aegree of indeterminacy in the interpretation of choice-

    stinence from cocaine use in rats. In the disease-basedof addiction, this behavior would rule out addictionsence (i.e., cocaine preference)would point to an addic-n contrast, in the choice-based conception of addiction,ced cocaine abstinence would suggest instead thathough not all, can be treated by targeted interven-ironmental contingencies. Arguably, the sameprobleminacy seems also to affect the interpretation of otherstinence in experimental animals such as, for instance,t-induced abstinence from cocaine self-administrationSchuster, 1974; Smith and Davis, 1974; Johanson,

    man and Johanson, 1981). It has been recently shownlever-pressing for cocaine is punished by footshock,top cocaine self-administration while few other ratseroche-Gamonet et al., 2004; Pelloux et al., 2007).

    t-induced cocaine abstinence can also receive two dif-pretations, depending on ones conception of addiction.e disease-based conception of addiction, this behav-ule out addiction while its absence (i.e., resistance tot) would point to a compulsion or addiction state. Inthe choice-based conception of addiction, punishment-aine abstinence would suggest instead that most rats,all, can be treated by punishment-based therapy. Ateems that there exists no objective criterion for exclud-rpretation in favor of the other. In addition, it should behere thatpunishment contingenciesdonot represent anerapeutic option in humans. Perhaps one way out froma would be to postulate that there exist out there in thenot one but several forms of drug addiction, includingrm that would be rare and resistant to environmentalies (i.e., alternative choices; punishment) and other vol-s that would be more prevalent and sensitive to these

    ies (Redish et al., 2008).

    preclinical research on choice and drug addiction

    , more obvious way to resolve this indeterminacy is tosearch effort to better understand the role of choice ing self-administration. First, in most previous research,pe of alternative to drug self-administration was tested,-related rewarding activities (e.g., drinking sweetenedill be important in the future to test other kinds of

    alternatives such as, for instance, novelty explorationteraction. Second, it will also be interesting to assessof nondrug alternatives on different aspects of drugstration or reinforcement, including drug-induced rein-f drug seeking after extinction. There is already some

    nce showing that supply of an alternative after extinc-matically inuence drug reinstatement (Liu et al., 2005;uzich, 2008). This observation has important implica-e current interpretation of drug reinstatement in termsor compulsive drug seeking but more research is clearlyecure the generality of these ndings. Third, the effectsring drug exposure or access should be systematicallyother major drugs of abuse. As a matter of fact, similar

    e recently obtained in rats following extensive heroinstration and escalation of heroin consumption (Lenoir). In addition, after long-term, heavy alcohol consump-

  • 182 S.H. Ahmed / Neuroscience and Biobehavioral Reviews 35 (2010) 172184

    tion, rats thatwere selected for high-ethanol intake readily stoppeddrinking alcohol when offered a sweet solution as an alternativechoice (Terenina-Rigaldie et al., 2004). Fourth, the effects of choiceon drug self-administration should be generalized across differentstrain of ratwere all conwidely usednal articlesWistar ratssitive to cocwill be alsoself-adminiinterest, inkeys wereand differenthat most mamount of foutcome thpresent revies in monkvirtually choose btively smalland BalsterNader et al.Gasior et althose condicocaine. In(i.e., FR10)thereby favNegus andsaccharin iscocaine (Caand behavioresearch toin rats gene


    This wo(CNRS), theResearch Acontre les DdAquitaineThe authorgroup for thSallouha Aimanuscriptthoughtful


    Ahmed, S.H., 2major risk

    Ahmed, S.H., inods: Anim

    Ahmed, S.H., Cpulsive co

    Ahmed, S.H.,for hedoni625626.

    Ahmed, S.H., Kchange in

    Ahmed, S.H.,administradopamine

    Ahmed, S.H., Lutjens, R., van der Stap, L.D., Lekic, D., Romano-Spica, V., Morales, M.,Koob, G.F., Repunte-Canonigo, V., Sanna, P.P., 2005. Gene expression evidencefor remodeling of lateral hypothalamic circuitry in cocaine addiction. Proc. Natl.Acad. Sci. U.S.A. 102, 1153311538.

    Aigner, T.G., Balster, R.L., 1978. Choice behavior in rhesus monkeys: cocaine versus. ScienG.,, B.Krd Un, A., 20s: a nG.S., M700.., M

    ulsivit135har, O, 2009er1b

    ex. Syn, J., Jo

    ed by

    , K.C.,ehav.V., 1915, 35.A., Fl2008aeceptine. NL.A.,inistrNeuroll, U.Centa325.., Lenals thlable.M., O1452M.E.,ts ofl.) 110M.E.,forcerforcedshekaamm

    sen, Cand csen, Cntial vand. Psen, Cocain, Schusion in., Joh

    etite 2., Nov014, H.Wpe trale, T.,aucrajo, I.Elelis, Maling.G., Yatance-Gamn the r, Statha-analJ. Psyc, S., Grine-readmin, T.F.,ke in b731., 200icatios. The series of choice experiments summarized aboveducted in only one strain of rats: the Wistar strainarats strain in the eld (i.e., about 500 primary jour-

    in the PubMed Central database reported having usedas subjects fordrug self-administration) that is very sen-aine self-administration (Freeman et al., 2009). Fifth, itinteresting to compare the effects of choice during drugstration across several animal species. Of particularone particularly signicant study, food-restricted mon-allowed to choose between different doses of cocainet number of non-sweetened food pellets. It was foundonkeys (i.e., 3 out of a total of 4) preferred the highestood (41-g pellets) to the maximal dose of cocaine, anat is fully consistent with the main conclusions of theiew (Nader andWoolverton, 1991). Among choice stud-eys, this study seems to be an exception, however. Inother studies, the focus was on cocaine preference and,ly, experimental conditions were designed to favor itsFor instance, in many studies, monkeys were allowedetween increasing doses of cocaine and a xed, rela-, amount of food (Aigner and Balster, 1978; Woolverton, 1979; Nader and Woolverton, 1990, 1991, 1992a,b;, 1993; Paronis et al., 2002; Negus, 2003, 2004, 2005a,b;., 2004; Negus and Mello, 2004). As one could expect, intions, almost all monkeys preferred the highest dose ofaddition, in several recent studies, the cost of cocainewas much lower than the cost of food (i.e., FR100),oring cocaine preference (Negus, 2003, 2004, 2005a,b;Mello, 2004). As summarized here, when the cost ofmuch higher than the cost of cocaine, rats too prefer

    ntin et al., 2009). Becauseof their phylogenetic, genomicral proximity to humans, it will be interesting in futuredetermine whether the pattern of choice data obtainedralizes to nonhuman primates.


    rk was supported by the French Research CouncilUniversit Victor-Segalen Bordeaux 2, the National

    gency (ANR), the Mission Interministerielle de Lutterogues et la Toxicomanie (MILDT), the Conseil Regionaland the Fondation pour la Recherche Mdicale (FRM).thanks the present and past members of his researcheir dedication, commitment and effort. I also thank Dr.doudi for her comments on a previous version of the. Finally, I thank the two anonymous reviewers for theirand constructive criticisms.

    005. Imbalance between drug and non-drug reward availability: afactor for addiction. Eur. J. Pharmacol. 526, Escalation of drug use. In: Olmstead, M. C. (Ed.), Neurometh-

    al Models of Drug Addiction. Humana Press.ador, M., 2006. Dissociation of psychomotor sensitization from com-caine consumption. Neuropsychopharmacology 31, 563571.Kenny, P.J., Koob, G.F., Markou, A., 2002. Neurobiological evidencec allostasis associated with escalating cocaine use. Nat. Neurosci. 5,

    oob, G.F., 1998. Transition from moderate to excessive drug intake:hedonic set point. Science 282, 298300.Lin, D., Koob, G.F., Parsons, L.H., 2003. Escalation of cocaine self-tion does not depend on altered cocaine-induced nucleus accumbenslevels. J. Neurochem. 86, 102113.





    675Belin, D





    Brady, J.Rev.

    Briand, LT.E.,D2 rcoca



    Cantin, LreveAvai

    Carroll, K162,



    Chandrafor m



    Christenfor c

    Clark, R.infu

    Collier, GApp

    Collier, G64, 4



    de ArauNicosign


    Derocheior i

    Dutra, L.metAm.



    EMCDDAPublce 201, 534535.00. A research-based theory of addictive motivation. Law Philos. 19,

    ., 2008. TheGlobalisationofAddiction:A Study in Poverty of the Spirit.iversity Press, New York.05. Decision making, impulse control and loss of willpower to resisteurocognitive perspective. Nat. Neurosci. 8, 14581463.urphy, K.M., 1988. A theory of rational addiction. J. Polit. Econ. 96,

    ar, A.C., Dalley, J.W., Robbins, T.W., Everitt, B.J., 2008. Highy predicts the switch to compulsive cocaine-taking. Science 320,5.., Obara, I., Ary, A.W.,Ma, N.,Mangiardi,M.A.,Medina, R.L., Szumlinski,. Extended daily access to cocaine results in distinct alterations in/c andNMDAreceptor subunit expressionwithin themedialprefrontalapse 63, 598609.hanson, C.E., 1981. The effects of electric shock on responding main-cocaine in rhesus monkeys. Pharmacol. Biochem. Behav. 14, 423

    1996. Food reward: brain substrates of wanting and liking. Neurosci.Rev. 20, 125.91. Animal models for assessing drugs of abuse. Neurosci. Biobehav.43.

    agel, S.B., Garcia-Fuster,M.J.,Watson, S.J., Akil, H., Sarter,M., Robinson,. Persistent alterations in cognitive function and prefrontal dopamineors following extended, but not limited, access to self-administeredeuropsychopharmacology 33, 29692980.Flagel, S.B., Seeman, P., Robinson, T.E., 2008b. Cocaine self-

    ation produces a persistent increase in dopamine D2 High receptors.psychopharmacol. 18, 551556.., Carroll, M.E., 2000. Acquisition of drug self-administration: envi-l and pharmacological interventions. Exp. Clin. Psychopharmacol. 8,

    oir, M., Dubreucq, S., Serre, F., Vouillac, C., Ahmed, S.H., 2009. Choiceat rats are majoritarily resilient to cocaine addiction. Nat. Precedings,from http://hdlhandlenet/10101/npre200937381.nken, L.S., 2005. Behavioral therapies for drug abuse. Am. J. Psychiatry1460.Lac, S.T., 1993. Autoshaping i.v. cocaine self-administration in rats:nondrug alternative reinforcers on acquisition. Psychopharmacology, 512.Lac, S.T., Nygaard, S.L., 1989. A concurrently available nondrugprevents the acquisition or decreases the maintenance of cocaine-behavior. Psychopharmacology (Berl.) 97, 2329.r, J., Hoon, M.A., Ryba, N.J., Zuker, C.S., 2006. The receptors and cellsalian taste. Nature 444, 288294..J., Kohut, S.J., Handler, S., Silberberg, A., Riley, A.L., 2009. Demand forocaine in Fischer and Lewis rats. Behav. Neurosci. 123, 165171..J., Silberberg, A., Hursh, S.R., Huntsberry, M.E., Riley, A.L., 2008a.alue of cocaine and food in rats: tests of the exponential model ofsychopharmacology (Berl.) 198, 221229..J., Silberberg, A., Hursh, S.R., Roma, P.G., Riley, A.L., 2008b. Demande and food over time. Pharmacol. Biochem. Behav. 91, 209216.ster, C.R., Brady, J.V., 1961. Instrumental conditioning of jugular self-the rhesus monkey. Science 133, 18291830.

    nson, D.F., 1997. Who is in charge? Animal vs experimenter control.9, 159180.ell, K., 1967. Saccharin as a sugar surrogate. J. Comp. Physiol. Psychol.08.., Headlee, C.P., Nichols, J.R., 1956. Drug addiction. I. Addiction byining. J. Am. Pharm. Assoc. (Baltim.) 45, 788791.2006. Romancing Opiates: Pharmacological lies and the Addiction

    cy. Encounter Books, New York.., Oliveira-Maia, A.J., Sotnikova, T.D., Gainetdinov, R.R., Caron, M.G.,

    .A., Simon, S.A., 2008. Food reward in the absence of taste receptorNeuron 57, 930941.nagita, T., Seevers, M.H., 1969. Self-administration of psychoactive

    s by the monkey. Psychopharmacologia 16, 3048.onet, V., Belin, D., Piazza, P.V., 2004. Evidence for addiction-like behav-at. Science 305, 10141017.opoulou, G., Basden, S.L., Leyro, T.M., Powers,M.B., Otto,M.W., 2008. Aytic review of psychosocial interventions for substance use disorders.hiatry 165, 179187.aham,D.L., Bachtell, R.K., Self, D.W., 2007. Region-specic tolerance togulated cAMP-dependent protein phosphorylation following chronicistration. Eur. J. Neurosci. 25, 22012213.Fletcher, G.V., Conrad, D.G., Sodetz, F.J., 1980. Reduction of heroinaboons by an economic constraint. Pharmacol. Biochem. Behav. 13,

    9. Annual Report 2009: The State of the Drugs Problem in Europe.ns Ofce of the European Union, Luxembourg, pp. 99.

  • S.H. Ahmed / Neuroscience and Biobehavioral Reviews 35 (2010) 172184 183

    Epstein, D.H., Preston, K.L., Stewart, J., Shaham, Y., 2006. Toward a model of drugrelapse: an assessment of the validity of the reinstatement procedure. Psy-chopharmacology (Berl.) 189, 116.

    Evans, A.H., Lees, A.J., 2004. Dopamine dysregulation syndrome in Parkinsons dis-ease. Curr. Opin. Neurol. 17, 393398.

    Ferrario, C.R., Gbehavioralcocaine us

    Fitch, T.E., Robperiodicity119128.

    Freeman, K.B.,of drug-inNeurosci. 1

    Gasior, M., Paof choice bdelivery in

    George, O., Maself-adminmemory im

    Goldberg, S.R.,farb, J. (Ed

    Grifths, R.R.,humandruBehaviora

    Grifths, R.R.,effects of nmacol. Rev

    Grifths, R.R.,effects ofm

    Grove, R.N., Sextinction

    Harding, W.MAbuse 3, 1

    Herrnstein, R.JHerrnstein, R.J

    Perspec. 5Heyman, G.M.

    561610.Heyman, G.M

    CambridgeHiggins, S.T., B


    Higgins, S.T., DJ.W., 1991Psychiatry

    Hursh, S.R., 1934, 21923

    Hyman, S.E., 2162, 1414

    Hyman, S.E., 2rosci. 8, 72

    Hyman, S.E., 2trol of beh

    Hyman, S.E., Mrole of rew

    Jellinek, E.M., 1Johanson, C.E.

    cocaine inmacology

    Johanson, C.E.,temporary325390.

    Kalivas, P.W.,Neurosci. 1

    Katz, J.L., 1989Liebman, JClarendon

    Katz, J.L., 1990utility. Beh

    Kippin, T.E., Funoncontinin rats. Psy

    Knackstedt, L.Aenhancesmacol. Exp

    Koob, G.F., AhParsons, Lfrom drug

    Koob, G.F., Le MLenoir, M., Ah

    pulsive heNeuropsyc

    Lenoir, M., Ahheroin con

    Lenoir, M., Cantin, L., Serre, F., Ahmed, S.H., 2008. The value of heroin increases withextended use but not above the value of a non-essential alternative reward. In:38th Annual Meeting of the Society for Neuroscience, Washington, DC, USA.

    Lenoir, M., Serre, F., Cantin, L., Ahmed, S.H., 2007. Intense sweetness surpassescocaine reward. PLoS One 2, e698.

    .G., 2inforcve nonobertsdeprivgy (BeJ.P., Heucher192.J., Ca

    9, 131., 200

    rpretag, A.,r, M.Dticity-, J.F., D

    , J.R.,xtendeine-ingy (BeC.S., Criteria575., A.T.nic muation., Holiled. S.A., H

    ce: efhol De.A., Wts of i.A., W

    nativeharm.A., W

    monk638..A., W

    hoicel.) 108.S., 20monkphet

    .S., 20gonistkeys..S., 20us mo.S., 20rug-vhopha.S., Mfood-urren309.C.P., Ve in DEdwarabinoitionsC.A., Gsche

    keys., N.E.,escal

    M.P., 2c procY., Evishme137.R., Mee rein.), Han, pp. 1, Kruhamph924orny, G., Crombag,H.S., Li, Y., Kolb, B., Robinson, T.E., 2005.Neural andplasticity associated with the transition from controlled to escalatede. Biol. Psychiatry 58, 751759.erts, D.C., 1993. The effects of dose and access restrictions on theof cocaine self-administration in the rat. Drug Alcohol Depend. 33,

    Kearns, D.N., Kohut, S.J., Riley, A.L., 2009. Strain differences in patternstake during prolonged access to cocaine self-administration. Behav.23, 156164.

    ronis, C.A., Bergman, J., 2004. Modication by dopaminergic drugsehavior under concurrent schedules of intravenous saline and foodmonkeys. J. Pharmacol. Exp. Ther. 308, 249259.ndyam, C.D., Wee, S., Koob, G.F., 2008. Extended access to cocaineistrationproduces long-lastingprefrontal cortex-dependentworkingpairments. Neuropsychopharmacology 33, 24742482.

    1976. The behavioral analysis of drug addiction. In: Glick, S.D., Gold-s.), Behavioral Pharmacology. C.V. Mosby, Saint Louis, pp. 283316.Bigelow, G.E., Henningeld, J.E., 1980. Similarities in animal andg-taking behavior. In:Mello, N.K. (Ed.), Advances in SubstanceAbuse:

    l and Biological Research, 1. JAI Press, Greenwich, CT, pp. 190.Wurster, R.M., Brady, J.V., 1975. Discrete-trial choice procedure:aloxone and methadone on choice between food and heroin. Phar-. 27, 357365.Wurster, R.M., Brady, J.V., 1981. Choice between food and heroin:orphine, naloxone, and secobarbital. J. Exp. Anal. Behav. 35, 335351.

    chuster, C.R., 1974. Suppression of cocaine self-administration byand punishment. Pharmacol. Biochem. Behav. 2, 199208.., 1983. Controlled opiate use: fact or artifact? Adv. Alcohol Subst.05118.., 1970. On the law of effect. J. Exp. Anal. Behav. 13, 243266.., Prelec, D., 1991. Melioration: a theory of distributed choice. J. Econ., 137156., 1996. Resolving the contradictions of addiction. Behav. Brain Sci. 19,

    ., 2009. Addiction: A Disorder of Choice. Harvard University Press,.udney, A.J., Bickel, W.K., Foerg, F.E., Donham, R., Badger, G.J., 1994.improve outcome in outpatient behavioral treatment of cocaine

    ce. Arch. Gen. Psychiatry 51, 568576.elaney, D.D., Budney, A.J., Bickel, W.K., Hughes, J.R., Foerg, F., Fenwick,. A behavioral approach to achieving initial cocaine abstinence. Am. J.148, 12181224.

    80. Economic concepts for the analysis of behavior. J. Exp. Anal. Behav.8.005. Addiction: a disease of learning and memory. Am. J. Psychiatry1422.

    007a. Can neuroscience be integrated into the DSM-V? Nat. Rev. Neu-5732.007b. The neurobiology of addiction: implications for voluntary con-avior. Am. J. Bioeth. 7, 811.alenka, R.C., Nestler, E.J., 2006. Neural mechanisms of addiction: theard-related learning and memory. Annu. Rev. Neurosci. 29, 565598.952. Phases of alcohol addiction. Q. J. Stud. Alcohol 13, 673684.

    , 1977. The effects of electric shock on responding maintained byjections in a choice procedure in the rhesus monkey. Psychophar-(Berl.) 53, 277282.1978. Drugs as reinforcers. In: Blackman, D.E., Sanger, D.J. (Eds.), Con-Research in Behavioral Pharmacology. Plenum Press, New York, pp.

    2009. The glutamate homeostasis hypothesis of addiction. Nat. Rev.0, 561572.. Drugs as reinforcers: pharmacological and behavioural factors. In:.M., Cooper, S.J. (Eds.), The Neuropharmacological Basis of Reward.Press, Oxford, pp. 164213.. Models of relative reinforcing efcacy of drugs and their predictiveav. Pharmacol. 1, 283301.chs, R.A., See, R.E., 2006. Contributions of prolonged contingent andgent cocaine exposure to enhanced reinstatement of cocaine seekingchopharmacology (Berl.) 187, 6067.., Kalivas, P.W., 2007. Extended access to cocaine self-administration

    drug-primed reinstatement but not behavioral sensitization. J. Phar-. Ther. 322,, S.H., Boutrel, B., Chen, S.A., Kenny, P.J., Markou, A., ODell, L.E.,.H., Sanna, P.P., 2004. Neurobiological mechanisms in the transitionuse to drug dependence. Neurosci. Biobehav. Rev. 27, 739749.oal, M., 2006. Neurobiology of Addiction. Academic Press, San Diego.

    med, S.H., 2007. Heroin-induced reinstatement is specic to com-roin use and dissociable from heroin reward and sensitization.hopharmacology 32,, S.H., 2008. Supply of a nondrug substitute reduces escalatedsumption. Neuropsychopharmacology 33, 22722282.

    Lesage,Mof renati

    Liu, Y., Randcolo

    Lussier,of vo101,

    Lynch, Wcol.




    Mantschof ecocacolo

    Martin,tic c561


    Miller, Gunve

    Nader, MchoiAlco

    Nader, Meffec

    Nader, Malterchop

    Nader, Msus635

    Nader, Mon c(Ber

    Negus, Ssusd-am

    Negus, Santamon

    Negus, Srhes

    Negus, Sin a dPsyc

    Negus, Sandconc297


    Orio, L.,canncond





    Pickens,of th(EdsYork

    Ping, A.met90, 4009. Toward a nonhumanmodel of contingencymanagement: effectsing abstinence fromnicotine self-administration in ratswith an alter-drug reinforcer. Psychopharmacology (Berl.) 203, 1322.,D.C.,Morgan,D., 2005. Effectsof extended-access self-administrationation on breakpoints maintained by cocaine in rats. Psychopharma-rl.) 179,, S.H., Mongeon, J.A., Badger, G.J., Higgins, S.T., 2006. Ameta-analysis-based reinforcement therapy for substance use disorders. Addiction203.rroll, M.E., 2001. Regulation of drug intake. Exp. Clin. Psychopharma-143.0. Loss of control in alcoholismanddrug addiction: aneuroscientiction. Exp. Clin. Psychopharmacol. 8, 225249.Lobner, D., Kau, K.S., Mantsch, J.R., Abdulhameed, O., Hearing, M.,., Baker, D.A., 2007. Repeated N-acetylcysteine administration altersdependent effects of cocaine. J. Neurosci. 27, 1396813976.esmond, D.P., 2000. Addiction or dependence? Addiction 95, 661

    Yuferov, V., Mathieu-Kia, A.M., Ho, A., Kreek, M.J., 2004. Effectsd access to high versus low cocaine doses on self-administration,duced reinstatement and brain mRNA levels in rats. Psychopharma-rl.) 175, 2636.hung, T., Langenbucher, J.W., 2008. How should we revise diagnos-for substance use disorders in the DSM-V? J. Abnorm. Psychol. 117,

    , Lewis, D.C., OBrien, C.P., Kleber, H.D., 2000. Drug dependence, aedical illness: implications for treatment, insurance, and outcomes. JAMA 284, 16891695.den, C., 2010. Psychiatry. Proposed revisions to psychiatrys canoncience 327, 770771.edeker, D., Woolverton, W.L., 1993. Behavioral economics and drugfects of unit price on cocaine self-administration by monkeys. Drugpend. 33, 193199.oolverton, W.L., 1990. Cocaine vs. food choice in rhesus monkeys:

    ncreasing the response cost for cocaine. NIDA Res. Monogr. 105, 621.oolverton, W.L., 1991. Effects of increasing the magnitude of anreinforcer on drug choice in a discrete-trials choice procedure. Psy-

    acology (Berl.) 105, 169174.oolverton, W.L., 1992a. Choice between cocaine and food by rhe-

    eys: effects of conditions of food availability. Behav. Pharmacol. 3,

    oolverton, W.L., 1992b. Effects of increasing response requirementbetween cocaine and food in rhesus monkeys. Psychopharmacology, 295300.03. Rapid assessment of choice between cocaine and food in rhe-eys: effects of environmental manipulations and treatment withamine and upenthixol. Neuropsychopharmacology 28, 919931.04. Effects of the kappa opioid agonist U50,488 and the kappa opioidnor-binaltorphimine on choice between cocaine and food in rhesus

    Psychopharmacology (Berl.) 176, 204213.05a. Effects of punishment on choice between cocaine and food innkeys. Psychopharmacology (Berl.) 181, 244252.05b. Interactionsbetween the reinforcing effects of cocaine andheroins-food choice procedure in rhesusmonkeys: a dose-addition analysis.rmacology (Berl.) 180, 115124.ello, N.K., 2004. Effects of chronic methadone treatment on cocaine-maintained responding under second-order, progressive-ratio andt-choice schedules in rhesus monkeys. Drug Alcohol Depend. 74,

    olkow, N., Li, T.K., 2006. Whats in a word? Addiction versus depen-SM-V. Am. J. Psychiatry 163, 764765.ds, S., George, O., Parsons, L.H., Koob, G.F., 2009. A role for the endo-id system in the increased motivation for cocaine in extended-access. J. Neurosci. 29, 48464857.asior, M., Bergman, J., 2002. Effects of cocaine under concurrent xeddules of food and IV drug availability: a novel choice procedure inPsychopharmacology (Berl.) 163, 283291.Markou, A., 2003. Increased motivation for self-administered cocaineated cocaine intake. Neuroreport 14, 22292232.007. Decision-making dysfunctions in psychiatryaltered homeo-essing? Science 318, 602606.eritt, B.J., Dickinson, A., 2007. Compulsive drug seeking by rats undernt: effects of drug taking history. Psychopharmacology (Berl.) 194,

    isch, R.A., Thompson, T., 1978. Drug self-administration: an analysisfrocing effects of drugs. In: Iversen, L.L., Iversen, S.D., Solomon, S.H.dbook of Psychopharmacology: Drugs of Abuse. Plenum Press, New37.zich, P.J., 2008. Concurrent access to sucrose pellets decreasesetamine-seeking behavior in Lewis rats. Pharmacol. Biochem. Behav.


  • 184 S.H. Ahmed / Neuroscience and Biobehavioral Reviews 35 (2010) 172184

    Reboussin, B.A., Anthony, J.C., 2006. Is there epidemiological evidence to support theidea that a cocaine dependence syndrome emerges soon after onset of cocaineuse? Neuropsychopharmacology 31, 20552064.

    Redish, A.D., Jensen, S., Johnson, A., 2008. A unied framework for addiction: vul-nerabilities in the decision process. Behav. Brain Sci. 31, 415437, discussion437487.

    Roberts, D.C., Goeders, N.E., 1989. Drug self-administration: experimental methodsand determinants. In: Boulton, A.A., Baker, G.B., Greenshaw, A.J. (Eds.), Neu-romethods: Psychopharmacology. Humana Press, Clifton, pp. 349398.

    Robins, L.N., 1993. The sixth Thomas James Okey Memorial Lecture. Vietnam vet-erans rapid recovery from heroin addiction: a uke or normal expectation?Addiction 88, 10411054.

    Robins, L.N., Davis, D.H., Goodwin, D.W., 1974. Drug use by U.S. Army enlisted menin Vietnam: a follow-up on their return home. Am. J. Epidemiol. 99, 235249.

    Robinson, T.E., Berridge, K.C., 2008. Review. The incentive sensitization theory ofaddiction: some current issues. Philos. Trans. R. Soc. Lond. B: Biol. Sci. 363,31373146.

    Schaler, J.A., 2000. Addiction is a Choice. Open Court, Chicago.Schelling, T.C., 1980. The intimate contest for self-command. Public Interest 60,

    94118.Schuster, C.R., Johanson, C.E., 1981. An analysis of drug-seeking behavior in animals.

    Neurosci. Biobehav. Rev. 5, 315323.Schuster, C.R., Thompson, T., 1969. Self administrationof andbehavioral dependence

    on drugs. Annu. Rev. Pharmacol. 9, 483502.Schwartz, B., 2004. The Paradox of Choice: Why more is Less. Harper Perennial, New

    York.Shalev, U., Grimm, J.W., Shaham, Y., 2002. Neurobiology of relapse to heroin and

    cocaine seeking: a review. Pharmacol. Rev. 54, 142.Shewan,D., Dalgarno, P., 2005. Evidence for controlledheroinuse? Low levels of neg-

    ative health and social outcomes among non-treatment heroin users in Glasgow(Scotland). Br. J. Health Psychol. 10, 3348.

    Shiffman, S., 1989. Tobacco chippersindividual differences in tobacco depen-dence. Psychopharmacology (Berl.) 97, 539547.

    Smith, G.S., Davis, M., 1974. Punishment of amphetamine and morphine self-administration behavior. Psychol. Rec. 24, 477480.

    Smith, J.C., Sclafani, A., 2002. Saccharin as a sugar surrogate revisited. Appetite 38,155160.

    Spealman, R.Dmals: cont313339.

    Spragg, S.D.S.,15, 1132.

    Stitzer, M., Peabuse. Ann

    Terenina-Rigarat as a moPharmaco

    Thaler, R.H., S89, 39240

    Thompson, T.,compariso

    Thompson, T.,and avoida

    Vanderschurelonged coc

    Vanderschuren, L.J., Kalivas, P.W., 2000. Alterations in dopaminergic and glu-tamatergic transmission in the induction and expression of behavioralsensitization: a critical reviewofpreclinical studies. Psychopharmacology (Berl.)151, 99120.

    Volkow, N.D., Fowler, J.S., 2000. Addiction, a disease of compulsion and drive:involvement of the orbitofrontal cortex. Cereb. Cortex 10, 318325.

    Volkow, N.D., Fowler, J.S., Wolf, A.P., Hitzemann, R., Dewey, S., Bendriem, B., Alpert,R., Hoff, A., 1991. Changes in brain glucose metabolism in cocaine dependenceand withdrawal. Am. J. Psychiatry 148, 621626.

    Volkow, N.D., Wang, G.J., Ma, Y., Fowler, J.S., Wong, C., Ding, Y.S., Hitzemann, R.,Swanson, J.M., Kalivas, P., 2005.Activationoforbital andmedial prefrontal cortexby methylphenidate in cocaine-addicted subjects but not in controls: relevanceto addiction. J. Neurosci. 25, 39323939.

    Voon, V., Fernagut, P.O., Wickens, J., Baunez, C., Rodriguez, M., Pavon, N., Juncos,J.L., Obeso, J.A., Bezard, E., 2009. Chronic dopaminergic stimulation in Parkin-sons disease: from dyskinesias to impulse control disorders. Lancet Neurol. 8,11401149.

    Wakeeld, J.C., 2007. The concept of mental disorder: diagnostic implications of theharmful dysfunction analysis. World Psychiatry 6, 149156.

    Wakeeld, J.C., Pottick, K.J., Kirk, S.A., 2002. Should the DSM-IV diagnostic criteriafor conduct disorder consider social context? Am. J. Psychiatry 159, 380386.

    Wakeeld, J.C., Schmitz,M.F., First,M.B., Horwitz, A.V., 2007. Extending the bereave-ment exclusion formajor depression to other losses: evidence from theNationalComorbidity Survey. Arch. Gen. Psychiatry 64, 433440.

    Walsh, S.L., Donny, E.C., Nuzzo, P.A., Umbricht, A., Bigelow, G.E., 2010. Cocaine abuseversus cocaine dependence: cocaine self-administration and pharmacodynamicresponse in the human laboratory. Drug Alcohol Depend. 106, 2837.

    Warburton, H., Turnbull, P.J., Hough, M., 2005. Occasional and Controlled HeroinUse: Not a Problem? Joseph Rowntree Foundation, York.

    Weeks, J.R., 1962. Experimental morphine addiction: method for automatic intra-venous injections in unrestrained rats. Science 138, 143144.

    Wise, R.A., 1987. Intravenous drug self-administration: a special case of positivereinforcement. In: Bozarth, M.A. (Ed.), Methods of Assessing the ReinforcingProperties of Abused Drugs. Springer-Verlag, New York, pp. 117141.

    Woods, J.H., 1983. Some thoughts on the relations between animal andhumandrug-taking. Prog. Neuropsychopharmacol. Biol. Psychiatry 7, 577584.

    ton, Wine an

    , R.M.inistritions, T.,ogr., 1, T., 19maco.A., 19macoof AssYork.M., HoldbeemicN.E.,Unive., Goldberg, S.R., 1978. Drug self-administration by laboratory ani-rol by schedules of reinforcement. Annu. Rev. Pharmacol. Toxicol. 18,

    1940. Morphine addiction in chimpanzees. Comp. Psychol. Monogr.

    try, N., 2006. Contingency management for treatment of substanceu. Rev. Clin. Psychol. 2, 411434.

    ldie, E., Jones, B.C., Mormede, P., 2004. The high-ethanol preferringdel to study the shift between alcohol abuse and dependence. Eur. J.

    l. 504, 199206.hefrin, H.M., 1981. An economic theory of self-control. J. Polit. Econ.6.Pickens, R., 1970. Stimulant self-administration by animals: somens with opiate self-administration. Fed. Proc. 29, 612.Schuster, C.R., 1964. Morphine self-administration. Food-reinforced,nce behaviors in rhesus monkeys. Psychopharmacologia 5, 8794.

    n, L.J., Everitt, B.J., 2004. Drug seeking becomes compulsive after pro-aine self-administration. Science 305, 10171019.





    Yokel, RpharodsNew

    Young, AIn: GAcad

    Zinberg,Yale.L., Balster, R.L., 1979. The effects of lithium on choice betweend food in the rhesus monkey. Commun. Psychopharmacol. 3, 309

    , Grifths, R.R., Findley, J.D., Brady, J.V., 1977. Reduction of heroin self-ation in baboons by manipulation of behavioral and pharmacological. Pharmacol. Biochem. Behav. 7, 519528.1978. Drug dependence studies in laboratory animals. NIDA Res.79190.80. Self-administration studies on psychological dependence. Trends

    l. Sci. 1, 161164.87. Intravenous self-administration: response rates, the effects oflogical challenges, and drug preference. In: Bozarth, M.A. (Ed.), Meth-essing the Reinforcing Properties of Abused Drugs. Springer-Verlag,, pp. 133.erling, S., 1986. Drugs as reinforcers: studies in laboratory animals.rg, S.R., Stolerman, I. (Eds.), Behavioral Analysis of Drug Dependence.Press, Orlando, pp. 967.1984. Drug, Set, and Setting: The Basis of Controlled Intoxicant Use.rsity Press, New Haven.

    Validation crisis in animal models of drug addiction: Beyond non-disordered drug use toward drug addictionLabeling, defining and modeling cocaine addictionDependence or addiction: words of choice and choice of wordsRates of cocaine use and addictionCocaine addiction from a rational choice perspectiveModeling cocaine addiction in experimental animals: doubts and pitfalls

    Deconstruction of animal models of cocaine addictionA brief history of experimental research on animal drug self-administrationCocaine self-administration in animals: compulsion or expectable response to lack of choice

    Having the choice during access to cocaine self-administrationIntroducing choice during access to cocaine: a methodological prolegomenonMost animals stop cocaine use when given a choiceAnimals abstain from cocaine use no matter how heavy was past drug useOnly a minority of animals continue to take cocaine despite choice

    Choice as a sieve for cocaine addictionDisease- versus choice-based conceptions of cocaine addictionResilience and vulnerability to cocaine addiction in animals and humansCocaine abstinence in animals and behavioral treatment for cocaine addictionCurrent indeterminacy in the interpretation of cocaine abstinence in animalsFuture preclinical research on choice and drug addiction



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