Evidence for Sugar Addiction_ Behavioral and Neurochemical Effects of Intermittent, Excessive Sugar Intake

21/04/2015 Evidenceforsugaraddiction:Behavioralandneurochemicaleffectsofintermittent,excessivesugarintake

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2235907/?tool=pmcentrez 1/25

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NeurosciBiobehavRev.AuthormanuscriptavailableinPMC2009Jan1.Publishedinfinaleditedformas:

NeurosciBiobehavRev.200832(1):2039.Publishedonline2007May18.doi:10.1016/j.neubiorev.2007.04.019

PMCID:PMC2235907NIHMSID:NIHMS36189

Evidenceforsugaraddiction:Behavioralandneurochemicaleffectsofintermittent,excessivesugarintakeNicoleM.Avena,PedroRada,andBartleyG.Hoebel

DepartmentofPsychology,PrincetonUniversity,Princeton,NJ08540USA*Sendcorrespondenceto:Dr.BartHoebel,PrincetonUniversity,DepartmentofPsychology,Princeton,NJ08540,Phone:(609)2584463,Fax:(609)2581113,Email:[email protected]

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Abstract

Theexperimentalquestioniswhetherornotsugarcanbeasubstanceofabuseandleadtoanaturalformofaddiction.Foodaddictionseemsplausiblebecausebrainpathwaysthatevolvedtorespondtonaturalrewardsarealsoactivatedbyaddictivedrugs.Sugarisnoteworthyasasubstancethatreleasesopioidsanddopamineandthusmightbeexpectedtohaveaddictivepotential.Thisreviewsummarizesevidenceofsugardependenceinananimalmodel.Fourcomponentsofaddictionareanalyzed.Bingeing,withdrawal,cravingandcrosssensitizationareeachgivenoperationaldefinitionsanddemonstratedbehaviorallywithsugarbingeingasthereinforcer.Thesebehaviorsarethenrelatedtoneurochemicalchangesinthebrainthatalsooccurwithaddictivedrugs.Neuraladaptationsincludechangesindopamineandopioidreceptorbinding,enkephalinmRNAexpressionanddopamineandacetylcholinereleaseinthenucleusaccumbens.Theevidencesupportsthehypothesisthatundercertaincircumstancesratscanbecomesugardependent.Thismaytranslatetosomehumanconditionsassuggestedbytheliteratureoneatingdisordersandobesity.

Keywords:bingeeating,dopamine,acetylcholine,opioid,nucleusaccumbens,withdrawal,craving,behavioralsensitization,rat

1.OVERVIEW

Neuralsystemsthatevolvedtomotivateandreinforceforagingandfoodintakealsounderliedrugseekingandselfadministration.Thefactthatsomeofthesedrugscancauseaddictionraisesthelogicalpossibilitythatsomefoodsmightalsocauseaddcition.Manypeopleclaimthattheyfeelcompelledtoeatsweetfoods,similarinsomewaystohowanalcoholicmightfeelcompelledtodrink.Therefore,wedevelopedananimalmodeltoinvestigatewhysomepeoplehavedifficultymoderatingtheirintakeofpalatablefoods,suchassweetbeverages.

Inthisanimalmodel,ratsarefooddepriveddailyfor12h,thenafteradelayof4hintotheirnormalcircadiandrivenactiveperiod,theyaregiven12haccesstoasugarsolutionandchow.Asaresult,theylearntodrinkthesugarsolutioncopiously,especiallywhenitfirstbecomesavailableeachday.

Afteramonthonthisintermittentfeedingschedule,theanimalsshowaseriesofbehaviorssimilartotheeffectsofdrugsofabuse.Thesearecategorizedasbingeing,meaningunusuallylargeboutsofintake,opiatelikewithdrawalindicatedbysignsofanxietyandbehavioraldepression(Colantuonietal.,2001,2002),andcravingmeasuredduringsugarabstinenceasenhancedrespondingforsugar(Avenaetal.,2005).Therearealsosignsofbothlocomotorandconsummatorycrosssensitizationfromsugartodrugsofabuse(Avenaetal.,2004,

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AvenaandHoebel,2003b).Havingfoundthesebehaviorsthatarecommontodrugdependencywithsupportingevidencefromotherlaboratories(Gosnell,2005,Grimmetal.,2005,Widemanetal.,2005),thenextquestioniswhythishappens.

Awellknowncharacteristicofaddictivedrugsistheirabilitytocauserepeated,intermittentincreasesinextracellulardopamine(DA)inthenucleusaccumbens(NAc)(DiChiaraandImperato,1988,HernandezandHoebel,1988,Wiseetal.,1995).WefindthatratswithintermittentaccesstosugarwilldrinkinabingelikemannerthatreleasesDAintheNAceachtime,liketheclassiceffectofmostsubstancesofabuse(Avenaetal.,2006,Radaetal.,2005b).ThisconsequentlyleadstochangesintheexpressionoravailabilityofDAreceptors(Colantuonietal.,2001,Spangleretal.,2004).

Intermittentsugaraccessalsoactsbywayofopioidsinthebrain.TherearechangesinopioidsystemssuchasdecreasedenkephalinmRNAexpressionintheaccumbens(Spangleretal.,2004).Signsofwithdrawalseemtobelargelyduetotheopioidmodificationssincewithdrawalcanbeobtainedwiththeopioidantagonistnaloxone.Fooddeprivationisalsosufficienttoprecipitateopiatelikewithdrawalsigns(Avena,Bocarsly,Rada,KimandHoebel,unpublished,Colantuonietal.,2002).Thiswithdrawalstateinvolvesatleasttwoneurochemicalmanifestations.FirstisadecreaseinextracellularDAintheaccumbens,andsecondisthereleaseofacetylcholine(ACh)fromaccumbensinterneurons.Theseneurochemicaladaptationsinresponsetointermittentsugarintakemimictheeffectsofopiates.

Thetheoryisformulatedthatintermittent,excessiveintakeofsugarcanhavedopaminergic,cholinergicandopioideffectsthataresimilartopsychostimulantsandopiates,albeitsmallerinmagnitude.Theoveralleffectoftheseneurochemicaladaptationsismild,butwelldefined,dependency(Hoebeletal.,1999,LeibowitzandHoebel,2004,Radaetal.,2005a).Thisreviewcompilesstudiesfromourlaboratoryandintegratesrelatedresultsobtainedbyothersusinganimalmodels,clinicalaccountsandbrainimagingtoanswerthequestion:cansugar,insomeconditions,beaddictive?

2.DEFININGADDICTION

Throughoutthisreviewweuseseveraltermswithdefinitionsforwhichthereisnotuniversalagreement.Addictionresearchtraditionallyfocusesondrugsofabuse,suchasmorphine,cocaine,nicotineandalcohol.However,recentlyavarietyofaddictionstonondrugentities,includinggambling,sex,andinthisreview,food,havebeeninvestigated(BancroftandVukadinovic,2004,Comingsetal.,2001,Petry,2006).Thetermaddictionimpliespsychologicaldependenceandthusisamentalorcognitiveproblem,notjustaphysicalailment.Addictionisoftenusedsynonymouslywiththetermdependence(Nelsonetal.,1982)asdefinedbyDSMIVTR(AmericanPsychiatricAssociation,2000).Wewillusethetermdependenceinitsallencompassingmeaningtodescribetheresultsofabatteryofanimalstudiesthatmodelhumandrugaddictionineachofitsmajorphases(KoobandLeMoal,2005).

Drugdependenceischaracterizedbycompulsive,sometimesuncontrollable,behaviorsthatoccurattheexpenseofotheractivitiesandintensifywithrepeatedaccess.Dependenceisdifficulttodemonstrateconvincinglyinlaboratoryanimals,butcriteriahavebeensuggestedusinganimalmodels.Wehaveusedmodelsthatweredevelopedwithratsforstudyingdrugdependenceandadaptedthemtotestforsignsofsugardependence.

Bingeing

Thediagnosticcriteriaforaddictioncanbegroupedintothreestages(AmericanPsychiatricAssociation,2000,KoobandLeMoal,1997).Thefirst,bingeing,isdefinedastheescalationofintakewithahighproportionofintakeatonetime,usuallyafteraperiodofvoluntaryabstinenceorforceddeprivation.Enhancedintakeintheformofbingesmayresultfrombothsensitizationandtolerancetothesensorypropertiesofasubstanceofabusethatoccurswithitsrepeateddelivery.Sensitization,whichisdescribedingreaterdetailbelow,isanincreaseinresponsivenesstoarepeatedlypresentedstimulus.Toleranceisagradualdecreaseinresponsiveness,suchthatmoreofthesubstanceisneededtoproducethesameeffect(McSweeneyetal.,2005).Botharethoughttoinfluencethepowerful,acutereinforcingeffectsofdrugsofabuseandareimportantatthebeginningoftheaddictioncyclesincebothcanincreaserespondingandintake(KoobandLeMoal,2005).

Withdrawal



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Signsofwithdrawalbecomeapparentwhentheabusedsubstanceisnolongeravailableorchemicallyblocked.Wewilldiscusswithdrawalintermsofopiatewithdrawal,whichhasaclearlydefinedsetofsymptoms(Martinetal.,1963,Wayetal.,1969).Anxietycanbeoperationallydefinedandmeasuredinanimalsusingtheelevatedplusmaze,inwhichanxiousanimalswillavoidspendingtimeontheopenarmsofthemaze(Fileetal.,2004).Thistesthasbeenextensivelyvalidatedforbothgeneralanxiety(Pellowetal.,1985)andanxietyinducedbydrugwithdrawal(FileandAndrews,1991).Behavioraldepressioninanimalscanalsobeinferred,withoutreferencetoemotion,usingtheforcedswimtest,whichmeasuresswimmingescapeeffortsvs.passivefloating(Porsoltetal.,1978).Whensignsofopiatewithdrawalareprecipitatedwithnaloxone,itsuggeststhatinactivationofopioidreceptorsisthecause.Whenthesamesignsareproducedspontaneouslyduringabstinence,onecansurmisethatitisduetolackofstimulationofsomeopioidsystem.

Craving

Thethirdstageofaddiction,craving,occurswhenmotivationisenhanced,usuallyafteranabstinenceperiod(VanderschurenandEveritt,2005,Weiss,2005).Cravingremainsapoorlydefinedtermthatisoftenusedtodescribetheintensedesiretoselfadministerdrugsinhumans(Wise,1988).Forlackofabetterword,wewillusethetermcravingasdefinedbyincreasedeffortstoobtainasubstanceofabuseoritsassociatedcuesasaresultofaddictionandabstinence.Cravingoftenhasreferencetoextrememotivation,whichcanbemeasuredusingoperantconditioning.Ifabstinencemakestheanimalsignificantlyincreaseitsleverpressing,onecantakethisasasignofenhancedmotivation.

Sensitization

Inadditiontotheabovediagnosticcriteria,behavioralsensitizationisthoughttounderliesomeaspectsofdrugdependence(VanderschurenandKalivas,2000).Behavioralsensitizationistypicallymeasuredasincreasedlocomotioninresponsetorepeatedadministrationsofadrug.Forexample,afterrepeateddosesofamphetaminefollowedbyabstinence,achallengedose,whichhaslittleornoeffectinnaveanimals,causesmarkedhyperactivity(AntelmanandCaggiula,1996,Glicketal.,1986).Animalssensitizedtoonesubstanceoftenshowcrosssensitization,whichisdefinedasanincreasedlocomotorresponsetoadifferentdrugorsubstance.Crosssensitizationcanalsobemanifestinconsummatorybehavior(Piazzaetal.,1989).Animalssensitizedtoonedrugmayshowincreasedintakeofadifferentdrug.Inotherwords,onedrugactsasagatewaytoanother.Forexample,animalssensitizedtoamphetamineshowacceleratedescalationofcocaineintake(FerrarioandRobinson,2007),andanimalssensitizedtonicotineconsumemorealcoholcomparedwithnonsensitizedanimals(Blomqvistetal.,1996).Thisbehavioristhoughttooccurwhendifferentdrugsactivatethesameneuralcircuitry,anditisthereasonwhymanycliniciansrequirecompletedrugabstentionasaconditionoftreatmentforaddicts(Wise,1988).

Thefirstquestionaddressedbythisreviewiswhetheranyoftheseoperationallydefinedbehavioralcharacteristicsofsubstancedependencecanbefoundwithintermittentsugaraccess.Thesecondquestionexploresneuralsystemstodiscoverhowsugarcouldhaveeffectslikeadrugofabuse.

3.DRUGSOFABUSEANDPALATABLEFOODACTIVATEACOMMONSUBSETOFNEURALSYSTEMS

Overlapsinthebraincircuitryactivatedbyfoodanddrugintakesuggeststhatdifferenttypesofreinforcers(naturalandartificial)stimulatesomeofthesameneuralsystems(Hoebel,1985,HernandezandHoebel,1988,Kelleyetal.,2002,LeMagnen,1990,VolkowandWise,2005,Wise,1988,1989).Thereareseveralregionsinthebraininvolvedinthereinforcementofbothfeedinganddrugintake(HernandezandHoebel,1988,KalivasandVolkow,2005,Kelleyetal.,2005,KoobandLeMoal,2005,MogensonandYang,1991,Wise,1997,Yeomans,1995),andmanyneurotransmitters,aswellashormones,havebeenstudiedintheseandrelatedbrainregions(Harrisetal.,2005,Kalivas,2004,LeibowitzandHoebel,2004,Schoffelmeeretal.,2001,SteinandBelluzzi,1979).ThisreviewwillfocusonDA,theopioids,andAChintheNAcshell,whichsofar,aretheneurotransmittersthatwehavefoundtobeinvolvedwiththereinforcingeffectsofintermittentsugarintake.

3.A.Dopamine

ItiswellestablishedthataddictivedrugsactivateDAcontainingneuronsinareasofthebrainthatprocessbehaviorreinforcement.Thiswasshownfordrugsdeliveredsystemically(DiChiaraandImperato,1988,Radhakishunet



al.,1983),andfordrugsmicroinjectedorinfusedlocally(HernandezandHoebel,1988,Mifsudetal.,1989).ThemesolimbicDAprojectionfromtheventraltegmentalarea(VTA)totheNAcisfrequentlyimplicatedinreinforcementfunctions(WiseandBozarth,1984).TheNAcisimportantforseveralcomponentsofrewardincludingfoodseekingandreinforcementoflearning,incentivemotivation,stimulussalienceandsignalingastimuluschange(BassareoandDiChiara,1999,BerridgeandRobinson,1998,Salamone,1992,Schultzetal.,1997,Wise,1988).AnyneurotransmitterthatdirectlyorindirectlystimulatesDAcellbodiesintheVTAreinforceslocalselfadministration,includingopioidssuchasenkephalin(Glimcheretal.,1984),nonopioidpeptidessuchasneurotensin(Glimcheretal.,1987)andmanydrugsofabuse(BozarthandWise,1981,Gessaetal.,1985,McBrideetal.,1999).SomeaddictivedrugsalsoactatDAterminals(Cheeretal.,2004,Mifsudetal.,1989,Niselletal.,1994,Westerinketal.,1987,Yoshimotoetal.,1992).Thus,anysubstancethatrepeatedlycausesthereleaseofDAorreducesDAreuptakeatterminalsviathesecircuitsmaybeacandidateforabuse.

AvarietyoffoodscanreleaseDAintheNAc,includinglabchow,sugar,saccharin,andcornoil(BassareoandDiChiara,1997,Hajnaletal.,2004,Liangetal.,2006,Marketal.,1991,Radaetal.,2005b).TheriseinextracellularDAcanoutlastthemealinfooddeprivedrats(HernandezandHoebel,1988).However,insatiatedanimals,thisDAreleaseappearstobecontingentonnoveltysinceitwaneswithrepeatedaccess,evenwhenthefoodispalatable(BassareoandDiChiara,1997,Radaetal.,2005b).Anexception,whichisdescribedbelow(Section5.C.),iswhenanimalsarefooddeprivedandfedsugarintermittently.

ExtracellularDAdecreasesinreactiontodrugwithdrawal(Acquasetal.,1991,AcquasandDiChiara,1992,Radaetal.,2004,Rossettietal.,1992).Thesymptomsofwithdrawalfromdopaminergicdrugsarelesswelldefinedthanthoseobservedduringwithdrawalfromopiates.Therefore,itmaybeeasiertodiscernthesignsofwithdrawalwhenusingfoodsthatreleasebothDAandopioids.Sugarisonesuchfood.

3.B.Opioids

OpioidpeptidesareheavilyexpressedthroughoutthelimbicsystemandlinkedtoDAsystemsinmanypartsoftheforebrain(HaberandLu,1995,LevineandBillington,2004,MillerandPickel,1980).TheendogenousopioidsystemsexertsomeoftheireffectsonreinforcementprocessingbyinteractingwithDAsystems(BozarthandWise,1986,DiChiaraandImperato,1986,LeibowitzandHoebel,2004).TheopioidpeptideenkephalinintheNAchasbeenrelatedtoreward(BalsKubiketal.,1989,BozarthandWise,1981,Olds,1982,Spanageletal.,1990)andcanactivatebothmuanddeltareceptorstoincreasethereleaseofDA(Spanageletal.,1990).MorphinealtersgeneexpressionofendogenousopioidpeptideswhileincreasingopioidpeptideproductionintheNAc(Przewlockaetal.,1996,Spangleretal.,2003,Turchanetal.,1997).OpioidsarealsoimportantcomponentsofthissystemascotransmitterswithGABAinsomeaccumbensanddorsalstriataloutputs(Kelleyetal.,2005).

Repeateduseofopiates,orevensomenonopiatedrugs,canresultinmuopioidreceptorsensitizationinseveralregions,includingtheNAc(Koobetal.,1992,Unterwald,2001).AmureceptorantagonistinjectedintotheNAcwillattenuatetherewardingeffectsofheroin(Vaccarinoetal.,1985),andsystemicallysuchdrugshavebeenusedasatreatmentforalcoholismandheroindependence(Deasetal.,2005,Fosteretal.,2003,Martin,1975,OBrien,2005,Volpicellietal.,1992).

Ingestionofpalatablefoodshaseffectsviaendogenousopioidsinavarietyofsites(Dumetal.,1983,MercerandHolder,1997,TandaandDiChiara,1998),andtheinjectionofmuopioidagonistsintheNAcincreasesintakeofpalatablefoodsrichinfatorsugar(Zhangetal.,1998,ZhangandKelley,2002).Opioidantagonists,ontheotherhand,decreaseingestionofsweetfoodandshortenmealsofpalatable,preferredfoods,evenatdosesthathavenoeffectonstandardchowintake(Glassetal.,1999).Thisopioidpalatabilitylinkisfurthercharacterizedbytheoriesinwhichthereinforcingeffectisdissociatedintoadopaminergicsystemforincentivemotivationandanopioidlikingorpleasuresystemforhedonicresponses(Berridge,1996,RobinsonandBerridge,1993,Stein,1978).EvidencethatopioidsintheNAcinfluencehedonicreactionscomesfromdatashowingthatmorphineenhancesratspositivefacialtastereactivityforasweetsolutioninthemouth(PecinaandBerridge,1995).Thedissociationbetweenthewantingandlikingsystemsisalsosuggestedbystudiesinhumans(Finlaysonetal.,2007).

3.C.Acetylcholine

Severalcholinergicsystemsinthebrainhavebeenimplicatedinbothfoodanddrugintake,andrelatedtoDAand



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theopioids(Kelleyetal.,2005,Radaetal.,2000,Yeomans,1995).FocusingonAChinterneuronsintheNAc,systemicadministrationofmorphinedecreasesAChturnover(Smithetal.,1984),afindingthatwasconfirmedbyinvivomicrodialysisinfreelybehavingrats(Fiserovaetal.,1999,Radaetal.,1991a,1996).CholinergicinterneuronsintheNAcmayselectivelymodulateenkephalingeneexpressionandpeptiderelease(Kelleyetal.,2005).Duringmorphinewithdrawal,extracellularAChincreasesintheNAcwhileDAislow,suggestingthatthisneurochemicalstatecouldbeinvolvedintheaversiveaspectsofwithdrawal(Pothosetal.,1991,Radaetal.,1991b,1996).Likewise,bothnicotineandalcoholwithdrawalincreaseextracellularACh,whiledecreasingDAintheNAc(DeWitteetal.,2003,Radaetal.,2001,2004).Thiswithdrawalstatemayinvolvebehavioraldepression,becauseM1receptoragonistsinjectedintheNAccancausedepressionintheforcedswimtest(Chauetal.,1999).TheroleofAChindrugwithdrawalhasbeenfurtherdemonstratedwithsystemicallyadministeredacetylcholinesteraseinhibitors,whichcanprecipitatewithdrawalsignsinnondependentanimals(KatzandValentino,1984,Turskietal.,1984).

AChintheNAchasalsobeenimplicatedinfoodintake.WetheorizethatitsoverallmuscariniceffectistoinhibitfeedingatM1receptorssincelocalinjectionofthemixedmuscarinicagonistarecholinewillinhibitfeeding,andthiseffectcanbeblockedbytherelativelyspecificM1antagonistpirenzapine(RadaandHoebel,unpublished).FeedingtosatietyincreasesextracellularAChintheNAc(Avenaetal.,2006,Marketal.,1992).AconditionedtasteaversionalsoincreasesAChintheNAcandsimultaneouslylowersDA(Marketal.,1991,1995).Dfenfluraminecombinedwithphentermine(FenPhen)increasesextracellularAChintheNAcatadosethatinhibitsbotheatingandcocaineselfadministration(Glowaetal.,1997,RadaandHoebel,2000).RatswithaccumbalAChtoxininducedlesionsarehyperphagicrelativetononlesionedrats(Hajnaletal.,2000).

DA/AChbalanceiscontrolledinpartbyhypothalamicsystemsforfeedingandsatiety.Norepinephrineandgalanin,whichinduceeatingwheninjectedintheparaventricularnucleus(PVN),loweraccumbensACh(Hajnaletal.,1997,Radaetal.,1998).AnexceptionisneuropeptideY,whichfosterseatingwheninjectedintothePVN,butdoesnotincreaseDAreleasenorlowerACh(Radaetal.,1998).Inaccordwiththetheory,thesatietyproducingcombinationofserotoninplusCCKinjectionintothePVNincreasesaccumbensACh(Helmetal.,2003).

ItisveryinterestingthatwhenDAislowandextracellularAChishigh,thisapparentlycreatesnotsatiety,butinsteadanaversivestate(Hoebeletal.,1999),asduringbehavioraldepression(Zangenetal.,2001,Radaetal.,2006),drugwithdrawal(Radaetal.,1991b,1996,2001,2004)andconditionedtasteaversion(Marketal.,1995).WeconcludethatwhenAChactsasapostsynapticM1agonistithaseffectsoppositetoDA,andthusmayactasabrakeondopaminergicfunctions(Hoebeletal.,1999,Radaetal.,2007)causingsatietywhenDAishighandbehavioraldepressionwhenDAisrelativelylow.

4.BEHAVIORALSIMILARITIESBETWEENDRUGSELFADMINISTRATIONANDINTERMITTENT,EXCESSIVESUGARINTAKE

Theconceptofsugaraddictionhasbeenbandiedaboutformanyyears.Clinicalaccountsofsugaraddictionhavebeenthetopicofmanybestsellingbooksandthefocusforpopulardietprograms(Appleton,1996,DesMaisons,2001,Katherine,1996,Rufus,2004).Intheseaccounts,peopledescribesymptomsofwithdrawalwhentheydeprivethemselvesofsugarrichfoods.Theyalsodescribefoodcraving,particularlyforcarbohydrates,chocolate,andsugar,whichcantriggerrelapseandimpulsiveeating.Thisleadstoaviciouscycleofselfmedicationwithsweetfoodsthatmayresultinobesityoraneatingdisorder.

Althoughfoodaddictionhasbeenpopularinthemediaandproposedtobebasedonbrainneurochemistry(Hoebeletal.,1989,LeMagnen,1990),thisphenomenonhasonlyrecentlybeensystematicallystudiedinthelaboratory.

AsoutlinedintheoverviewinSection1,weuseafeedingschedulethatinducesratstobingeonasugarsolution,thenapplythecriteriafordrugdependencethatarepresentedinSection2andtestforthebehavioralandneurochemicalcommonaltiesgiveninSection3.Ratsaregiven12hdailyaccesstoanaqueous10%sucrosesolution(25%glucoseinsomeexperiments)andlabchow,followedby12hofdeprivationforthreeormoreweeks(i.e.,DailyIntermittentSugarandChow).TheseratsarecomparedwithcontrolgroupssuchasAdlibitumSugarandChow,AdlibitumChow,orDailyIntermittentChow(12hdeprivationfollowedby12haccesstolabchow).Fortheintermittentaccessgroups,availabilityisdelayed4hintotheanimalsactiveperiodinorderto



stimulatefeeding,whichnormallyensuesattheonsetofthedarkcycle.RatsmaintainedontheDailyIntermittentSugarandChowregimenenterastatethatresemblesdrugdependenceonseveraldimensions.Thesearedividedintobehavioral(Section4)andneurochemical(Section5)similaritiestodrugdependence.

4.A.Bingeing:Escalationofdailysugarintakeandlargemeals

Escalationofintakeisacharacteristicofdrugsofabuse.Thismaybeacombinationoftolerance,inwhichmoreofanabusedsubstanceisneededtoproducethesameeuphoriceffects(KoobandLeMoal,2005),andsensitization,suchaslocomotorsensitization,inwhichthesubstanceproducesenhancedbehavioralactivation(Vezinaetal.,1989).Studiesusingdrugselfadministrationusuallylimitaccesstoafewhoursperday,duringwhichanimalswillselfadministerinregularintervalsthatvaryasafunctionofthedosereceived(GerberandWise,1989)andinamannerthatkeepsextracellularDAelevatedaboveabaseline,ortriggerpointintheNAc(Ranaldietal.,1999,Wiseetal.,1995).Thelengthofdailyaccesshasbeenshowntocriticallyaffectsubsequentselfadministrationbehavior.Forexample,themostcocaineisselfadministeredduringthefirst10minofasessionwhenaccessisatleast6hperday(AhmedandKoob,1998).Limitedperiodsofaccess,tocreatebinges,havebeenuseful,becausethepatternofselfadministrationbehaviorthatemergesissimilartothatofacompulsivedruguser(Markouetal.,1993,MutschlerandMiczek,1998,OBrienetal.,1998).Evenwhendrugs,suchascocaine,aregivenwithunlimitedaccess,humansorlaboratoryanimalswillselfadministertheminrepetitiveepisodesorbinges(BozarthandWise,1985,Deneauetal.,1969).However,experimenterimposedintermittentaccessisbetterthanadlibitumaccessforexperimentalpurposes,sinceitbecomesverylikelythattheanimalwilltakeatleastonelargebingeattheonsetofthedrugavailabilityperiod.Moreover,aperiodoffoodrestrictioncanenhancedrugintake(Carr,2006,Carroll,1985)andhasbeenshowntoproducecompensatoryneruoadaptationsinthemesoaccumbensDAsystem(Panetal.,2006).

Thebehavioralfindingswithsugararesimilartothoseobservedwithdrugsofabuse.Ratsfeddailyintermittentsugarandchowescalatetheirsugarintakeandincreasetheirintakeduringthefirsthourofdailyaccess,whichwedefineasabinge(Colantuonietal.,2001).Theanimalswithadlibitumaccesstoasugarsolutiontendtodrinkitthroughouttheday,includingtheirinactiveperiod.Bothgroupsincreasetheiroverallintake,butthelimitedaccessanimalsconsumeasmuchsugarin12hasadlibitumfedanimalsdoin24h.Detailedmealpatternanalysisusingoperantconditioning(fixedratio1)revealsthatthelimitedanimalsconsumealargemealofsugarattheonsetofaccess,andlarger,fewermealsofsugarthroughouttheaccessperiod,comparedwithanimalsdrinkingsugaradlibitum(Fig.1AvenaandHoebel,unpublished).RatsfedDailyIntermittentSugarandChowregulatetheircaloricintakebydecreasingtheirchowintaketocompensatefortheextracaloriesobtainedfromsugar,whichresultsinanormalbodyweight(Avena,Bocarsly,Rada,KimandHoebel,unpublished,Avenaetal.,2003b,Colantuonietal.,2002).

Figure1Mealanalysisoftworepresentativeratslivinginoperantchambers.TheonemaintainedonDailyIntermittentSucroseandChow(blacklines)hadanincreasedintakeofsugarcomparedwithonegivenAdlibitumSucroseandChow(greylines).Hour0is4...

4.B.Withdrawal:Anxietyandbehavioraldepressioninducedbyanopioidantagonistorfooddeprivation

AsdescribedinSection2,animalscanshowsignsofopiatewithdrawalafterrepeatedexposurewhenthesubstanceofabuseisremoved,ortheappropriatesynapticreceptorisblocked.Forexample,anopioidantagonistcanbeusedtoprecipitatewithdrawalinthecaseofopiatedependency(Espejoetal.,1994,Koobetal.,1992).Inrats,opiatewithdrawalcausesseveresomaticsigns(Martinetal.,1963,Wayetal.,1969),decreasesinbodytemperature(Aryetal.,1976),aggression(KantakandMiczek,1986),andanxiety(Schulteisetal.,1998),aswellasamotivationalsyndromecharacterizedbydysphoriaanddepression(DeVriesandShippenberg,2002,KoobandLeMoal,1997).

Thesesignsofopioidwithdrawalhavebeennotedafterintermittentaccesstosugarwhenwithdrawalisprecipitatedwithanopioidantagonist,orwhenfoodandsugarareremoved.Whenadministeredarelativelyhighdoseofthe



opioidantagonistnaloxone(3mg/kg,s.c.),somaticsignsofwithdrawal,suchasteethchattering,forepawtremor,andheadshakesareobserved(Colantuonietal.,2002).Theseanimalsarealsoanxious,asmeasuredbyreducedtimespentontheexposedarmofanelevatedplusmaze(Colantuonietal.,2002)(Fig.2).

Figure2Timespentontheopenarmsofanelevatedplusmaze.Fourgroupsofratsweremaintainedontheirrespectivedietsforonemonthandthenreceivednaloxone(3mg/kg,s.c.).TheDailyIntermittentGlucoseandChowgroupspentlesstimeontheopenarms...

Behavioraldepressionhasalsobeenfoundduringnaloxoneprecipitatedwithdrawalinintermittentsugarfedrats.Inthisexperiment,ratsweregivenaninitial5minforcedswimtestinwhichescape(swimmingandclimbing)andpassive(floating)behaviorsweremeasured.ThentheratsweredividedintofourgroupsthatwerefedDailyIntermittentSucroseandChow,DailyIntermittentChow,AdlibitumSucroseandChow,orAdlibitumChowfor21days.Onday22,atthetimethattheintermittentfedratswouldnormallyreceivetheirsugarand/orchow,allratswereinsteadinjectedwithnaloxone(3mg/kg,s.c.)toprecipitatewithdrawalandwerethenplacedinthewateragainforanothertest.InthegroupthathadbeenfedDailyIntermittentSucroseandChow,escapebehaviorsweresignificantlysuppressedcomparedwithAdlibitumSucroseandChowandAdlibitumChowcontrols(Fig.3Kim,AvenaandHoebel,unpublished).Thisdecreaseinescapeeffortsthatwerereplacedbypassivefloatingsuggeststheratswereexperiencingbehavioraldepressionduringwithdrawal.

Figure3RatsthathavebeenmaintainedonDailyIntermittentSucroseandChowaremoreimmobilethancontrolgroupsinaforcedswimtestduringnaloxoneprecipitatedwithdrawal.*p



impactofsugarthatpersiststhroughouttwoweeksofabstinence,leadingtoenhancedintake.

Figure4After14daysofabstinencefromsugar,ratsthatpreviouslyhad12hdailyaccesssignificantlyincreasedleverpressingforglucoseto123%ofpreabstinenceresponding,indicatingincreasedmotivationforsugar.Thegroupwith0.5hdailyaccessdid...

Additionally,likethedrugsdescribedabove,themotivationtoobtainsugarappearstoincubate,orgrow,withthelengthofabstinence(Shalevetal.,2001).Usingoperantconditioning,Grimmandcolleagues(2005)findthatsucroseseeking(leverpressinginextinctionandthenforasucrosepairedcue)increasesduringabstinenceinratsafterintermittentsugaraccessfor10days.Remarkably,respondingforthecuewasgreaterafter30daysofsugarabstinencecomparedwith1weekor1day.Theseresultssuggestthegradualemergenceoflongtermchangesintheneuralcircuitryunderlyingmotivationasaresultofsugarselfadministrationandabstinence.

4.D.Crosssensitization:Increasedlocomotorresponsetopsychostimulantsduringsugarabstinence

Druginducedsensitizationmayplayaroleintheenhancementofdrugselfadministrationandisimplicatedasafactorcontributingtodrugaddiction(RobinsonandBerridge,1993).Inatypicalsensitizationexperiment,theanimalreceivesadrugdailyforaboutaweek,thentheprocedurestops.However,inthebraintherearelasting,evengrowing,changesapparentaweekormorelaterwhenalow,challengedoseofthedrugresultsinhyperlocomotion(Kalivasetal.,1992).Additionally,crosssensitizationfromonedrugtoanotherhasbeendemonstratedwithseveraldrugsofabuse,includingamphetaminesensitizingratstococaineorphencyclidine(GreenbergandSegal,1985,KalivasandWeber,1988,PierceandKalivas,1995,Schenketal.,1991),cocainecrosssensitizingwithalcohol(ItzhakandMartin,1999),andheroinwithcannabis(Pontierietal.,2001).Otherstudieshavefoundthiseffectwithnondrugsubstances.Behavioralcrosssensitizationbetweencocaineandstresshasbeendemonstrated(AntelmanandCaggiula,1977,CovingtonandMiczek,2001,Prasadetal.,1998).Also,increasesinfoodintake(BakshiandKelley,1994)orsexualbehaviors(FiorinoandPhillips,1999,NocjarandPanksepp,2002)havebeenobservedinanimalswithahistoryofdrugsensitization.

WeandothershavefoundthatIntermittentsugarintakecrosssensitizeswithdrugsofabuse.Ratssensitizedwithdailyamphetamineinjections(3mg/kg,i.p.)arehyperactiveoneweeklaterinresponsetotasting10%sucrose(AvenaandHoebel,2003a).Conversely,ratsfedDailyIntermittentSugarandChowshowlocomotorcrosssensitizationtoamphetamine.Specifically,suchanimalsarehyperactiveinresponsetoalow,challengedoseofamphetamine(0.5mg/kg,i.p.)thathasnoeffectonnaveanimals,evenafter8daysofabstinencefromsugar(Fig.5AvenaandHoebel,2003b).Ratsmaintainedonthisfeedingschedulebutadministeredsalinewerenothyperactive,norwereratsincontrolgroups(DailyIntermittentChow,AdlibitumSugarandChow,AdlibitumChow)giventhechallengedoseofamphetamine.Intermittentsucroseaccessalsocrosssensitizeswithcocaine(Gosnell,2005)andfacilitatesthedevelopmentofsensitizationtotheDAagonistquinpirole(Foleyetal.,2006).Thus,resultswiththreedifferentDAagonistsfromthreedifferentlaboratoriessupportthetheorythattheDAsystemissensitizedbyintermittentsugaraccess,asevidencedbycrosssensitization.Thisisimportantsinceenhancedmesolimbicdopaminergicneurotransmissionplaysamajorroleinthebehavioraleffectsofsensitizationaswellascrosssensitization(RobinsonandBerridge,1993),andmaycontributetoaddictionandcomorbiditywithpolysubstanceabuse.

Figure5Locomotoractivityinaphotocellcageplottedaspercentofbaselinebeambreaksonday0.Ratsweremaintainedfor21daysonthespecifieddietsregimens.RatsmaintainedonDailyIntermittentSucroseandChowwerehyperactiveninedayslaterinresponse...

4.E.Gatewayeffect:Increasedalcoholintakeduringsugarabstinence

Numerousstudieshavefoundthatsensitizationtoonedrugcanleadnotonlytohyperactivity,butalsotosubsequentincreasedintakeofanotherdrugorsubstance(Ellgrenetal.,2006,Henningfieldetal.,1990,Hubbellet



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al.,1993,Liguorietal.,1997,Nicholsetal.,1991,Piazzaetal.,1989,Vezina,2004,Vezinaetal.,2002,Volpicellietal.,1991).Werefertothisphenomenonasconsummatorycrosssensitization.Intheclinicalliterature,whenonedrugleadstotakinganother,thisisknownasagatewayeffect.Itisparticularlynoteworthywhenalegaldrug(e.g.nicotine)actsasagatewaytoanillegaldrug(e.g.cocaine)(Laietal.,2000).

Ratsmaintainedonintermittentsugaraccessandthenforcedtoabstain,subsequentlyshowenhancedintakeof9%alcohol(Avenaetal.,2004).Thissuggeststhatintermittentaccesstosugarcanbeagatewaytoalcoholuse.Othershaveshownthatanimalsthatprefersweettastewillselfadministercocaineatahigherrate(Carrolletal.,2006).Aswiththelocomotorcrosssensitizationdescribedabove,underlyingthisbehaviorarepresumablyneurochemicalalterationsinthebrain,suchasadaptationsinDAandperhapsopioidfunctions.

5.NEUROCHEMICALSIMILARITIESBETWEENDRUGSELFADMINISTRATIONANDINTERMITTENTSUGARINTAKE

Thestudiesdescribedabovesuggestthatintermittentsugaraccesscanproducenumerousbehaviorsthataresimilartothoseobservedindrugdependentrats.Inthissection,wedescribeneurochemicalfindingsthatmayunderliesugardependency.Totheextentthatthesebrainalterationsmatchtheeffectsofdrugsofabuse,itstrengthensthecasethatsugarcanresembleasubstanceofabuse.

5.A.IntermittentsugarintakealtersD ,D andmuopioidreceptorbindingandmRNAexpression

DrugsofabusecanalterDAandopioidreceptorsinthemesolimbicregionsofthebrain.PharmacologicalstudieswithselectiveD ,D andD receptorantagonistsandgeneknockoutstudieshaverevealedthatallthreereceptorsubtypesmediatethereinforcingeffectsdrugsofabuse.ThereisanupregulationofD receptors(Unterwaldetal.,1994)andincreaseinD receptorbinding(Alburgesetal.,1993,Unterwaldetal.,2001)inresponsetococaine.Conversely,D receptordensityislowerinNAcofmonkeysthathaveahistoryofcocaineuse(Mooreetal.,1998).DrugsofabusecanalsoproducechangesingeneexpressionofDAreceptors.MorphineandcocainehavebeenshowntodecreaseaccumbensD receptormRNA(Georgesetal.,1999,Turchanetal.,1997),andanincreaseinD receptormRNA(Spangleretal.,2003).Thesefindingwithlaboratoryanimalssupportclinicalstudies,whichhaverevealedthatD receptorsaredownregulatedincocaineaddicts(Volkowetal.,1996a,1996b,2006).

Similarchangeshavebeenreportedwithintermittentaccesstosugar.AutoradiographyrevealsincreasedD intheNAcanddecreasedD receptorbindinginthestriatum(Fig.6Colantuonietal.,2001).Thiswasrelativetochowfedrats,soitisnotknownwhetheradlibitumsugarwouldalsoshowthiseffect.OthershavereportedadecreaseinD receptorbindingintheNAcofratswithrestrictedaccesstosucroseandchowcomparedwithratsfedrestricedchowonly(Belloetal.,2002).RatswithintermittentsugarandchowaccessalsohavedecreasesinDreceptormRNAintheNAccomparedwithadlibitumchowcontrols(Spangleretal.,2004).mRNAlevelsofDreceptormRNAintheNAcareincreasedintheNAcandcaudateputamen.

Figure6IntermittentsugaraccessaltersDAreceptorbindingatthelevelofthestriatum.D receptorbinding(toppanel)increasesintheNAccoreandshellofanimalsexposedtoDailyIntermittentGlucoseandChow(blackbars)for30dayscomparedwithcontrol...

Regardingtheopioidreceptors,mureceptorbindingisincreasedinresponsetococaineandmorphine(Baileyetal.,2005,Unterwaldetal.,2001,Viganoetal.,2003).Muopioidreceptorbindingisalsosignificantlyenhancedafterthreeweeksontheintermittentsugardiet,comparedwithadlibitumchow.Thiseffectwasobservedintheaccumbensshell,cingulate,hippocampusandlocuscoeruleus(Colantuonietal.,2001).

5.B.IntermittentsugarintakealtersenkephalinmRNAexpression

EnkephalinmRNAinthestriatumandtheNAcisdecreasedinresponsetorepeatedinjectionsofmorphine(Georgesetal.,1999,Turchanetal.,1997,Uhletal.,1988).Thesechangeswithinopioidsystemsaresimilartothoseobservedincocainedependenthumansubjects(Zubietaetal.,1996).

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RatswithintermittentsugaraccessalsodisplayasignificantdecreaseinenkephalinmRNA,althoughitisdifficulttojudgeitsfunctionalsignificance(Spangleretal.,2004).ThisdecreaseinenkephalinmRNAisconsistentwithfindingsobservedinratswithlimiteddailyaccesstoasweetfat,liquiddiet(Kelleyetal.,2003).AssumingthisdecreaseinmRNAresultsinlessenkephalinpeptidebeingsynthesizedandreleased,itcouldaccountforacompensatoryincreaseinmuopioidreceptors,ascitedabove.

5.C.Dailyintermittentsugarintakerepeatedlyreleasesdopamineintheaccumbens

OneofthestrongestneurochemicalcommonalitiesbetweenintermittentsugaraccessanddrugsofabusehasbeenfoundusinginvivomicrodialysistomeasureextracellularDA.TherepeatedincreaseinextracellularDAisahallmarkofdrugsthatareabused.ExtracellularDAincreasesintheNAcinresponsetobothaddictivedrugs(DeVriesandShippenberg,2002,DiChiaraandImperato,1988,EverittandWolf,2002,HernandezandHoebel,1988,Hurdetal.,1988,PicciottoandCorrigall,2002,Pothosetal.,1991,Radaetal.,1991a)anddrugassociatedstimuli(Itoetal.,2000).Unlikedrugsofabuse,whichexerttheireffectsonDAreleaseeachtimetheyareadministered(Pothosetal.,1991,Wiseetal.,1995),theeffectofeatingpalatablefoodonDAreleasewaneswithrepeatedaccesswhenthefoodisnolongernovel,unlesstheanimalisfooddeprived(BassareoandDiChiara,1999,DiChiaraandTanda,1997,Radaetal.,2005b).ThusnormallyfeedingisverydifferentthantakingdrugsbecausetheDAresponseduringfeedingisphasedout.

However,andthisisveryimportant,ratsfeddailyintermittentsugarandchowapparentlyreleaseDAeverydayasmeasuredondays1,2and21ofaccess(Fig.7Radaetal.,2005b).Ascontrols,ratsfedsugarorchowadlibitum,ratswithintermittentaccesstojustchow,orratsthattastesugaronlytwotimes,developabluntedDAresponseasistypicalofafoodthatloosesitnovelty.TheseresultsaresupportedbyfindingsofalterationsinaccumbensDAturnoverandDAtransporterinratsmaintainedonanintermittentsugarfeedingschedule(Belloetal.,2003,HajnalandNorgren,2002).Together,theseresultssuggestthatintermittentaccesstosugarandchowcausesrecurrentincreasesinextracellularDAinamannerthatismorelikeadrugofabusethanafood.

Figure7RatswithintermittentaccesstosugarreleaseDAinresponsetodrinkingsucrosefor60minonday21.Dopamine,asmeasuredbyinvivomicrodialysis,increasesfortheDailyIntermittentSucroseandChowrats(opencircles)ondays1,2and21incontrast,...

Aninterestingquestioniswhethertheneurochemicaleffectsobservedwithintermittentsugaraccessareduetoitspostingestivepropertiesorwhetherthetasteofsugarcanbesufficient.Toinvestigateorosensoryeffectsofsugar,weusedtheshamfeedingpreparation.Ratsthatareshamfeedingwithanopengastricfistulacaningestfoodsbutnotfullydigestthem(Smith,1998).Shamfeedingdoesnotcompletelyeliminatepostingestiveeffects(BerthoudandJeanrenaud,1982,SclafaniandNissenbaum,1985),howeveritdoesallowtheanimalstotastethesugarwhileretainingalmostnocalories.

TheresultsofshamfeedingsugarforthefirsthourofaccesseachdayshowthatDAisreleasedintheNAc,evenafterthreeweeksofdailybingeing,simplyduetothetasteofsucrose(Avenaetal.,2006).ShamfeedingdoesnotfurtherenhancethetypicalsugarinducedDArelease.ThissupportsotherworkshowingthattheamountofDAreleaseintheNAcisproportionaltothesucroseconcentration,notthevolumeconsumed(Hajnaletal.,2004).

5.D.Accumbensacetylcholinereleaseisdelayedduringsugarbingesandeliminatedduringshamfeeding

ShamfeedingrevealedinterestingresultswithACh.AsdescribedinSection3.C.,accumbensAChincreasesinthemidstofamealwhenfeedingslowsdownandthenstops(Marketal.,1992).Onecouldpredictthatwhenananimaltakesaverylargemeal,aswiththefirstmealofasugarsolutionandchow,thereleaseofAChshouldbedelayeduntilthesatiationprocessbeginsasreflectedingradualterminationofthemeal.ThisiswhatwasobservedAChreleaseoccurredwhenthisinitialbingemealwasdrawingtoaclose(Radaetal.,2005b).

NextwemeasuredAChreleasewhentheanimalcouldtakealargemealofsugarwhileshamfeeding.PurgingthestomachcontentsdrasticallyreducedthereleaseofACh(Avenaetal.,2006).Thisispredictablebasedonthe



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theorythatAChisnormallyimportantforthesatiationprocess(Hoebeletal.,1999,Marketal.,1992).Italsosuggeststhatbypurging,oneeliminatestheAChresponsethatopposesDA.Thuswhenbingeingonsugarisaccompaniedbypurging,thebehaviorisreinforcedbyDAwithoutACh,whichismoreliketakingadrugandlesslikenormaleating.

5.E.Sugarwithdrawalupsetsdopamine/acetylcholinebalanceintheaccumbens

BehavioralsignsofdrugwithdrawalareusuallyaccompaniedbyalterationsinDA/AChbalanceintheNAc.Duringwithdrawal,DAdecreaseswhileAChisincreased.Thisimbalancehasbeenshownduringchemicallyinducedwithdrawalwithseveraldrugsofabuse,includingmorphine,nicotineandalcohol(Radaetal.,1996,2001,2004).Mereabstinencefromanabusedsubstanceisalsosufficienttoelicitneurochemicalsignsofwithdrawal.Forexample,ratsthatareforcedtoabstainfrommorphineoralcoholhavedecreasedextracellularDAintheNAc(AcquasandDiChiara,1992,Rossettietal.,1992)andAChincreasesduringspontaneousmorphinewithdrawal(Fiserovaetal.,1999).Whilewithdrawalfromananxyoliticdrug(diazepam)precipitatedbyabendodiazepinereceptorantagonistdoesnotlowerextracellularDA,itdoesreleaseaccumbensACh,whichmaycontributetobenzodiazepinedependency(RadaandHoebel,2005)

RatsthathaveintermittentaccesstosugarandchowshowthemorphinelikeneurochemicalimbalanceinDA/AChduringwithdrawal.Thiswasproducedtwoways.AsshowninFig.8,whentheyaregivennaloxonetoprecipitateopioidwithdrawal,thereisadecreaseinaccumbensDAreleasecoupledwithanincreaseinAChrelease(Colantuonietal.,2002).Thesamethingoccursafter36hoffooddeprivation(Avena,Bocarsly,Rada,Kim,Hoebel,unpublished).Onewaytointerpretdeprivationinducedwithdrawalistosuggestthatwithoutfoodtoreleaseopioids,theanimalsuffersthesametypeofwithdrawalseenwhentheupregulatedmuopioidreceptorsareblockedwithnaloxone.

Figure8ExtracellularDA(uppergraph)decreasedto81%ofbaselineafternaloxoneinjection(3mg/kg,s.c.)inratswithahistoryofDailyIntermittentSucroseandChow.Acetylcholine(lowergraph)increasedto157%inthesameintermittentsugaraccessrats....

6.DISCUSSIONANDCLINICALIMPLICATIONS

Foodisnotordinarilylikeasubstanceofabuse,butintermittentbingeinganddeprivationchangesthat.Basedontheobservedbehavioralandneurochemicalsimilaritiesbetweentheeffectsofintermittentsugaraccessanddrugsofabuse,wesuggestthatsugar,ascommonasitis,nonethelessmeetsthecriteriaforasubstanceofabuseandmaybeaddictiveforsomeindividualswhenconsumedinabingelikemanner.Thisconclusionisreinforcedbythechangesinlimbicsystemneurochemistrythataresimilarforthedrugsandforsugar.Theeffectsweobservearesmallerinmagnitudethanthoseproducedbydrugofabusesuchascocaineormorphinehowever,thefactthatthesebehaviorsandneurochemicalchangescanbeelicitedwithanaturalreinforcerisinteresting.ItisnotclearfromthisanimalmodelifintermittentsugaraccesscanresultinneglectofsocialactivitiesasrequiredbythedefinitionofdependencyintheDSMIVTR(AmericanPsychiatricAssociation,2000).Norisitknownwhetherratswillcontinuetoselfadministersugardespitephysicalobstacles,suchasenduringpaintoobtainsugar,assomeratsdoforcocaine(DerocheGamonetetal.,2004).Nonetheless,theextensiveseriesofexperimentsrevealingsimilaritiesbetweensugarinducedanddruginducedbehaviorandneurochemistry,aschronicledinSections4and5,lendscredencetotheconceptofsugaraddiction,givesprecisiontoitsdefinition,andprovidesatestablemodel.

6.A.Bulimianervosa

ThefeedingregimenofDailyIntermittentSugarandChowsharessomeaspectsofthebehavioralpatternofpeoplediagnosedwithbingeeatingdisorderorbulimia.Bulimicsoftenrestrictintakeearlyinthedayandthenbingelaterintheevening,usuallyonpalatablefoods(Drewnowskietal.,1992,Gendalletal.,1997).Thesepatientslater



Sugarandobesity

purgethefood,eitherbyvomitingorlaxativeuse,orinsomecasesbystrenuousexercise(AmericanPsychiatricAssociation,2000).Bulimicpatientshavelowendorphinlevels(Brewertonetal.,1992,Walleretal.,1986),whichmightfostereatingwithapreferenceorcravingforsweets.Theyalsohavedecreasedmuopioidreceptorbindingintheinsulacomparedwithcontrols,whichcorrelateswithrecentfastingbehavior(Bencherifetal.,2005).Thiscontrastswiththeincreaseobservedinratsfollowingabinge.Cyclicbingeingandfooddeprivationmayproducealterationsinmuopioidreceptors,whichhelpperpetuatebingeingbehavior.

Weusedtheshamfeedingpreparationtomimicthepurgingassociatedwithbulimia.ThefindingdescribedinSection5.C.,thatintermittentsugaraccessrepeatedlyreleasesDAinresponsetothetasteofsugar,maybeimportantforunderstandingthebingeingbehaviorsassociatedwithbulimia.DAhasbeenimplicatedinbulimiabycomparingittohypothalamicselfstimulation,whichalsoreleasesDAwithoutcalories(Hoebeletal.,1992).BulimicpatientshavelowcentralDAactivityasreflectedinanalysisofDAmetabolitesinthespinalfluid,whichalsoindicatesaroleforDAintheirabnormalresponsestofood(Jimersonetal.,1992).

Theoverallsimilarlitesinbehaviorandbrainadaptationswithsugarbingeinganddrugintakedescribedabovesupportthetheorythatobesityandeatingdisorders,suchasbulimiaandanorexia,mayhavepropertiesofanaddictioninsomeindividuals(DavisandClaridge,1998,GillmanandLichtigfeld,1986,MarrazziandLuby,1986,MercerandHolder,1997,Rivaetal.,2006).Theautoaddictiontheoryproposedthatsomeeatingdisorderscanbeanaddictiontoendogenousopioids(Heubner,1993,MarrazziandLuby,1986,1990).Insupport,appetitedysfunctionsintheformofbingeeatingandselfstarvationcanstimulateendogenousopioidactivity(Aravichetal.,1993).

Bulimicpatientswillbingeonexcessiveamountsofnoncaloricsweeteners(Kleinetal.,2006),suggestingthattheyderivebenefitsfromsweetorosensorystimulation.WehaveshownthatpurgingleavesDAunopposedbysatietyassociatedAChintheaccumbens(Section5.D.).Thisneurochemicalstatemaybeconducivetoexaggeratedbingeeating.Moreover,thefindingsthatintermittentsugarintakecrosssensitizeswithamphetamineandfostersalcoholintake(Sections4.D.and4.E.)mayberelatedtothecomorbiditybetweenbulimiaandsubstanceabuse(Holdernessetal.,1994).

6.B.Obesity

ObesityisoneoftheleadingpreventablecausesofdeathintheUS(Mokdadetal.,2004).Severalstudieshavecorrelatedtheriseintheincidenceofobesitywithanincreaseinsugarconsumption(Brayetal.,1992,Elliottetal.,2002,HowardandWylieRosett,2002,Ludwigetal.,2001).TheUSDepartmentofAgriculturehasreportedthatpercapitasoftdrinkconsumptionhasincreasedbyalmost500%inthepast50years(PutnamandAllhouse,1999).Sugarintakemayleadtoanincreasednumberofand/oraffinityforopioidreceptors,whichinturnleadstofurtheringestionofsugarandmaycontributetoobesity(Fullertonetal.,1985).Indeed,ratsmaintainedonthedietofintermittentsugaraccessshowopioidreceptorchanges(Section5.A.)however,afteronemonthonthedietusing10%sucroseor25%glucose,theseanimalsdonotbecomeoverweight(Colantuonietal.,2001,AvenaandHoebel,2003b),althoughothershavereportedametabolicsyndrome(Toidaetal.,1996),alossoffuelefficiency(Levineetal.,2003)andanincreaseinbodyweightinratsfedsucrose(Bocketal.,1995,Kawasakietal.,2005)andglucose(Widemanetal.,2005).Moststudiesofsugarintakeandbodyweightdonotuseabingeinducingdiet,andthetranslationtohumanobesityiscomplex(Levineetal.,2003).AsdescribedinSection4.A.,itappearsthatratsinourmodelcompensateforsucroseorglucosecaloriesbydecreasingchowintake(Avena,Bocarsly,Rada,KimandHoebel,unpublished).Theygainweightatanormalrate(Colantuonietal.,2002).Thismaynotbetrueofallsugars.

Fructoseisauniquesweetenerthathasdifferentmetaboliceffectsonthebodythanglucoseorsucrose.Fructoseisabsorbedfurtherdowntheintestine,andwhereascirculatingglucosereleasesinsulinfromthepancreas(Satoetal.,1996,Vilsbolletal.,2003),fructosestimulatesinsulinsynthesisbutdoesnotreleaseit(Curry,1989,LeandTappy,2006,Satoetal.,1996).Insulinmodifiesfoodintakebyinhibitingeating(Schwartzetal.,2000)andbyincreasingleptinrelease(Saadetal.,1998),whichalsocaninhibitfoodintake.Mealsofhighfructosecornsyrupcanreducecirculatinginsulinandleptinlevels(Teffetal.,2004),contributingtoincreasedbodyweight.Thus,fructoseintakemightnotresultinthedegreeofsatietythatwouldnormallyensuewithanequallycaloricmealofglucoseorsucrose.SincehighfructosecornsyruphasbecomeamajorconstituentintheAmericandiet(Brayetal.,2004)and



Fatandobesity

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lackssomeeffectsoninsulinandleptin,itmaybeapotentialagentforproducingobesitywhengivenintermittentlytorats.Whetherornotsignsofdependencyonfructoseareapparentwhenitisofferedintermittentlyhasyettobedetermined.However,basedonourresultsshowingthatsweettasteissufficienttoelicittherepeatedreleaseofDAintheNAc(seeSection5.C.),wehypothesizethatanysweettasteconsumedinabingelikemannerisacandidateforproducingsignsofdependence.

Whilewehavechosentofocusonsugar,thequestionarisesastowhethernonsweet,palatablefoodscouldproducesignsordependence.Theevidenceismixed.Itappearsthatsomesignsofdependenceareapparentwithfat,whileothershavenotbeenshown.Fatbingeinginratsoccurswithintermittentaccesstopurefat(vegetableshortening),sweetfatcookies(Boggianoetal.,2005,Corwin,2006),orsweetfatchow(Berner,AvenaandHoebel,unpublished).Repeated,intermittentaccesstooilreleasesDAintheNAc(Liangetal.,2006).Likesugar,bingeingonafatrichdietisknowntoaffecttheopioidsystemintheaccumbensbydecreasingenkephalinmRNA,aneffectthatisnotobservedwithacuteaccess(Kelleyetal.,2003).Also,treatmentwithbaclofen(GABABagonist),whichreducesdrugintake,alsoreducesbingeeatingoffat(BudaLevinetal.,2005).

Thisallimpliesthatfatdependencyisarealpossibility,butwithdrawalfromfatbingeingisnotasapparentasitiswithsugar.LeMagnen(1990)notednaloxonecouldprecipitatewithdrawalinratsonacafeteriastylediet,whichcontainsavarietyoffatandsugarrichfoods(e.g.,cheese,cookies,chocolatechips).However,wehavenotobservedsignsofnaloxoneprecipitatedorspontaneouswithdrawalinratsfedpurefat(vegetableshortening)orasugarfatcombination,norhassucharesultbeenpublishedbyothers.Furtherstudiesareneededtofullyunderstandthedifferencesbetweensugarandfatbingeingandtheirsubsequenteffectsonbehavior.Justasdifferentclassesofdrugs(e.g.,dopamineagonistsvs.opiates)havespecificbehavioralandphysiologicalwithdrawalsigns,itmaybethatdifferentmacronutrientsmayalsoproducespecificwithdrawalsigns.Sincecravingoffatorcrosssensitizationbetweenfatintakeanddrugsofabusehasyettobedocumentedinanimals,sugariscurrentlytheonlypalatablesubstanceforwhichbingeing,withdrawal,abstinenceinducedenhancedmotivationandcrosssensitizationhaveallbeendemonstrated(Sections4and5).

Recentfindingsusingpositronemissiontomography(PET)andfunctionalmagneticresonanceimaging(fMRI)inhumanshavesupportedtheideathataberranteatingbehaviors,includingthoseobservedinobesity,mayhavesimilaritiestodrugdependence.CravingrelatedchangesinfMRIsignalhavebeenidentifiedinresponsetopalatablefoods,similartodrugcraving.Thisoverlapoccurredinthehippocampus,insula,andcaudate(Pelchatetal.,2004).Similarly,PETscansrevealthatobesesubjectsshowareductioninstriatalD receptoravailabilitythatisassociatedwiththebodyweightofthesubject(Wangetal.,2004b).ThisdecreaseinDreceptorsinobesesubjectsissimilarinmagnitudetothereductionsreportedindrugaddictedsubjects(Wangetal.,2001).TheinvolvementoftheDAsysteminrewardandreinforcementhasledtothehypothesisthatalterationsinDAactivityinobesesubjectsdisposethemtoexcessiveuseoffood.Exposuretoespeciallypalatablefoods,suchascakeandicecream,activatestheseveralbrainregionsincludingtheanteriorinsulaandrightorbitofrontalcortex(Wangetal.,2004a),whichmayunderliethemotivationtoprocurefood(Rolls,2006).

7.CONCLUSION

Fromanevolutionaryperspective,itisinthebestinterestofhumanstohaveaninherentdesireforfoodforsurvival.However,thisdesiremaygoawry,andcertainpeople,includingsomeobeseandbulimicpatientsinparticular,maydevelopanunhealthydependenceonpalatablefoodthatinterfereswithwellbeing.Theconceptoffoodaddictionmaterializedinthedietindustryonthebasisofsubjectivereports,clinicalaccountsandcasestudiesdescribedinselfhelpbooks.Theriseinobesity,coupledwiththeemergenceofscientificfindingsofparallelsbetweendrugsofabuseandpalatablefoodshasgivencredibilitytothisidea.Thereviewedevidencesupportsthetheorythat,insomecircumstances,intermittentaccesstosugarcanleadtobehaviorandneurochemicalchangesthatresembletheeffectsofasubstanceofabuse.Accordingtotheevidenceinrats,intermittentaccesstosugarandchowiscapableofproducingadependency.Thiswasoperationallydefinedbytestsforbingeing,withdrawal,cravingandcrosssensitizationtoamphetamineandalcohol.Thecorrespondencetosomepeoplewithbingeeatingdisorderorbulimiaisstriking,butwhetherornotitisagoodideatocallthisafoodaddictioninpeopleisbothascientificandsocietalquestionthathasyettobeanswered.Whatthisreviewdemonstratesisthatratswithintermittentaccesstofoodandasugarsolutioncanshowbothaconstellationofbehaviorsandparallelbrainchangesthatarecharacteristicofratsthatvoluntarilyselfadministeraddictivedrugs.Intheaggregrate,thisis

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evidencethatsugarcanbeaddictive.

Acknowledgments

ThisreseachwassupportedbyUSPHSgrantMH65024(B.G.H.),DA10608(B.G.H.),DA16458(fellowshiptoN.M.A)andtheLaneFoundation.

FootnotesPublisher'sDisclaimer:ThisisaPDFfileofanuneditedmanuscriptthathasbeenacceptedforpublication.Asaservicetoourcustomersweareprovidingthisearlyversionofthemanuscript.Themanuscriptwillundergocopyediting,typesetting,andreviewoftheresultingproofbeforeitispublishedinitsfinalcitableform.Pleasenotethatduringtheproductionprocesserrorsmaybediscoveredwhichcouldaffectthecontent,andalllegaldisclaimersthatapplytothejournalpertain.

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