Suggar Addiction

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Neuroscience and Biobehavioral Reviews 32 (2008) 2039

Review

Evidence for sugar addiction: Behavioral and neurochemical effects of intermittent, excessive sugar intake

Nicole M. Avena, Pedro Rada, Bartley G. HoebelDepartment of Psychology, Princeton University, Princeton, NJ 08540, USA

Received 14 September 2006; received in revised form 19 April 2007; accepted 28 April 2007

Abstract

[Avena, N.M., Rada, P., Hoebel B.G., 2007. Evidence for sugar addiction: Behavioral and neurochemical effects of intermittent,excessive sugar intake. Neuroscience and Biobehavioral Reviews XX(X), XXXXXX]. The experimental question is whether or notsugar can be a substance of abuse and lead to a natural form of addiction. Food addiction seems plausible because brain pathways thatevolved to respond to natural rewards are also activated by addictive drugs. Sugar is noteworthy as a substance that releases opioids anddopamine and thus might be expected to have addictive potential. This review summarizes evidence of sugar dependence in an animalmodel. Four components of addiction are analyzed. Bingeing, withdrawal, craving and cross-sensitization are each givenoperational denitions and demonstrated behaviorally with sugar bingeing as the reinforcer. These behaviors are then related toneurochemical changes in the brain that also occur with addictive drugs. Neural adaptations include changes in dopamine and opioidreceptor binding, enkephalin mRNA expression and dopamine and acetylcholine release in the nucleus accumbens. The evidencesupports the hypothesis that under certain circumstances rats can become sugar dependent. This may translate to some humanconditions as suggested by the literature on eating disorders and obesity.r 2007 Elsevier Ltd. All rights reserved.

Keywords: Binge eating; Dopamine; Acetylcholine; Opioids; Nucleus accumbens; Withdrawal; Craving; Behavioral sensitization; Rat

Contents

1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212. Dening addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

2.1. Bingeing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222.2. Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222.3. Craving . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222.4. Sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

3. Drugs of abuse and palatable food activate a common subset of neural systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

3.1. Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233.2. Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233.3. Acetylcholine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

4. Behavioral similarities between drug self-administration and intermittent, excessive sugar intake. . . . . . . . . . . . . . . . . . . . . 244.1. Bingeing: escalation of daily sugar intake and large meals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244.2. Withdrawal: anxiety and behavioral depression induced by an opioid antagonist or food deprivation . . . . . . . . . . . 254.3. Craving: enhanced responding for sugar following abstinence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264.4. Cross-sensitization: increased locomotor response to psychostimulants during sugar abstinence . . . . . . . . . . . . . . . 274.5. Gateway effect: increased alcohol intake during sugar abstinence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

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Corresponding author. Tel.: +1 609258 4463; fax: +1609258 1113.E-mail address: [email protected] (B.G. Hoebel).
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5. Neurochemical similarities between drug self-administration and intermittent sugar intake. . . . . . . . . . . . . . . . . . . . . . . . . 285.1. Intermittent sugar intake alters D 1 , D 2 and mu-opioid receptor binding and mRNA expression. . . . . . . . . . . . . . . . . 285.2. Intermittent sugar intake alters enkephalin mRNA expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285.3. Daily intermittent sugar intake repeatedly releases dopamine in the accumbens . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285.4. Accumbens acetylcholine release is delayed during sugar binges and eliminated during sham feeding . . . . . . . . . . . . . 295.5. Sugar withdrawal upsets dopamine/acetylcholine balance in the accumbens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

6. Discussion and clinical implications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306.1. Bulimia nervosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306.2. Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

6.2.1. Sugar and obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316.2.2. Fat and obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326.2.3. Brain imaging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

1. Overview

Neural systems that evolved to motivate and reinforceforaging and food intake also underlie drug seeking andself-administration. The fact that some of these drugs cancause addiction raises the logical possibility that somefoods might also cause addiction. Many people claim thatthey feel compelled to eat sweet foods, similar in some waysto how an alcoholic might feel compelled to drink.Therefore, we developed an animal model to investigatewhy some people have difculty moderating their intake of palatable foods, such as sweet beverages.

In this animal model, rats are food deprived daily for12 h, then after a delay of 4 h into their normal circadian-

driven active period, they are given 12-h access to a sugarsolution and chow. As a result, they learn to drink thesugar solution copiously, especially when it rst becomesavailable each day.

After a month on this intermittent-feeding schedule, theanimals show a series of behaviors similar to the effects of drugs of abuse. These are categorized as bingeing,meaning unusually large bouts of intake ( Colantuoniet al., 2001 ), opiate-like withdrawal indicated by signsof anxiety ( Colantuoni et al., 2002 ) and behavioraldepression, and craving measured during sugar absti-nence as enhanced responding for sugar ( Avena et al.,2005 ). There are also signs of both locomotor andconsummatory cross-sensitization from sugar to drugsof abuse ( Avena et al., 2004 ; Avena and Hoebel, 2003b ).Having found these behaviors that are common to drugdependency with supporting evidence from other labora-tories ( Gosnell, 2005 ; Grimm et al., 2005 ; Wideman et al.,2005 ), the next question is why this happens.

A well-known characteristic of addictive drugs is theirability to cause repeated, intermittent increases in extra-cellular dopamine (DA) in the nucleus accumbens (NAc)(Di Chiara and Imperato, 1988 ; Hernandez and Hoebel,1988 ; Wise et al., 1995 ). We nd that rats with intermittentaccess to sugar will drink in a binge-like manner thatreleases DA in the NAc each time, like the classic effect of

most substances of abuse ( Avena et al., 2006 ; Rada et al.,2005b ). This consequently leads to changes in the expres-sion or availability of DA receptors ( Colantuoni et al.,2001 ; Spangler et al., 2004 ).

Intermittent sugar access also acts by way of opioids inthe brain. There are changes in opioid systems such asdecreased enkephalin mRNA expression in the accumbens(Spangler et al., 2004 ). Signs of withdrawal seem to belargely due to the opioid modications since withdrawalcan be obtained with the opioid antagonist naloxone. Fooddeprivation is also sufcient to precipitate opiate-likewithdrawal signs (Avena et al., unpublished; Colantuoniet al., 2002 ). This withdrawal state involves at least twoneurochemical manifestations. First is a decrease in

extracellular DA in the accumbens, and second is therelease of acetylcholine (ACh) from accumbens interneur-ons. These neurochemical adaptations in response tointermittent sugar intake mimic the effects of opiates.

The theory is formulated that intermittent, excessiveintake of sugar can have dopaminergic, cholinergic andopioid effects that are similar to psychostimulants andopiates, albeit smaller in magnitude. The overall effect of these neurochemical adaptations is mild, but well-dened,dependency ( Hoebel et al., 1999 ; Leibowitz and Hoebel,2004 ; Rada et al., 2005a ). This review compiles studiesfrom our laboratory and integrates related results obtainedby others using animal models, clinical accounts and brainimaging to answer the question: can sugar, in someconditions, be addictive?

2. Dening addiction

Throughout this review we use several terms withdenitions for which there is not universal agreement.Addiction research traditionally focuses on drugs of abuse,such as morphine, cocaine, nicotine and alcohol. However,recently a variety of addictions to non-drug entities,including gambling, sex, and in this review, food, have beeninvestigated ( Bancroft and Vukadinovic, 2004 ; Comingset al., 2001 ; Petry, 2006 ). The term addiction implies

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psychological dependence and thus is a mental or cognitiveproblem, not just a physical ailment. Addiction is oftenused synonymously with the term dependence ( Nelsonet al., 1982 ) as dened by DSM-IV-TR ( AmericanPsychiatric Association, 2000 ). We will use the termdependence in its all-encompassing meaning to describe

the results of a battery of animal studies that model humandrug addiction in each of its major phases ( Koob and LeMoal, 2005 ).

Drug dependence is characterized by compulsive, some-times uncontrollable, behaviors that occur at the expenseof other activities and intensify with repeated access.Dependence is difcult to demonstrate convincingly inlaboratory animals, but criteria have been suggested usinganimal models. We have used models that were developedwith rats for studying drug dependence and adapted themto test for signs of sugar dependence.

2.1. Bingeing

The diagnostic criteria for dependence can be groupedinto three stages ( American Psychiatric Association, 2000 ;Koob and Le Moal, 1997 ). The rst, bingeing, is dened asthe escalation of intake with a high proportion of intake atone time, usually after a period of voluntary abstinence orforced deprivation. Enhanced intake in the form of bingesmay result from both sensitization and tolerance to thesensory properties of a substance of abuse that occurs withits repeated delivery. Sensitization, which is described ingreater detail below, is an increase in responsiveness to arepeatedly presented stimulus. Tolerance is a gradual

decrease in responsiveness, such that more of the substanceis needed to produce the same effect ( McSweeney et al.,2005 ). Both are thought to inuence the powerful, acutereinforcing effects of drugs of abuse and are important atthe beginning of the addiction cycle since both can increaseresponding and intake ( Koob and Le Moal, 2005 ).

2.2. Withdrawal

Signs of withdrawal become apparent when the abusedsubstance is no longer available or is chemically blocked.We will discuss withdrawal in terms of opiate withdrawal,which has a clearly dened set of symptoms ( Martin et al.,1963 ; Way et al., 1969 ). Anxiety can be operationallydened and measured in animals using the elevated plus-maze, in which anxious animals will avoid spending timeon the open arms of the maze ( File et al., 2004 ). This testhas been extensively validated for both general anxiety(Pellow et al., 1985 ) and anxiety induced by drug with-drawal ( File and Andrews, 1991 ). Behavioral depression inanimals can also be inferred using the forced-swim test,which measures swimming escape efforts vs. passiveoating ( Porsolt et al., 1978 ). When signs of opiatewithdrawal are precipitated with naloxone, it suggests thatinactivation of opioid receptors is the cause. When thesame signs are produced spontaneously during abstinence,

one can surmise that it is due to lack of stimulation of someopioid system.

2.3. Craving

The third stage of dependence, craving, occurs when

motivation is enhanced, usually after an abstinence period(Vanderschuren and Everitt, 2005 ; Weiss, 2005 ). Cravingremains a poorly dened term that is often used to describethe intense desire to self-administer drugs in humans ( Wise,1988 ). For lack of a better word, we will use the termcraving as dened by increased efforts to obtain asubstance of abuse or its associated cues as a result of dependence and abstinence. Craving often has referenceto motivation, which can be measured using operantconditioning. If abstinence makes the animal signicantlyincrease its lever pressing, one can take this as a sign of enhanced motivation.

2.4. Sensitization

In addition to the above diagnostic criteria, behavioralsensitization is thought to underlie some aspects of drugdependence ( Vanderschuren and Kalivas, 2000 ). Behavior-al sensitization is typically measured as increased locomo-tion in response to repeated administrations of a drug. Forexample, after repeated doses of amphetamine followed byabstinence, a challenge dose, which has little or no effect inna ve animals, causes marked hyperactivity ( Antelman andCaggiula, 1996 ; Glick et al., 1986 ). Animals sensitized toone substance often show cross-sensitization, which is

dened as an increased locomotor response to a differentdrug or substance. Cross-sensitization can also be manifestin consummatory behavior ( Piazza et al., 1989 ). Animalssensitized to one drug may show increased intake of adifferent drug. In other words, one drug acts as agateway to another. For example, animals sensitized toamphetamine show accelerated escalation of cocaine intake(Ferrario and Robinson, 2007 ), and animals sensitized tonicotine consume more alcohol compared with non-sensitized animals ( Blomqvist et al., 1996 ). This behavioris thought to occur when different drugs activate the sameneural circuitry, and it is a reason why many cliniciansrequire complete drug abstention as a condition of treat-ment for addicts ( Wise, 1988 ).

The rst question addressed by this review is whetherany of these operationally dened behavioral character-istics of substance dependence can be found with inter-mittent sugar access. The second question explores neuralsystems to discover how sugar might have effects like adrug of abuse.

3. Drugs of abuse and palatable food activate a commonsubset of neural systems

Overlaps in the brain circuitry activated by food anddrug intake suggests that different types of reinforcers

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(natural and articial) stimulate some of the same neuralsystems ( Hoebel, 1985 ; Hernandez and Hoebel, 1988 ;Kelley et al., 2002 ; Le Magnen, 1990 ; Volkow and Wise,2005 ; Wise, 1989 ). There are several regions in the braininvolved in the reinforcement of both feeding and drugintake ( Kalivas and Volkow, 2005 ; Kelley et al., 2005 ;

Koob and Le Moal, 2005 ; Mogenson and Yang, 1991 ;Wise, 1997 ; Yeomans, 1995 ), and many neurotransmittershave been studied in these and related brain regions ( Harriset al., 2005 ; Kalivas, 2004 ; Leibowitz and Hoebel, 2004 ;Schoffelmeer et al., 2001 ; Stein and Belluzzi, 1979 ). Thisreview will focus on DA, the opioids, and ACh in theNAc shell, which so far, are the neurotransmitters that wehave found to be involved with the reinforcing effects of intermittent sugar intake.

3.1. Dopamine

It is well established that addictive drugs activate DA-containing neurons in areas of the brain that process behaviorreinforcement. This has been shown for drugs deliveredsystemically ( Di Chiara and Imperato, 1988 ; Radhakishunet al., 1983 ), and for drugs infused locally ( Hernandez andHoebel, 1988 ; Mifsud et al., 1989 ). The mesolimbic DAprojection from the ventral tegmental area (VTA) to the NAchas a role in reinforcement functions ( Wise and Bozarth,1984 ). The NAc is important for several components of reward including food seeking and reinforcement of learning, incentive motivation, stimulus salience and signalinga stimulus change ( Bassareo and Di Chiara, 1999 ; Berridgeand Robinson, 1998 ; Salamone, 1992 ; Schultz et al., 1997 ;

Wise, 1988 ). Agents that directly or indirectly stimulate DAcell bodies in the VTA reinforce local self-administration,including opioids such as enkephalin ( Glimcher et al., 1984 ),non-opioid peptides such as neurotensin ( Glimcher et al.,1987 ) and many drugs of abuse ( Bozarth and Wise, 1981 ;Gessa et al., 1985 ; McBride et al., 1999 ). Some addictivedrugs also act at DA terminals ( Cheer et al., 2004 ; Mifsudet al., 1989 ; Nisell et al., 1994 ; Westerink et al., 1987 ;Yoshimoto et al., 1992 ). Thus, any substance that repeatedlycauses the release of DA or reduces DA reuptake at terminalsvia these circuits may be a candidate for abuse.

A variety of foods can release DA in the NAc, includinglab chow, sugar, saccharin, and corn oil ( Bassareo and DiChiara, 1997 ; Hajnal et al., 2004 ; Liang et al., 2006 ; Market al., 1991 ; Rada et al., 2005b ). The rise in extracellularDA can outlast the meal in food-deprived rats ( Hernandezand Hoebel, 1988 ). However, in satiated animals, this DArelease appears to be contingent on novelty since it waneswith repeated access, even when the food is palatable(Bassareo and Di Chiara, 1997 ; Rada et al., 2005b ). Anexception, which is described below (Section 5.3), is whenanimals are food deprived and fed sugar intermittently.

Extracellular DA decreases in reaction to drug with-drawal ( Acquas et al., 1991 ; Acquas and Di Chiara, 1992 ;Rada et al., 2004 ; Rossetti et al., 1992 ). The behavioralsymptoms of withdrawal from dopaminergic drugs are less

well dened than those observed during withdrawal fromopiates. Therefore, it may be easier to discern the signs of withdrawal when using foods that release both DA andopioids. Sugar is one such food.

3.2. Opioids

Opioid peptides are heavily expressed throughout thelimbic system and exert some of their effects on reinforce-ment processing by interacting with DA systems ( Bozarthand Wise, 1986 ; Di Chiara and Imperato, 1986 ; Haberand Lu, 1995 ; Leibowitz and Hoebel, 2004 ; Levine andBillington, 2004 ; Miller and Picket, 1980 ). The opioidpeptide enkephalin in the NAc has been related to reward(Bals-Kubik et al., 1989 ; Bozarth and Wise, 1981 ; Olds,1982) and can activate both mu and delta receptors toincrease the release of DA ( Spanagel et al., 1990 ). Morphinealters gene expression of endogenous opioid peptideswhile increasing opioid peptide production in the NAc(Przewlocka et al., 1996 ; Spangler et al., 2003 ; Turchan et al.,1997). Opioids are also important components of this systemas cotransmitters with GABA in some accumbens and dorsalstriatal outputs ( Kelley et al., 2005 ).

Repeated use of opiates, or even some non-opiate drugs,can result in mu-opioid receptor sensitization in severalregions, including the NAc ( Koob et al., 1992 ; Unterwald,2001 ). A mu-receptor antagonist injected into the NAc willattenuate the rewarding effects of heroin ( Vaccarino et al.,1985 ), and systemically such drugs have been used as atreatment for alcoholism and heroin dependence ( Deaset al., 2005 ; Foster et al., 2003 ; Martin, 1975 ; OBrien,

2005 ; Volpicelli et al., 1992 ).Ingestion of palatable foods has effects via endogenous

opioids in a variety of sites ( Dum et al., 1983 ; Mercer andHolder, 1997 ; Tanda and Di Chiara, 1998 ), and the injectionof mu-opioid agonists in the NAc increases intake of palatable foods rich in fat or sugar ( Zhang et al., 1998 ;Zhang and Kelley, 2002 ). Opioid antagonists, on the otherhand, decrease ingestion of sweet food and shorten meals of palatable, preferred foods, even at doses that have no effecton standard chow intake ( Glass et al., 1999 ). Thisopioidpalatability link is further characterized by theoriesin which the reinforcing effect is dissociated into adopaminergic system for incentive motivation and an opioidliking or pleasure system for hedonic responses(Berridge, 1996 ; Robinson and Berridge, 1993 ; Stein, 1978 ).Evidence that opioids in the NAc inuence hedonic reactionscomes from data showing that morphine enhances ratspositive facial taste reactivity for a sweet solution in themouth ( Pecina and Berridge, 1995 ). The dissociation betweenthe wanting and liking systems is also suggested bystudies in humans ( Finlayson et al., 2007 ).

3.3. Acetylcholine

Several cholinergic systems in the brain have beenimplicated in both food and drug intake, and related to

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DA and the opioids ( Katz and Valentino, 1984 ; Kelleyet al., 2005 ; Rada et al., 2000 ; Yeomans, 1995 ). Focusingon ACh interneurons in the NAc, systemic administrationof morphine decreases ACh turnover ( Smith et al., 1984 ), anding that was conrmed by in vivo microdialysis infreely-behaving rats ( Fiserova et al., 1999 ; Rada et al.,

1991a, 1996 ). Cholinergic interneurons in the NAc mayselectively modulate enkephalin gene expression andpeptide release ( Kelley et al., 2005 ). During morphinewithdrawal, extracellular ACh increases in the NAc whileDA is low, suggesting that this neurochemical state couldbe involved in the aversive aspects of withdrawal ( Pothoset al., 1991 ; Rada et al., 1991b, 1996 ). Likewise, bothnicotine and alcohol withdrawal increase extracellularACh, while decreasing DA in the NAc ( De Witte et al.,2003 ; Rada et al., 2001, 2004 ). This withdrawal state mayinvolve depression, since M1-receptor agonists injected inthe NAc can cause behavioral depression in the forced-swim test ( Chau et al., 1999 ).

ACh in the NAc has also been implicated in food intake.We theorize that its overall muscarinic effect is to inhibitfeeding at M1 receptors since local injection of the mixedmuscarinic agonist arecholine will inhibit feeding, and thiseffect can be blocked by the relatively specic M1antagonist pirenzapine (Rada and Hoebel, unpublished).Feeding to satiety increases extracellular ACh in the NAc(Avena et al., 2006 ; Mark et al., 1992 ). A conditioned tasteaversion also increases ACh in the NAc and simulta-neously lowers DA ( Mark et al., 1991, 1995 ). D-fenur-amine combined with phentermine (Fen-Phen) increasesextracellular ACh in the NAc at a dose that inhibits both

eating and cocaine self-administration ( Glowa et al., 1997 ;Rada and Hoebel, 2000 ). Rats with accumbal ACh, toxin-induced lesions are hyperphagic relative to non-lesionedrats ( Hajnal et al., 2000 ).

DA/ACh balance is controlled in part by hypothalamicsystems for feeding and satiety. Norepinephrine andgalanin, which induce eating when injected in theparaventricular nucleus (PVN), lower accumbens ACh(Hajnal et al., 1997 ; Rada et al., 1998 ). An exception isneuropeptide-Y, which fosters eating when injected into thePVN, but does not increase DA release nor lower ACh(Rada et al., 1998 ). In accord with the theory, the satiety-producing combination of serotonin plus CCK injectioninto the PVN increases accumbens ACh ( Helm et al.,2003 ).

It is very interesting that when DA is low and extra-cellular ACh is high, this apparently creates not satiety, butinstead an aversive state ( Hoebel et al., 1999 ), as duringbehavioral depression ( Rada et al., 2006 ), drug withdrawal(Rada et al., 1991b, 1996, 2001, 2004 ) and conditionedtaste aversion ( Mark et al., 1995 ). We conclude that whenACh acts as a post-synaptic M1 agonist it has effectsopposite to DA, and thus may act to impede dopaminergicfunctions ( Hoebel et al., 1999 ; Rada et al., 2007 ) causingsatiety when DA is high and behavioral depression whenDA is relatively low.

4. Behavioral similarities between drug self-administrationand intermittent, excessive sugar intake

The concept of sugar addiction has been bandiedabout for many years. Clinical accounts of sugaraddiction have been the topic of many best-selling books

and the focus of popular diet programs ( Appleton, 1996 ;DesMaisons, 2001 ; Katherine, 1996 ; Rufus, 2004 ). In theseaccounts, people describe symptoms of withdrawal whenthey deprive themselves of sugar-rich foods. They alsodescribe food craving, particularly for sugar and othercarbohydrates, which can trigger impulsive eating. Thisleads to a vicious cycle of self-medication with sweet foodsthat may result in obesity or an eating disorder.

Although the idea of food addiction has been popular inthe media and proposed to be based on brain neurochem-istry ( Hoebel et al., 1989 ; Le Magnen, 1990 ), thisphenomenon has only recently been systematically studiedin the laboratory.

As outlined in the overview in Section 1, we use a feedingschedule that induces rats to binge on a sugar solution,then apply the criteria for drug dependence that arepresented in Section 2 and test for the behavioral andneurochemical commonalities given in Section 3. Rats aregiven 12-h access to an aqueous 10% sucrose solution(25% glucose in some experiments) and lab chow, followedby 12 h of deprivation daily for three or more weeks (i.e.,Daily Intermittent Sugar and Chow). These rats arecompared with control groups such as Ad libitum Sugarand Chow, Ad libitum Chow, or Daily Intermittent Chow(12-h access to lab chow followed by 12-h deprivation). For

the intermittent access groups, availability is delayed 4 hinto the animals active period in order to stimulatefeeding, which normally ensues at the onset of the darkcycle. Rats maintained on the Daily Intermittent Sugar andChow regimen enter a state that resembles drug depen-dence on several dimensions. These are divided intobehavioral (Section 4) and neurochemical (Section 5)similarities to drug dependence.

4.1. Bingeing: escalation of daily sugar intake and largemeals

Escalation of intake is a characteristic of drugs of abuse.This may be a combination of tolerance, in which more of an abused substance is needed to produce the sameeuphoric effects ( Koob and Le Moal, 2005 ), and sensiti-zation, such as locomotor sensitization, in which thesubstance produces enhanced behavioral activation(Vezina et al., 1989 ). Studies using drug self-administrationusually limit access to a few hours per day, duringwhich animals will self-administer in regular intervalsthat vary as a function of the dose received ( Gerber andWise, 1989 ) and in a manner that keeps extracellular DAelevated above a baseline, or trigger point, in the NAc(Ranaldi et al., 1999 ; Wise et al., 1995 ). The length of daily access has been shown to critically affect subsequent

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self-administration behavior. For example, the mostcocaine is self-administered during the rst 10 min of asession when access is at least 6 h per day ( Ahmed andKoob, 1998 ). Limited periods of access, to create binges,have been useful, because the pattern of self-administrationbehavior that emerges is similar to that of a compulsive

drug user ( Markou et al., 1993 ; Mutschler and Miczek,1998 ; OBrien et al., 1998 ). Even when drugs, such ascocaine, are given with unlimited access, humans orlaboratory animals will self-administer them in repetitiveepisodes or binges ( Bozarth and Wise, 1985 ; Deneauet al., 1969 ). However, experimenter-imposed intermittentaccess is better than ad libitum access for experimentalpurposes, since it becomes very likely that the animal willtake at least one large binge at the onset of the drug-availability period. Moreover, a period of food restrictioncan enhance drug intake ( Carr, 2006 ; Carroll, 1985 ) andhas been shown to produce compensatory neuroadapta-tions in the mesoaccumbens DA system ( Pan et al., 2006 ).

The behavioral ndings with sugar are similar to thoseobserved with drugs of abuse. Rats fed daily intermittentsugar and chow escalate their sugar intake and increasetheir intake during the rst hour of daily access, which wedene as a binge ( Colantuoni et al., 2001 ). The animalswith ad libitum access to a sugar solution tend to drink itthroughout the day, including during their inactive period.

Both groups increase their overall intake, but the limited-access animals consume as much sugar in 12h as adlibitum-fed animals do in 24 h. Detailed meal patternanalysis using operant conditioning (xed-ratio 1) revealsthat the animals with limited access consume a large mealof sugar at the onset of availability and larger, fewer meals

of sugar throughout the access period, compared withanimals drinking sugar ad libitum ( Fig. 1 ; Avena andHoebel, unpublished). Rats fed Daily Intermittent Sugarand Chow regulate their caloric intake by decreasing theirchow intake to compensate for the extra calories obtainedfrom sugar, which results in a normal body weight ( Avenaand Hoebel, 2003b ; Colantuoni et al., 2002 ).

4.2. Withdrawal: anxiety and behavioral depressioninduced by an opioid antagonist or food deprivation

As described in Section 2, animals can show signs of opiate withdrawal after repeated exposure when thesubstance of abuse is removed, or the appropriate synapticreceptor is blocked. For example, an opioid antagonist canbe used to precipitate withdrawal in the case of opiatedependency ( Epejo et al., 1994 ; Koob et al., 1992 ). In rats,opiate withdrawal causes severe somatic signs ( Martinet al., 1963 ; Way et al., 1969 ), aggression ( Kantak andMiczek, 1986 ), and anxiety ( Schulteis et al., 1998 ),

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Fig. 1. Meal analysis of two representative rats living in operant chambers. The one maintained on Daily Intermittent Sucrose and Chow (blue/blacklines) had increased intake of sugar compared with the one given Ad libitum Sucrose and Chow (orange/gray lines). Hour 0 is 4 h into the dark phase. Eachlever press delivered 0.1 mL of 10% sucrose. A sugar meal is dened as ending when the rat does not press for 2 min. Both rats consumed several meals of about equal size on day 1 (top panel). Note that the rat with sugar available 24h also drinks during the inactive (light) phase. By day 21 (bottom panel), therat with sucrose and chow available for only 12 h consumed an initial binge of sucrose (indicated by the rst arrow), followed by fewer, but larger meals,than the rat with sucrose and chow available ad libitum. Sugar-bingeing rats are the ones that show signs of dependency in a battery of tests.



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decreases in body temperature ( Ary et al., 1976 ), as well asa motivational syndrome characterized by dysphoria anddepression ( De Vries and Shippenberg, 2002 ; Koob and LeMoal, 1997 ).

Some of these signs have been noted after intermittentaccess to sugar when withdrawal is precipitated with an

opioid antagonist, or when food and sugar are removed.When administered a relatively high-dose of the opioidantagonist naloxone (3 mg/kg, s.c.), somatic signs of withdrawal, such as teeth chattering, forepaw tremor,and head shakes are observed ( Colantuoni et al., 2002 ).These animals are also anxious, as measured by reducedtime spent on the exposed arm of an elevated plus-maze(Fig. 2 ; Colantuoni et al., 2002 ).

Behavioral depression has also been found followingnaloxone administration in intermittent sugar-fed rats. Inthis experiment, rats were given an initial 5-min forced-swim test in which escape (swimming and climbing) andpassive (oating) behaviors were measured. Then therats were divided into four groups that were fed DailyIntermittent Sucrose and Chow, Daily Intermittent Chow,Ad libitum Sucrose and Chow, or Ad libitum Chow for 21days. On day 22, at the time that the intermittent-fed ratswould normally receive their sugar and/or chow, all ratswere instead injected with naloxone (3 mg/kg, s.c.) andwere then placed in the water again for another test. In thegroup that had been fed Daily Intermittent Sucrose andChow, escape behaviors were signicantly suppressedcompared with Ad libitum Sucrose and Chow or Adlibitum Chow controls ( Fig. 3 ; Kim, Avena and Hoebel,unpublished). This decrease in escape efforts, which were

replaced by passive oating, suggests the rats wereexperiencing behavioral depression.

Signs of opiate-like withdrawal also emerge when foodand sugar are removed for 24h. Again this includessomatic signs such as teeth chattering, forepaw tremorand head shaking ( Colantuoni et al., 2002 ) and anxiety asmeasured with an elevated plus-maze (Avena et al.,unpublished). Spontaneous withdrawal from the mere

removal of sugar has been reported using decreased bodytemperature as the criterion ( Wideman et al., 2005 ). Also,signs of aggressive behavior have been found in response toremoving a diet that involves intermittent sugar access(Galic and Persinger, 2002 ).

4.3. Craving: enhanced responding for sugar followingabstinence

As described in Section 2, craving in laboratoryanimals can be dened as enhanced motivation to procurean abused substance ( Koob and Le Moal, 2005 ). After self-administering drugs of abuse and then being forced toabstain, animals often persist in unrewarded operantresponding (i.e., resistance to response extinction), andincrease their responding over time for cues previouslyassociated with the drug (i.e., incubation) ( Bienkowskiet al., 2004 ; Grimm et al., 2001 ; Lu et al., 2004 ).Additionally, if the drug becomes available again, animalswill take more than they did prior to abstinence (i.e., thedeprivation effect) ( Sinclair and Senter, 1968 ). Thisincrease in motivation to procure a substance of abuse maycontribute to relapse. The power of craving is evidencedby results showing that animals will sometimes face adverseconsequences to obtain a substance of abuse such ascocaine or alcohol ( Deroche-Gamonet et al., 2004 ; Dick-inson et al., 2002 ; Vanderschuren and Everitt, 2004 ). Thesesigns in laboratory animals mimic those observed withhumans in which the presentation of stimuli previouslyassociated with a drug of abuse increases self-reports of craving and the likelihood of relapse ( OBrien et al., 1977,1998 ).

We used the deprivation effect paradigm to investigatesugar consumption after abstinence in sugar-bingeing rats.Following 12-h daily access to glucose for four weeks, rats

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Fig. 2. Time spent on the open arms of an elevated plus-maze. Fourgroups of rats were maintained on their respective diets for one month andthen received naloxone (3 mg/kg, s.c.). The Daily Intermittent Glucose andChow group spent less time on the open arms of the maze. * po 0.05compared with the Ad libitum Chow group. From Colantuoni et al., 2002 .

Fig. 3. Rats that have been maintained on Daily Intermittent Sucrose andChow are more immobile than control groups in a forced-swim test duringnaloxone-precipitated withdrawal. * po 0.05 compared with Ad libitumSugar and Chow and Ad libitum Chow groups.



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lever press for 23% more glucose in a test after two weeksof abstinence than they ever did before ( Fig. 4 ; Avenaet al., 2005 ). A group with 0.5-h daily access to glucose didnot show the effect. This provides a cogent control groupin which rats are familiar with the taste of glucose, but havenot consumed it in a manner that leads to a deprivationeffect. The results suggest a change in the motivationalimpact of sugar that persists throughout two weeks of abstinence, leading to enhanced intake.

Additionally, like the drugs described above, themotivation to obtain sugar appears to incubate, or

grow, with the length of abstinence ( Shalev et al., 2001 ).Using operant conditioning, Grimm et al. (2005) foundthat sucrose seeking (lever pressing in extinction and thenfor a sucrose-paired cue) increases during abstinence in ratsafter intermittent sugar access for 10 days. Remarkably,responding for the cue was greater after 30 days of sugarabstinence compared with 1 week or 1 day. These resultssuggest the gradual emergence of long-term changes in theneural circuitry underlying motivation as a result of sugarself-administration and abstinence.

4.4. Cross-sensitization: increased locomotor response to psychostimulants during sugar abstinence

Drug-induced sensitization may play a role in theenhancement of drug self-administration and is implicatedas a factor contributing to drug addiction ( Robinson andBerridge, 1993 ). In a typical sensitization experiment, theanimal receives a drug daily for about a week, then theprocedure stops. However, in the brain there are lasting,even growing, changes apparent a week or more later whena low, challenge dose of the drug results in hyperlocomo-tion ( Kalivas et al., 1992 ). Additionally, cross-sensitizationfrom one drug to another has been demonstrated withseveral drugs of abuse, including amphetamine sensitizingrats to cocaine or phencyclidine ( Greenberg and Segal,

1985 ; Kalivas and Weber, 1988 ; Pierce and Kalivas, 1995 ;Schenk et al., 1991 ), cocaine cross-sensitizing with alcohol(Itzhak and Martin, 1999 ), and heroin with cannabis(Pontieri et al., 2001 ). Other studies have found this effectwith non-drug substances. Behavioral cross-sensitizationbetween cocaine and stress has been demonstrated ( Antel-

man and Caggiula, 1977 ; Covington and Miczek, 2001 ;Prasad et al., 1998 ). Also, increases in food intake ( Bakshiand Kelley, 1994 ) or sexual behaviors ( Fiorino andPhillips, 1999 ; Nocjar and Panksepp, 2002 ) have beenobserved in animals with a history of drug sensitization.

We and others have found that intermittent sugar intakecross-sensitizes with drugs of abuse. Rats sensitized withdaily amphetamine injections (3 mg/kg, i.p.) are hyperac-tive one week later in response to tasting 10% sucrose(Avena and Hoebel, 2003a ). Conversely, rats fed DailyIntermittent Sucrose and Chow show locomotor cross-sensitization to amphetamine. Specically, such animalsare hyperactive in response to a low, challenge dose of amphetamine (0.5 mg/kg, i.p.) that has no effect on na veanimals, even after 8 days of abstinence from sugar ( Fig. 5 ;Avena and Hoebel, 2003b ). Rats maintained on thisfeeding schedule but administered saline were not hyper-active, nor were rats in control groups (Daily IntermittentChow, Ad libitum Sucrose and Chow, Ad libitum Chow)given the challenge dose of amphetamine. Intermittentsucrose access also cross-sensitizes with cocaine ( Gosnell,2005 ) and facilitates the development of sensitization to theDA agonist quinpirole ( Foley et al., 2006 ). Thus, resultswith three different DA agonists from three differentlaboratories support the theory that the DA system is

sensitized by intermittent sugar access, as evidenced bycross-sensitization. This is important since enhancedmesolimbic dopaminergic neurotransmission plays a majorrole in the behavioral effects of sensitization as well ascross-sensitization ( Robinson and Berridge, 1993 ), andmay contribute to addiction and comorbidity with poly-substance abuse.

4.5. Gateway effect: increased alcohol intake duringsugar abstinence

Numerous studies have found that sensitization to onedrug can lead not only to hyperactivity, but also tosubsequent increased intake of another drug or substance(Ellgren et al., 2007 ; Henningeld et al., 1990 ; Hubbellet al., 1993 ; Liguori et al., 1997 ; Nichols et al., 1991 ; Piazzaet al., 1989 ; Vezina, 2004 ; Vezina et al., 2002 ; Volpicelliet al., 1991 ). We refer to this phenomenon as consumma-tory cross-sensitization. In the clinical literature, whenone drug leads to taking another, this is sometimes referredto as a gateway effect. It is particularly noteworthy whena legal drug (e.g., nicotine) acts as a gateway to an illegaldrug (e.g., cocaine) ( Lai et al., 2000 ).

Rats maintained on intermittent sugar access and thenforced to abstain, subsequently show enhanced intakeof 9% alcohol ( Avena et al., 2004 ). This suggests that

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Fig. 4. After 14 days of abstinence from sugar, rats that previously had12-h daily access signicantly increased lever pressing for glucose to 123%of pre-abstinence responding, indicating increased motivation for sugar.The group with 0.5-h daily access did not show increased responding afterabstinence. ** po 0.01. From Avena et al., 2005 .



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intermittent access to sugar can be a gateway to alcoholuse. Others have shown that animals that prefer sweet-tastewill self-administer cocaine at a higher rate ( Carroll et al.,2007 ). As with the locomotor cross-sensitization described

above, underlying this behavior are presumably neuro-chemical alterations in the brain, such as adaptations inDA and perhaps opioid functions.

5. Neurochemical similarities between drug self-administration and intermittent sugar intake

The studies described above suggest that intermittent sugaraccess can produce numerous behaviors that are similar tothose observed in drug-dependent rats. In this section, wedescribe neurochemical ndings that may underlie sugardependency. To the extent that these brain alterations matchthe effects of drugs of abuse, it strengthens the case thatsugar, in some cases, can resemble a substance of abuse.

5.1. Intermittent sugar intake alters D 1 , D 2 and mu-opioid receptor binding and mRNA expression

Drugs of abuse can alter DA and opioid receptors in themesolimbic regions of the brain. Pharmacological studieswith selective D 1, D 2 and D 3 receptor antagonists and geneknockout studies have revealed that all three receptorsubtypes mediate the reinforcing effects drugs of abuse.There is an up-regulation of D 1 receptors ( Unterwald et al.,1994 ) and increase in D 1 receptor binding ( Alburges et al.,1993 ; Unterwald et al., 2001 ) in response to cocaine.

Conversely, D 2 receptor density is lower in NAc of monkeys that have a history of cocaine use ( Moore et al.,1998 ). Drugs of abuse can also produce changes in geneexpression of DA receptors. Morphine and cocaine havebeen shown to decrease accumbens D 2 receptor mRNA(Georges et al., 1999 ; Turchan et al., 1997 ), and increase D 3

receptor mRNA ( Spangler et al., 2003 ). These ndings withlaboratory animals support clinical studies, which haverevealed that D 2 receptors are down-regulated in cocaineaddicts ( Volkow et al., 1996a, b, 2006 ).

Similar changes have been reported with intermittentaccess to sugar. Autoradiography reveals increased D 1receptor binding in the NAc and decreased D 2 receptorbinding in the striatum of rats fed Daily Intermittent Glucoseand Chow ( Fig. 6 ; Colantuoni et al., 2001 ). This was relativeto chow-fed rats, so it is not known whether ad libitumglucose would also produce this effect. Others have reported adecrease in D 2 receptor binding in the NAc of rats withrestricted access to sucrose and chow compared with rats fedrestricted chow ( Bello et al., 2002 ). Rats with intermittentsucrose and chow access also have decreased D 2 receptormRNA in the NAc compared with ad libitum chow controls(Spangler et al., 2004 ). In these animals, mRNA levels of theD 3 receptor are increased in the NAc and caudate-putamen.

Regarding the opioid receptors, mu-receptor binding isincreased in response to cocaine and morphine ( Baileyet al., 2005 ; Unterwald et al., 2001 ; Vigano et al., 2003 ).Mu-opioid receptor binding is also signicantly enhancedafter three weeks on the intermittent sugar diet, comparedwith ad libitum chow. This effect was observed in theaccumbens shell, cingulate, hippocampus and locus coer-

uleus ( Colantuoni et al., 2001 ).

5.2. Intermittent sugar intake alters enkephalin mRNAexpression

Enkephalin mRNA in the striatum and the NAc isdecreased in response to repeated injections of morphine(Georges et al., 1999 ; Turchan et al., 1997 ; Uhl et al., 1988 ).These changes within opioid systems are similar to thoseobserved in cocaine-dependent human subjects ( Zubietaet al., 1996 ).

Rats with intermittent sucrose access also display asignicant decrease in enkephalin mRNA, although it isdifcult to judge its functional signicance ( Spangler et al.,2004 ). This decrease in enkephalin mRNA is consistentwith ndings observed in rats with limited daily access to asweet-fat, liquid diet ( Kelley et al., 2003 ). Assuming thisdecrease in mRNA results in less enkephalin peptide beingsynthesized and released, it could account for a compensa-tory increase in mu-opioid receptors, as cited above.

5.3. Daily intermittent sugar intake repeatedly releasesdopamine in the accumbens

One of the strongest neurochemical commonalitiesbetween intermittent sugar access and drugs of abuse has

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Fig. 5. Locomotor activity in a photocell cage plotted as percent of baseline beam breaks on day 0. Rats were maintained for 21 days on the

specied diet regimens. Rats maintained on Daily Intermittent Sucroseand Chow were hyperactive 9 days later in response to a low dose of amphetamine, compared with control diet groups. ** po 0.01. Ratsmaintained on a diet of intermittent chow access were hyperactive inresponse to amphetamine compared with saline (data not shown), but notcompared with other groups that received amphetamine * po 0.01. FromAvena and Hoebel, 2003b .



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been found using in vivo microdialysis to measure extra-cellular DA. Repeated increase in extracellular DA is ahallmark of drugs that are abused. Extracellular DAincreases in the NAc in response to both addictive drugs(De Vries and Shippenberg, 2002 ; Di Chiara and Imperato,1988 ; Everitt and Wolf, 2002 ; Hernandez and Hoebel,1988 ; Hurd et al., 1988 ; Picciotto and Corrigall, 2002 ;Pothos et al., 1991 ) and drug-associated stimuli ( Ito et al.,2000 ). Unlike drugs of abuse, which exert their effects onDA release each time they are administered, the effect of eating palatable food on DA release wanes with repeatedaccess when the food is no longer novel, unless the animalis food deprived ( Bassareo and Di Chiara, 1999 ; Di Chiaraand Tanda, 1997 ; Rada et al., 2005b ). Thus normal feedingis very different than taking drugs because the DA responseduring feeding phases out.

However, and this is very important, rats fed dailyintermittent sucrose and chow apparently release DA everyday as measured on days 1, 2 and 21 of access ( Fig. 7 ; Radaet al., 2005b ). As controls, rats fed sucrose or chow adlibitum, rats with intermittent access to just chow, or ratsthat taste sucrose only two times, develop a blunted DAresponse as is typical of a food that loses it novelty. Theseresults are supported by ndings of alterations inaccumbens DA turnover and DA transporter in ratsmaintained on an intermittent sugar-feeding schedule

(Bello et al., 2003 ; Hajnal and Norgren, 2002 ). Together,these results suggest that intermittent access to sugar andchow causes recurrent increases in extracellular DA in amanner that is more like a drug of abuse than a food.

An interesting question is whether the neurochemicaleffects observed with intermittent sugar access are due to

its postingestive properties or whether the taste of sugarcan be sufcient. To investigate orosensory effects of sugar,we used the sham-feeding preparation. Rats that are shamfeeding with an open gastric stula can ingest foods but notfully digest them ( Smith, 1998 ). Although sham feedingdoes not completely eliminate post-ingestive effects(Berthoud and Jeanrenaud, 1982 ; Sclafani and Nissen-baum, 1985 ), it does allow the animals to taste the sugarwhile retaining almost no calories.

The results of sham feeding sugar for the rst hour of access each day show that DA is released in the NAc, evenafter 3 weeks of daily bingeing, simply due to the taste of sucrose ( Avena et al., 2006 ). Sham feeding does not furtherenhance the typical sugar-induced DA release. Thissupports other work showing that the amount of DArelease in the NAc is proportional to the sucroseconcentration, not the volume consumed ( Hajnal et al.,2004 ).

5.4. Accumbens acetylcholine release is delayed during sugarbinges and eliminated during sham feeding

As described in Section 3.3, accumbens ACh increaseswhen feeding slows down ( Mark et al., 1992 ). One couldpredict that when an animal takes a very large meal, as

with the rst sugar binge, the release of ACh should bedelayed until the satiation process begins as reected in thegradual termination of the meal. This is what wasobserved; ACh release peaked when this initial bingemeal was drawing to a close ( Rada et al., 2005b ).

Next we measured ACh release when the animal couldtake a large meal of sugar while sham feeding. Purging thestomach contents drastically reduced the release of ACh(Avena et al., 2006 ). This is predictable based on the theorythat ACh is normally important for the satiation process(Hoebel et al., 1999 ; Mark et al., 1992 ). It also suggests thatby purging, one eliminates the ACh response that opposesDA. Thus when bingeing on sugar is accompanied bypurging, the behavior is reinforced by accumbens DAwithout ACh, which is more like taking a drug and less likenormal eating.

5.5. Sugar withdrawal upsets dopamine/acetylcholinebalance in the accumbens

The behavioral signs of drug withdrawal described inSection 2.2 are usually accompanied by alterations inDA/ACh balance in the NAc. During withdrawal, DAdecreases while ACh is increased. This imbalance has beenshown during chemically induced withdrawal with severaldrugs of abuse, including morphine, nicotine and alcohol

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Fig. 6. Intermittent sugar access alters DA receptor binding at the level of the striatum. D 1 receptor binding (top panel) is increased in the NAc coreand shell of animals exposed to Daily Intermittent Glucose and Chow(black bars) for 30 days compared with control animals fed chow adlibitum (white bars). D 2 receptor binding (bottom panel) is decreased inthe dorsal striatum of the same animals. * po 0.05. From Colantuoni et al.,2001 .



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(Rada et al., 1996, 2001, 2004 ). Mere abstinence from anabused substance is also sufcient to elicit neurochemicalsigns of withdrawal. For example, rats that are forced toabstain from morphine or alcohol have decreased extra-cellular DA in the NAc ( Acquas and Di Chiara, 1992 ;

Rossetti et al., 1992 ) and ACh increases during sponta-neous morphine withdrawal ( Fiserova et al., 1999 ). Whilewithdrawal from an anxiolytic drug (diazepam) precipi-tated by a bendodiazepine-receptor antagonist does notlower extracellular DA, it does release accumbens ACh(Rada and Hoebel, 2005 ).

Rats that have intermittent access to sugar and chowshow the morphine-like neurochemical imbalance inDA/ACh during withdrawal. This was produced two ways.When given naloxone rats with intermittent sucrose accessshow a decrease in accumbens DA release coupled with anincrease in ACh release ( Colantuoni et al., 2002 ). The samething occurs after 36 h of food deprivation ( Fig. 8 ; Avenaet al., unpublished). One way to interpret deprivation-induced neurochemical imbalance is that perhaps withoutfood to release opioids, the animal suffers a similar type of withdrawal-like state as seen when the up-regulated mu-opioid receptors are blocked with naloxone.

6. Discussion and clinical implications

Food is not ordinarily like a substance of abuse, butintermittent bingeing and deprivation may change that.Based on the observed behavioral and neurochemicalsimilarities between the effects of intermittent sugar accessand drugs of abuse, we suggest that sugar, as common as it

is, nonetheless meets many of the criteria for a substance of abuse and may be addictive for some individuals whenconsumed in a binge-like manner. This conclusion isreinforced by the changes in limbic system neurochemistrythat are similar for drugs and for sugar. The effects we

observe are smaller in magnitude than those produced bydrugs of abuse such as cocaine or morphine; however, thefact that these behaviors and neurochemical changes can beelicited with a natural reinforcer is interesting. It is notclear from this animal model if intermittent sugar accesscan result in neglect of social activities as proposed by thedenition of dependency in the DSM-IV-TR ( AmericanPsychiatric Association, 2000 ). Nor is it known whetherrats will continue to self-administer sugar despite physicalobstacles, such as enduring pain to obtain sugar, as somerats do for cocaine ( Deroche-Gamonet et al., 2004 ).Nonetheless, the extensive series of experiments revealingsimilarities between sugar- and drug-induced behavior andneurochemistry, as chronicled in Sections 4 and 5, lendscredence to the concept of sugar addiction, givesprecision to its denition, and provides a testable model.

6.1. Bulimia nervosa

The feeding regimen of Daily Intermittent Sugar andChow shares some aspects of the behavioral pattern inpeople diagnosed with binge-eating disorder or bulimia.Bulimics often restrict intake early in the day and thenbinge later in the evening, usually on palatable foods(Drewnowski et al., 1992 ; Gendall et al., 1997 ). Bulimicpatients will binge on excessive amounts of non-caloric

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Fig. 7. Rats with intermittent access to sugar release DA in response to drinking sucrose for 60 min on day 21. Dopamine, as measured by in vivomicrodialysis, increased for the Daily Intermittent Sucrose and Chow rats (open circles) on days 1, 2 and 21; in contrast, DA release was attenuated on day21 in four control groups as follows: a group that only had 1-h access to sucrose on days 1 and 21 with ad libitum chow in the interim (lled circles), Adlibitum Sucrose and Chow group (lled squares), and Daily Intermittent Chow group (bottom panel). The bar on the ordinate indicates the hour(060 min) that sucrose or chow was available for the tests. * po 0.05. From Rada et al., 2005b .



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sweeteners ( Klein et al., 2006 ), suggesting that they derivebenets from sweet orosensory stimulation. These patientslater purge the food, either by vomiting or laxative use, orin some cases by strenuous exercise ( American PsychiatricAssociation, 2000 ). Bulimic patients have low b -endorphinlevels (Brewerton et al., 1992 ; Waller et al., 1986 ), whichmight foster eating with a preference or craving for sweets.They also have decreased mu-opioid receptor binding inthe insula compared with controls, which correlates withrecent fasting behavior ( Bencherif et al., 2005 ). Thiscontrasts with the increase in the NAc observed in ratsfollowing a binge. Cyclic bingeing and food deprivationmay produce alterations in mu-opioid receptors, whichhelp perpetuate bingeing behavior. In support, appetitedysfunctions in the form of binge eating and self-starvationcan stimulate endogenous opioid activity ( Aravich et al.,1993 ).

The nding described in Section 5.3, that intermittentsugar access repeatedly releases DA in response to the tasteof sugar, may be important for understanding the bingeingbehaviors associated with bulimia. DA has been implicatedin bulimia by comparing it to hypothalamic self-stimula-tion, which also releases DA without calories ( Hoebelet al., 1992 ). Bulimic patients have low central DA activity

as reected in analysis of DA metabolites in the spinaluid, which also indicates a role for DA in their abnormalresponses to food ( Jimerson et al., 1992 ). We have shownthat purging leaves DA unopposed by satiety-associatedACh in the accumbens (Section 5.4). This neurochemicalstate may be conducive to exaggerated binge eating. More-

over, the ndings that intermittent sugar intake cross-sensitizes with amphetamine and fosters alcohol intake(Sections 4.4 and 4.5) may be related to the comorbiditybetween bulimia and substance abuse ( Holderness et al.,1994 ).

The overall similarities in behavior and brain adapta-tions with sugar bingeing and drug intake described abovesupport the theory that some eating disorders, such asbulimia, may have properties of an addiction in certainindividuals ( Davis and Claridge, 1998 ; Gillman andLichtigfeld, 1986 ; Heubner, 1993 ; Marrazzi and Luby,1986, 1990 ; Mercer and Holder, 1997 ; Riva et al., 2006 ).

6.2. Obesity

6.2.1. Sugar and obesityObesity is one of the leading preventable causes of death

in the USA ( Mokdad et al., 2004 ). Several studies havecorrelated the rise in the incidence of obesity with anincrease in sugar consumption ( Bray et al., 1992 ; Elliottet al., 2002 ; Howard and Wylie-Rosett, 2002 ; Ludwig et al.,2001 ). The US Department of Agriculture has reportedthat per capita soft-drink consumption has increased byalmost 500% in the past 50 years ( Putnam and Allhouse,1999 ). Sugar intake may lead to an increased number of

and/or afnity for opioid receptors, which in turn leads tofurther ingestion of sugar and may contribute to obesity(Fullerton et al., 1985 ). Indeed, rats maintained on the dietof intermittent sugar access show opioid receptor changes(Section 5.1); however, after 1 month on the diet using 10%sucrose or 25% glucose, these animals do not becomeoverweight ( Colantuoni et al., 2001 ; Avena and Hoebel,2003b ), although others have reported a metabolicsyndrome ( Toida et al., 1996 ), a loss of fuel efciency(Levine et al., 2003 ) and an increase in body weight in ratsfed sucrose ( Bock et al., 1995 ; Kawasaki et al., 2005 ) orglucose ( Wideman et al., 2005 ). Most studies of sugarintake and body weight do not use a binge-inducing diet,and the translation to human obesity is complex ( Levineet al., 2003 ). As described in Section 4.1, it appears thatrats in our model compensate for sucrose or glucosecalories by decreasing chow intake. They gain weight at anormal rate. This may not be true of all sugars.

Fructose is a unique sweetener that has differentmetabolic effects on the body than glucose or sucrose.Fructose is absorbed further down the intestine, andwhereas circulating glucose releases insulin from thepancreas ( Sato et al., 1996 ; Vilsboll et al., 2003 ), fructosestimulates insulin synthesis but does not release it ( Curry,1989 ; Le and Tappy, 2006 ; Sato et al., 1996 ). Insulinmodies food intake by inhibiting eating ( Schwartz et al.,

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Fig. 8. Extracellular DA and ACh following 24 and 36 h of fasting. (A)After 36 h of fasting, DA release in the Daily Intermittent Sucrose andChow group (black bar) was signicantly less than both the intermittentchow (gray bar) and ad libitum chow (white bar) control groups. (B)Extracellular ACh was signicantly increased in the Daily IntermittentSucrose and Chow group at the 36 h fasting point compared with bothcontrol groups. * po 0.05.



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2000 ) and by increasing leptin release ( Saad et al., 1998 ),which also can inhibit food intake. Meals of high-fructosecorn syrup can reduce circulating insulin and leptin levels(Teff et al., 2004 ), contributing to increased body weight.Thus, fructose intake might not result in the degree of satiety that would normally ensue with an equally caloric

meal of glucose or sucrose. Since high-fructose cornsyrup has become a major constituent in the Americandiet ( Bray et al., 2004 ) and lacks some effects on insulinand leptin, it may be a potential agent for producingobesity when given intermittently to rats. Whether or notsigns of dependency on fructose are apparent when itis offered intermittently has yet to be determined. How-ever, based on our results showing that sweet taste issufcient to elicit the repeated release of DA in the NAc(see Section 5.3), we hypothesize that any sweet tasteconsumed in a binge-like manner is a candidate forproducing signs of dependence.

6.2.2. Fat and obesityWhile we have chosen to focus on sugar, the question

arises as to whether non-sweet, palatable foods couldproduce signs of dependence. The evidence is mixed. Itappears that some signs of dependence are apparent withfat, while others have not been shown. Fat bingeing in ratshas been modeled using intermittent access to pure fat(vegetable shortening), sweet-fat cookies ( Boggiano et al.,2005 ; Corwin, 2006 ), or sweet-fat chow (Berner et al.,unpublished). Repeated, intermittent access to oil releasesDA in the NAc ( Liang et al., 2006 ). Like sugar, bingeing ona fat-rich diet is known to affect the opioid system in the

accumbens by decreasing enkephalin mRNA, an effect thatis not observed with acute access ( Kelley et al., 2003 ). Also,treatment with baclofen (GABA-B agonist), which reducesdrug intake, also reduces binge eating of fat ( Buda-Levinet al., 2005 ).

This all implies that fat dependency is a possibility, butwithdrawal signs following fat-bingeing are not as apparentas with sugar. Le Magnen (1990) reported that naloxonecould precipitate opiate-like withdrawal in rats on acafeteria-style diet, which contains a variety of fat- andsugar-rich foods (e.g., cheese, cookies, chocolate chips).However, we have not observed signs of opiate-likewithdrawal following naloxone administration or fastingin rats fed pure fat (vegetable shortening) or a sugar-fatcombination. Further studies are needed to fully under-stand the differences between sugar and fat bingeing andtheir subsequent effects on behavior. Just as differentclasses of drugs (e.g., DA agonists vs. opiates) have specicbehavioral and physiological withdrawal signs, it may bethat different macronutrients also produce specic beha-vior alterations. Since craving of fat or cross-sensitiza-tion between fat intake and drugs of abuse has yet to bedocumented in laboratory animals, sugar is currently theonly palatable substance for which bingeing, withdrawalsigns, abstinence-induced enhanced motivation and cross-sensitization have all been demonstrated (Sections 4 and 5).

6.2.3. Brain imagingRecent ndings using positron emission tomography

(PET) and functional magnetic resonance imaging (fMRI)in humans have supported the idea that aberrant eatingbehaviors, including those observed in obesity, may havesimilarities to drug dependence. Craving-related changes in

fMRI signal have been identied in response to palatablefoods, similar to drug craving. This overlap occurred in thehippocampus, insula, and caudate ( Pelchat et al., 2004 ).Similarly, PET scans reveal that obese subjects show areduction in striatal D 2 receptor availability that isassociated with the body weight of the subject ( Wanget al., 2004b ). This decrease in D 2 receptors in obesesubjects is similar in magnitude to the reductions reportedin drug-dependent subjects ( Wang et al., 2001 ). Theinvolvement of the DA system in reward and reinforcementhas led to the hypothesis, that alterations in DA activity inobese subjects disposes them to excessive use of food.Exposure to especially palatable foods, such as cake and icecream, activates several brain regions including the anteriorinsula and right orbitofrontal cortex ( Wang et al., 2004a ),which may underlie the motivation to procure food ( Rolls,2006 ). Although binge eating was not directly addresses inthese imaging studies, it may nonetheless be a factor sincesome obese individuals engage in binge-eating behavior(Stunkard, 1959 ).

7. Conclusion

From an evolutionary perspective, it is in the bestinterest of humans to have an inherent desire for food for

survival. However, this desire may go awry, and certainpeople, including some obese and bulimic patients inparticular, may develop an unhealthy dependence onpalatable food that interferes with well-being. The conceptof food addiction materialized in the diet industry on thebasis of subjective reports, clinical accounts and casestudies described in self-help books. The rise in obesity,coupled with the emergence of scientic ndings of parallels between drugs of abuse and palatable foods hasgiven credibility to this idea. The reviewed evidencesupports the theory that, in some circumstances, inter-mittent access to sugar can lead to behavioral andneurochemical changes that resemble the effects of asubstance of abuse. Sugar dependency was operationallydened by tests for bingeing, withdrawal signs, craving andcross-sensitization to amphetamine and alcohol. Thecorrespondence to some people with binge-eating disorderor bulimia is notable, but whether or not it is a good idea tocall this a food addiction in people is both a scienticand societal question that has yet to be answered. Whatthis review demonstrates is that rats with intermittentaccess to a sugar solution can show both a constellation of behaviors and parallel brain changes that are characteristicof rats that voluntarily self-administer addictive drugs. Inconclusion, this is evidence that under some circumstancessugar can be addictive.

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Acknowledgments

This research was supported by USPHS Grants MH-65024 (to B.T. Walsh (Columbia) and B.G.H.), DA-10608(B.G.H.), DA-16458 (fellowship to N.M.A) and the MinnieB. and E.H. Lane Foundations.

References

Acquas, E., Di Chiara, G., 1992. Depression of mesolimbic dopaminetransmission and sensitization to morphine during opiate abstinence.Journal of Neurochemistry 58, 16201625.

Acquas, E., Carboni, E., Di Chiara, G., 1991. Profound depression of mesolimbic dopamine release after morphine withdrawal in dependentrats. European Journal of Pharmacology 193, 133134.

Ahmed, S.H., Koob, G.F., 1998. Transition from moderate to excessivedrug intake: change in hedonic set point. Science 282, 298300.

Alburges, M.E., Narang, N., Wamsley, J.K., 1993. Alterations in thedopaminergic receptor system after chronic administration of cocaine.

Synapse 14, 314323.American Psychiatric Association, 2000. Diagnostic and Statistical

Manual of Mental Disorders Fourth Edition Text Revision (DSM-IV-TR). American Psychiatric Association, Washington, DC.

Antelman, S.M., Caggiula, A.R., 1977. Norepinephrine-dopamine inter-actions and behavior. Science 195, 646653.

Antelman, S.M., Caggiula, A.R., 1996. Oscillation follows drug sensitiza-tion: implications. Critical Reviews in Neurobiology 10, 101117.

Appleton, N., 1996. Lick the Sugar Habit. Nancy Appleton, SantaMonica.

Aravich, P.F., Rieg, T.S., Lauterio, T.J., Doerries, L.E., 1993. Beta-endorphin and dynorphin abnormalities in rats subjected to exerciseand restricted feeding: relationship to anorexia nervosa? BrainResearch 622, 18.

Ary, M., Chesarek, W., Sorensen, S.M., Lomax, P., 1976. Naltrexone-

induced hypothermia in the rat. European Journal of Pharmacology39, 215220.

Avena, N.M., Hoebel, B.G., 2003a. Amphetamine-sensitized rats showsugar-induced hyperactivity (cross-sensitization) and sugar hyperpha-gia. Pharmacology Biochemistry and Behavior 74, 635639.

Avena, N.M., Hoebel, B.G., 2003b. A diet promoting sugar dependencycauses behavioral cross-sensitization to a low dose of amphetamine.Neuroscience 122, 1720.

Avena, N.M., Carrillo, C.A., Needham, L., Leibowitz, S.F., Hoebel, B.G.,2004. Sugar-dependent rats show enhanced intake of unsweetenedethanol. Alcohol 34, 203209.

Avena, N.M., Long, K.A., Hoebel, B.G., 2005. Sugar-dependent ratsshow enhanced responding for sugar after abstinence: evidence of asugar deprivation effect. Physiology & Behavior 84, 359362.

Avena, N.M., Rada, P., Moise, N., Hoebel, B.G., 2006. Sucrose sham

feeding on a binge schedule releases accumbens dopamine repeatedlyand eliminates the acetylcholine satiety response. Neuroscience 139,813820.

Bailey, A., Gianotti, R., Ho, A., Kreek, M.J., 2005. Persistent upregula-tion of mu-opioid, but not adenosine, receptors in brains of long-termwithdrawn escalating dose binge cocaine-treated rats. Synapse 57,160166.

Bakshi, V.P., Kelley, A.E., 1994. Sensitization and conditioning of feedingfollowing multiple morphine microinjections into the nucleus accum-bens. Brain Research 648, 342346.

Bals-Kubik, R., Herz, A., Shippenberg, T.S., 1989. Evidence that theaversive effects of opioid antagonists and kappa-agonists are centrallymediated. Psychopharmacology (Berl) 98, 203206.

Bancroft, J., Vukadinovic, Z., 2004. Sexual addiction, sexual compulsivity,sexual impulsivity, or what? Toward a theoretical model. Journal of Sex Research 41, 225234.

Bassareo, V., Di Chiara, G., 1997. Differential inuence of associative andnonassociative learning mechanisms on the responsiveness of pre-frontal and accumbal dopamine transmission to food stimuli in ratsfed ad libitum. Journal of Neuroscience 17, 851861.

Bassareo, V., Di Chiara, G., 1999. Modulation of feeding-inducedactivation of mesolimbic dopamine transmission by appetitive stimuliand its relation to motivational state. European Journal of Neu-

roscience 11, 43894397.Bello, N.T., Lucas, L.R., Hajnal, A., 2002. Repeated sucrose accessinuences dopamine D2 receptor density in the striatum. Neuroreport13, 15751578.

Bello, N.T., Sweigart, K.L., Lakoski, J.M., Norgren, R., Hajnal, A., 2003.Restricted feeding with scheduled sucrose access results in anupregulation of the rat dopamine transporter. American Journal of PhysiologyRegulatory Integrative and Comparative Physiology 284,R1260R1268.

Bencherif, B., Guarda, A.S., Colantuoni, C., Ravert, H.T., Dannals, R.F.,Frost, J.J., 2005. Regional mu-opioid receptor binding in insularcortex is decreased in bulimia nervosa and correlates inversely withfasting behavior. Journal of Nuclear Medicine 46, 13491351.

Berridge, K.C., 1996. Food reward: brain substrates of wanting and liking.Neuroscience and Biobehavioral Reviews 20, 125.

Berridge, K.C., Robinson, T.E., 1998. What is the role of dopamine inreward: hedonic impact, reward learning, or incentive salience? BrainResearch Reviews 28, 309369.

Berthoud, H.R., Jeanrenaud, B., 1982. Sham feeding-induced cephalicphase insulin release in the rat. American Journal of Physiology 242,E280E285.

Bienkowski, P., Rogowski, A., Korkosz, A., Mierzejewski, P., Radwans-ka, K., Kaczmarek, L., Bogucka-Bonikowska, A., Kostowski, W.,2004. Time-dependent changes in alcohol-seeking behaviour duringabstinence. European Neuropsychopharmacology 14, 355360.

Blomqvist, O., Ericson, M., Johnson, D.H., Engel, J.A., Soderpalm, B.,1996. Voluntary ethanol intake in the rat: effects of nicotinicacetylcholine receptor blockade or subchronic nicotine treatment.European Journal of Pharmacology 314, 257267.

Bock, B.C., Kanarek, R.B., Aprille, J.R., 1995. Mineral content of the diet

alters sucrose-induced obesity in rats. Physiology & Behavior 57,659668.

Boggiano, M.M., Chandler, P.C., Viana, J.B., Oswald, K.D., Maldonado,C.R., Wauford, P.K., 2005. Combined dieting and stress evokeexaggerated responses to opioids in binge-eating rats. BehavioralNeuroscience 119, 12071214.

Bozarth, M.A., Wise, R.A., 1981. Intracranial self-administration of morphine into the ventral tegmental area in rats. Life Sciences 28,551555.

Bozarth, M.A., Wise, R.A., 1985. Toxicity associated with long-termintravenous heroin and cocaine self-administration in the rat. Journalof the American Medical Association 254, 8183.

Bozarth, M.A., Wise, R.A., 1986. Involvement of the ventral tegmentaldopamine system in opioid and psychomotor stimulant reinforcement.NIDA Research Monographs 67, 190196.

Bray, G.A., York, B., DeLany, J., 1992. A survey of the opinions of obesity experts on the causes and treatment of obesity. AmericanJournal of Clinical Nutrition 55, 151S154S.

Bray, G.A., Nielsen, S.J., Popkin, B.M., 2004. Consumption of high-fructose corn syrup in beverages may play a role in theepidemic of obesity. American Journal of Clinical Nutrition 79,537543.

Brewerton, T.D., Lydiard, R.B., Laraia, M.T., Shook, J.E., Ballenger,J.C., 1992. CSF beta-endorphin and dynorphin in bulimia nervosa.American Journal of Psychiatry 149, 10861090.

Buda-Levin, A., Wojnicki, F.H., Corwin, R.L., 2005. Baclofen reduces fatintake under binge-type conditions. Physiology & Behavior 86,176184.

Carr, K.D., 2006. Chronic food restriction: Enhancing effects on drugreward and striatal cell signaling. Physiology & Behavior, Epub aheadof print.

ARTICLE IN PRESS



15/20

Carroll, M.E., 1985. The role of food deprivation in the maintenance andreinstatement of cocaine-seeking behavior in rats. Drug and AlcoholDependence 16, 95109.

Carroll, M.E., Anderson, M.M., Morgan, A.D., 2007. Regulation of intravenous cocaine self-administration in rats selectively bred for high(HiS) and low (LoS) saccharin intake. Psychopharmacology (Berl) 190,331341.

Chau, D., Rada, P.V., Kosloff, R.A., Hoebel, B.G., 1999. Cholinergic, M1receptors in the nucleus accumbens mediate behavioral depression. Apossible downstream target for uoxetine. Annals of the New YorkAcademy of Sciences 877, 769774.

Cheer, J.F., Wassum, K.M., Heien, M.L., Phillips, P.E., Wightman, R.M.,2004. Cannabinoids enhance subsecond dopamine release in thenucleus accumbens of awake rats. Journal of Neuroscience 24,43934400.

Colantuoni, C., Schwenker, J., McCarthy, J., Rada, P., Ladenheim, B.,Cadet, J.L., Schwartz, G.J., Moran, T.H., Hoebel, B.G., 2001.Excessive sugar intake alters binding to dopamine and mu-opioidreceptors in the brain. Neuroreport 12, 35493552.

Colantuoni, C., Rada, P., McCarthy, J., Patten, C., Avena, N.M.,Chadeayne, A., Hoebel, B.G., 2002. Evidence that intermittent,excessive sugar intake causes endogenous opioid dependence. Obesity

Research 10, 478488.Comings, D.E., Gade-Andavolu, R., Gonzalez, N., Wu, S., Muhleman,D., Chen, C., Koh, P., Farwell, K., Blake, H., Dietz, G., MacMurray,J.P., Lesieur, H.R., Rugle, L.J., Rosenthal, R.J., 2001. The additiveeffect of neurotransmitter genes in pathological gambling. ClinicalGenetics 60, 107116.

Corwin, R.L., 2006. Bingeing rats: a model of intermittent excessivebehavior? Appetite 46, 1115.

Covington, H.E., Miczek, K.A., 2001. Repeated social-defeat stress,cocaine or morphine. Effects on behavioral sensitization andintravenous cocaine self-administration binges. Psychopharmacol-ogy (Berl) 158, 388398.

Curry, D.L., 1989. Effects of mannose and fructose on the synthesis andsecretion of insulin. Pancreas 4, 29.

Davis, C., Claridge, G., 1998. The eating disorders as addiction: a

psychobiological perspective. Addictive Behaviors 23, 463475.De Vries, T.J., Shippenberg, T.S., 2002. Neural systems underlying opiate

addiction. Journal of Neuroscience 22, 33213325.De Witte, P., Pinto, E., Ansseau, M., Verbanck, P., 2003. Alcohol and

withdrawal: from animal research to clinical issues. Neuroscience andBiobehavioral Reviews 27, 189197.

Deas, D., May, M.P., Randall, C., Johnson, N., Anton, R., 2005.Naltrexone treatment of adolescent alcoholics: an open-label pilotstudy. Journal of Child and Adolescent Psychopharmacology 15,723728.

Deneau, G., Yanagita, T., Seevers, M.H., 1969. Self-administration of psychoactive substances by the monkey. Psychopharmacologia 16,3048.

Deroche-Gamonet, V., Belin, D., Piazza, P.V., 2004. Evidence foraddiction-like behavior in the rat. Science 305, 10141017.

DesMaisons, K., 2001. Your Last Diet!: The Sugar Addicts Weight-lossPlan. Random House, Toronto.

Di Chiara, G., Imperato, A., 1986. Preferential stimulation of dopaminerelease in the nucleus accumbens by opiates, alcohol, and barbiturates:studies with transcerebral dialysis in freely moving rats. Annals of theNew York Academy of Sciences 473, 367381.

Di Chiara, G., Imperato, A., 1988. Drugs abused by humans preferentiallyincrease synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proceedings of the National Academy of SciencesUSA 85, 52745278.

Di Chiara, G., Tanda, G., 1997. Blunting of reactivity of dopaminetransmission to palatable food: a biochemical marker of anhedonia inthe CMS model? Psychopharmacology (Berl) 134, 351353.

Dickinson, A., Wood, N., Smith, J.W., 2002. Alcohol seeking by rats:action or habit? Quarterly Journal of Experimental Psychology B 55,331348.

Drewnowski, A., Krahn, D.D., Demitrack, M.A., Nairn, K., Gosnell,B.A., 1992. Taste responses and preferences for sweet high-fat foods:evidence for opioid involvement. Physiology & Behavior 51, 371379.

Dum, J., Gramsch, C., Herz, A., 1983. Activation of hypothalamic beta-endorphin pools by reward induced by highly palatable food.Pharmacology Biochemistry and Behavior 18, 443447.

Ellgren, M., Spano, S.M., Hurd, Y.L., 2007. Adolescent cannabis

exposure alters opiate intake and opioid limbic neuronal populationsin adult rats. Neuropsychopharmacology 32, 607615.Elliott, S.S., Keim, N.L., Stern, J.S., Teff, K., Havel, P.J., 2002. Fructose,

weight gain, and the insulin resistance syndrome. American Journal of Clinical Nutrition 76, 911922.

Epejo, E.F., Stinus, L., Cador, M., Mir, D., 1994. Effects of morphine andnaloxone on behaviour in the hot plate test: an ethopharmacologicalstudy in the rat. Psychopharmacology (Berl) 113, 500510.

Everitt, B.J., Wolf, M.E., 2002. Psychomotor stimulant addiction: a neuralsystems perspective. Journal of Neuroscience 22, 33123320.

Ferrario, C.R., Robinson, T.E., 2007. Amphetamine pretreatmentaccelerates the subsequent escalation of cocaine self-administrationbehavior. European Neuropsychopharmacology 17, 352357.

File, S.E., Andrews, N., 1991. Low but not high doses of buspirone reducethe anxiogenic effects of diazepam withdrawal. Psychopharmacology

(Berl) 105, 578582.File, S.E., Lippa, A.S., Beer, B., Lippa, M.T., 2004. Unit 8.4 Animal testsof anxiety. In: Crawley, J.N., et al. (Eds.), Current Protocols inNeuroscience. John Wiley & Sons, Inc., Indianapolis.

Finlayson, G., King, N., Blundell, J.E., 2007. Is it possible to dissociateliking and wanting for foods in humans? A novel experimentalprocedure. Physiology & Behavior 90, 3642.

Fiorino, D.F., Phillips, A.G., 1999. Facilitation of sexual behavior andenhanced dopamine efux in the nucleus accumbens of male rats afterD-amphetamine-induced behavioral sensitization. Journal of Neu-roscience 19, 456463.

Fiserova, M., Consolo, S., Krsiak, M., 1999. Chronic morphine induceslong-lasting changes in acetylcholine release in rat nucleus accumbenscore and shell: an in vivo microdialysis study. Psychopharmacology(Berl) 142, 8594.

Foley, K.A., Fudge, M.A., Kavaliers, M., Ossenkopp, K.P., 2006.Quinpirole-induced behavioral sensitization is enhanced by priorscheduled exposure to sucrose: a multi-variable examination of locomotor activity. Behavioral Brain Research 167, 4956.

Foster, J., Brewer, C., Steele, T., 2003. Naltrexone implants cancompletely prevent early (1-month) relapse after opiate detoxication:a pilot study of two cohorts totalling 101 patients with a note onnaltrexone blood levels. Addiction Biology 8, 211217.

Fullerton, D.T., Getto, C.J., Swift, W.J., Carlson, I.H., 1985. Sugar,opioids and binge eating. Brain Research Bulletin 14, 673680.

Galic, M.A., Persinger, M.A., 2002. Voluminous sucrose consumption infemale rats: increased nippiness during periods of sucrose removaland possible oestrus periodicity. Psychological Reports 90, 5860.

Gendall, K.A., Sullivan, P.E., Joyce, P.R., Carter, F.A., Bulik, C.M.,1997. The nutrient intake of women with bulimia nervosa. Interna-

tional Journal of Eating Disorders 21, 115127.Georges, F., Stinus, L., Bloch, B., Le Moine, C., 1999. Chronic morphine

exposure and spontaneous withdrawal are associated with modica-tions of dopamine receptor and neuropeptide gene expression in the ratstriatum. European Journal of Neuroscience 11, 481490.

Gerber, G.J., Wise, R.A., 1989. Pharmacological regulation of intrave-nous cocaine and heroin self-administration in rats: a variable doseparadigm. Pharmacology Biochemistry and Behavior 32, 527531.

Gessa, G.L., Muntoni, F., Collu, M., Vargiu, L., Mereu, G., 1985. Lowdoses of ethanol activate dopaminergic neurons in the ventraltegmental area. Brain Research 348, 201203.

Gillman, M.A., Lichtigfeld, F.J., 1986. The opioids, dopamine, cholecys-tokinin, and eating disorders. Clinical Neuropharmacology 9, 9197.

Glass, M.J., Billington, C.J., Levine, A.S., 1999. Opioids and foodintake: distributed functional neural pathways? Neuropeptides 33,360368.

ARTICLE IN PRESS



16/20

Glick, S.D., Shapiro, R.M., Drew, K.L., Hinds, P.A., Carlson, J.N., 1986.Differences in spontaneous and amphetamine-induced rotationalbehavior, and in sensitization to amphetamine, among Sprague-Dawley derived rats from different sources. Physiology & Behavior38, 6770.

Glimcher, P.W., Giovino, A.A., Margolin, D.H., Hoebel, B.G., 1984.Endogenous opiate reward induced by an enkephalinase inhibitor,

thiorphan, injected into the ventral midbrain. Behavioral Neuroscience98, 262268.Glimcher, P.W., Giovino, A.A., Hoebel, B.G., 1987. Neurotensin

self-injection in the ventral tegmental area. Brain Research 403,147150.

Glowa, J.R., Rice, K.C., Matecka, D., Rothman, R.B., 1997. Phenter-mine/fenuramine decreases cocaine self-administration in rhesusmonkeys. Neuroreport 8, 13471351.

Gosnell, B.A., 2005. Sucrose intake enhances behavioral sensitizationproduced by cocaine. Brain Research 1031, 194201.

Greenberg, B.D., Segal, D.S., 1985. Acute and chronic behavioralinteractions between phencyclidine (PCP) and amphetamine: evidencefor a dopaminergic role in some PCP-induced behaviors. Pharmacol-ogy Biochemistry and Behavior 23, 99105.

Grimm, J.W., Hope, B.T., Wise, R.A., Shaham, Y., 2001. Neuroadapta-

tion. Incubation of cocaine craving after withdrawal. Nature 412,141142.Grimm, J.W., Fyall, A.M., Osincup, D.P., 2005. Incubation of sucrose

craving: effects of reduced training and sucrose pre-loading. Physiol-ogy & Behavior 84, 7379.

Haber, S.N., Lu, W., 1995. Distribution of preproenkephalin messengerRNA in the basal ganglia and limbic-associated regions of the monkeytelencephalon. Neuroscience 65, 417429.

Hajnal, A., Norgren, R., 2002. Repeated access to sucrose augmentsdopamine turnover in the nucleus accumbens. Neuroreport 13,22132216.

Hajnal, A., Mark, G.P., Rada, P.V., Lenard, L., Hoebel, B.G., 1997.Norepinephrine microinjections in the hypothalamic paraventricularnucleus increase extracellular dopamine and decrease acetylcholine inthe nucleus accumbens: relevance to feeding reinforcement. Journal of

Neurochemistry 68, 667674.Hajnal, A., Szekely, M., Galosi, R., Lenard, L., 2000. Accumbens

cholinergic interneurons play a role in the regulation of body weightand metabolism. Physiology & Behavior 70, 95103.

Hajnal, A., Smith, G.P., Norgren, R., 2004. Oral sucrose stimulationincreases accumbens dopamine in the rat. American Journal of PhysiologyRegulatory Integrative and Comparative Physiology286, R31R37.

Harris, G.C., Wimmer, M., Aston-Jones, G., 2005. A role for lateralhypothalamic orexin neurons in reward seeking. Nature 437, 556559.

Helm, K.A., Rada, P., Hoebel, B.G., 2003. Cholecystokinin combinedwith serotonin in the hypothalamus limits accumbens dopaminerelease while increasing acetylcholine: a possible satiation mechanism.Brain Research 963, 290297.

Henningeld, J.E., Clayton, R., Pollin, W., 1990. Involvement of tobacco

in alcoholism and illicit drug use. British Journal of Addiction 85,279291.

Hernandez, L., Hoebel, B.G., 1988. Food reward and cocaine increaseextracellular dopamine in the nucleus accumbens as measured bymicrodialysis. Life Sciences 42, 17051712.

Heubner, H., 1993. Endorphins, Eating Disorders and Other AddictiveBehaviors. W. W. Norton, New York.

Hoebel, B.G., 1985. Brain neurotransmitters in food and drug reward.American Journal of Clinical Nutrition 42, 11331150.

Hoebel, B.G., He

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