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Evidence for sugar addiction: Behavioral and neurochemical
effects of intermittent, excessive sugar intake
Nicole M. Avena, Pedro Rada, and Bartley G. Hoebel*
Department of Psychology, Princeton University, Princeton, NJ 08540 USA
Abstract
The experimental question is whether or not sugar can be a substance of abuse and lead to a natural
form of addiction. “Food addiction” seems plausible because brain pathways that evolved to respond
to natural rewards are also activated by addictive drugs. Sugar is noteworthy as a substance that
releases opioids and dopamine and thus might be expected to have addictive potential. This review
summarizes evidence of sugar dependence in an animal model. Four components of addiction are
analyzed. “Bingeing”, “withdrawal”, “craving” and cross-sensitization are each given operational
definitions and demonstrated behaviorally with sugar bingeing as the reinforcer. These behaviors are
then related to neurochemical changes in the brain that also occur with addictive drugs. Neural
adaptations include changes in dopamine and opioid receptor binding, enkephalin mRNA expression
and dopamine and acetylcholine release in the nucleus accumbens. The evidence supports the
hypothesis that under certain circumstances rats can become sugar dependent. This may translate to
some human conditions as suggested by the literature on eating disorders and obesity.
Keywords
binge eating; dopamine; acetylcholine; opioid; nucleus accumbens; withdrawal; craving; behavioral
sensitization; rat
1. OVERVIEW
Neural systems that evolved to motivate and reinforce foraging and food intake also underlie
drug-seeking and self-administration. The fact that some of these drugs can cause addiction
raises the logical possibility that some foods might also cause addcition. Many people claim
that they feel compelled to eat sweet foods, similar in some ways to how an alcoholic might
feel compelled to drink. Therefore, we developed an animal model to investigate why some
people have difficulty moderating their intake of palatable foods, such as sweet beverages.
In this animal model, rats are food deprived daily for 12 h, then after a delay of 4 h into their
normal circadian-driven active period, they are given 12-h access to a sugar solution and chow.
As a result, they learn to drink the sugar solution copiously, especially when it first becomes
available each day.
After a month on this intermittent-feeding schedule, the animals show a series of behaviors
similar to the effects of drugs of abuse. These are categorized as “bingeing”, meaning unusually
*Send correspondence to: Dr. Bart Hoebel, Princeton University, Department of Psychology, Princeton, NJ 08540, Phone: (609)
258-4463, Fax: (609) 258-1113, E-mail: hoebel@princeton.edu.
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Published in final edited form as:
Neurosci Biobehav Rev. 2008 ; 32(1): 20–39.
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large bouts of intake, opiate-like “withdrawal” indicated by signs of anxiety and behavioral
depression (Colantuoni et al., 2001, 2002), and “craving” measured during sugar abstinence
as enhanced responding for sugar (Avena et al., 2005). There are also signs of both locomotor
and consummatory “cross-sensitization” from sugar to drugs of abuse (Avena et al., 2004,
Avena and Hoebel, 2003b). Having found these behaviors that are common to drug dependency
with supporting evidence from other laboratories (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 their ability to cause repeated, intermittent
increases in extracellular dopamine (DA) in the nucleus accumbens (NAc) (Di Chiara and
Imperato, 1988, Hernandez and Hoebel, 1988, Wise et al., 1995). We find that rats with
intermittent access to sugar will drink in a binge-like manner that releases 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 expression or availability of DA receptors
(Colantuoni et al., 2001, Spangler et al., 2004).
Intermittent sugar access also acts by way of opioids in the brain. There are changes in opioid
systems such as decreased enkephalin mRNA expression in the accumbens (Spangler et al.,
2004). Signs of withdrawal seem to be largely due to the opioid modifications since withdrawal
can be obtained with the opioid antagonist naloxone. Food deprivation is also sufficient to
precipitate opiate-like withdrawal signs (Avena, Bocarsly, Rada, Kim and Hoebel,
unpublished, Colantuoni et al., 2002). This withdrawal state involves at least two
neurochemical manifestations. First is a decrease in extracellular DA in the accumbens, and
second is the release of acetylcholine (ACh) from accumbens interneurons. These
neurochemical adaptations in response to intermittent sugar intake mimic the effects of opiates.
The theory is formulated that intermittent, excessive intake of sugar can have dopaminergic,
cholinergic and opioid effects that are similar to psychostimulants and opiates, albeit smaller
in magnitude. The overall effect of these neurochemical adaptations is mild, but well-defined,
dependency (Hoebel et al., 1999, Leibowitz and Hoebel, 2004, Rada et al., 2005a). This review
compiles studies from our laboratory and integrates related results obtained by others using
animal models, clinical accounts and brain imaging to answer the question: can sugar, in some
conditions, be “addictive”?
2. DEFINING ADDICTION
Throughout this review we use several terms with definitions 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 been investigated (Bancroft and
Vukadinovic, 2004, Comings et al., 2001, Petry, 2006). The term “addiction” implies
psychological dependence and thus is a mental or cognitive problem, not just a physical
ailment. “Addiction” is often used synonymously with the term “dependence” (Nelson et al.,
1982) as defined by DSM-IV-TR (American Psychiatric Association, 2000). We will use the
term dependence in its all-encompassing meaning to describe the results of a battery of animal
studies that model human drug addiction in each of its major phases (Koob and Le Moal,
2005).
Drug dependence is characterized by compulsive, sometimes uncontrollable, behaviors that
occur at the expense of other activities and intensify with repeated access. Dependence is
difficult to demonstrate convincingly in laboratory animals, but criteria have been suggested
using animal models. We have used models that were developed with rats for studying drug
dependence and adapted them to test for signs of sugar dependence.
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Bingeing
The diagnostic criteria for addiction can be grouped into three stages (American Psychiatric
Association, 2000, Koob and Le Moal, 1997). The first, bingeing, is defined as the escalation
of intake with a high proportion of intake at one time, usually after a period of voluntary
abstinence or forced deprivation. Enhanced intake in the form of binges may result from both
sensitization and tolerance to the sensory properties of a substance of abuse that occurs with
its repeated delivery. Sensitization, which is described in greater detail below, is an increase
in responsiveness to a repeatedly presented stimulus. Tolerance is a gradual decrease in
responsiveness, such that more of the substance is needed to produce the same effect
(McSweeney et al., 2005). Both are thought to influence the powerful, acute reinforcing effects
of drugs of abuse and are important at the beginning of the addiction cycle since both can
increase responding and intake (Koob and Le Moal, 2005).
Withdrawal
Signs of withdrawal become apparent when the abused substance is no longer available or
chemically blocked. We will discuss withdrawal in terms of opiate withdrawal, which has a
clearly defined set of symptoms (Martin et al., 1963, Way et al., 1969). Anxiety can be
operationally defined and measured in animals using the elevated plus-maze, in which anxious
animals will avoid spending time on the open arms of the maze (File et al., 2004). This test has
been extensively validated for both general anxiety (Pellow et al., 1985) and anxiety induced
by drug withdrawal (File and Andrews, 1991). Behavioral depression in animals can also be
inferred, without reference to emotion, using the forced-swim test, which measures swimming
escape efforts vs. passive floating (Porsolt et al., 1978). When signs of opiate withdrawal are
precipitated with naloxone, it suggests that inactivation of opioid receptors is the cause. When
the same signs are produced spontaneously during abstinence, one can surmise that it is due to
lack of stimulation of some opioid system.
Craving
The third stage of addiction, craving, occurs when motivation is enhanced, usually after an
abstinence period (Vanderschuren and Everitt, 2005, Weiss, 2005). “Craving” remains a poorly
defined term that is often used to describe the intense desire to self-administer drugs in humans
(Wise, 1988). For lack of a better word, we will use the term “craving” as defined by increased
efforts to obtain a substance of abuse or its associated cues as a result of addiction and
abstinence. “Craving” often has reference to extreme motivation, which can be measured using
operant conditioning. If abstinence makes the animal significantly increase its lever pressing,
one can take this as a sign of enhanced motivation.
Sensitization
In addition to the above diagnostic criteria, behavioral sensitization is thought to underlie some
aspects of drug dependence (Vanderschuren and Kalivas, 2000). Behavioral sensitization is
typically measured as increased locomotion in response to repeated administrations of a drug.
For example, after repeated doses of amphetamine followed by abstinence, a challenge dose,
which has little or no effect in naïve animals, causes marked hyperactivity (Antelman and
Caggiula, 1996, Glick et al., 1986). Animals sensitized to one substance often show cross-
sensitization, which is defined as an increased locomotor response to a different drug or
substance. Cross-sensitization can also be manifest in consummatory behavior (Piazza et al.,
1989). Animals sensitized to one drug may show increased intake of a different drug. In other
words, one drug acts as a “gateway” to another. For example, animals sensitized to
amphetamine show accelerated escalation of cocaine intake (Ferrario and Robinson, 2007),
and animals sensitized to nicotine consume more alcohol compared with non-sensitized
animals (Blomqvist et al., 1996). This behavior is thought to occur when different drugs activate
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the same neural circuitry, and it is the reason why many clinicians require complete drug
abstention as a condition of treatment for addicts (Wise, 1988).
The first question addressed by this review is whether any of these operationally defined
behavioral characteristics of substance dependence can be found with intermittent sugar access.
The second question explores neural systems to discover how sugar could have effects like a
drug of abuse.
3. DRUGS OF ABUSE AND PALATABLE FOOD ACTIVATE A COMMON
SUBSET OF NEURAL SYSTEMS
Overlaps in the brain circuitry activated by food and drug intake suggests that different types
of reinforcers (natural and artificial) stimulate some of the same neural systems (Hoebel,
1985, Hernandez and Hoebel, 1988, Kelley et al., 2002, Le Magnen, 1990, Volkow and Wise,
2005, Wise, 1988, 1989). There are several regions in the brain involved in the reinforcement
of both feeding and drug intake (Hernandez and Hoebel, 1988, Kalivas and Volkow, 2005,
Kelley et al., 2005, Koob and Le Moal, 2005, Mogenson and Yang, 1991, Wise, 1997,
Yeomans, 1995), and many neurotransmitters, as well as hormones, have been studied in these
and related brain regions (Harris et al., 2005, Kalivas, 2004, Leibowitz and Hoebel, 2004,
Schoffelmeer et al., 2001, Stein and Belluzzi, 1979). This review will focus on DA, the opioids,
and ACh in the NAc shell, which so far, are the neurotransmitters that we have found to be
involved with the reinforcing effects of intermittent sugar intake.
3.A. Dopamine
It is well established that addictive drugs activate DA-containing neurons in areas of the brain
that process behavior reinforcement. This was shown for drugs delivered systemically (Di
Chiara and Imperato, 1988, Radhakishun et al., 1983), and for drugs micro-injected or infused
locally (Hernandez and Hoebel, 1988, Mifsud et al., 1989). The mesolimbic DA projection
from the ventral tegmental area (VTA) to the NAc is frequently implicated 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 signaling a stimulus change (Bassareo and Di Chiara, 1999, Berridge and Robinson,
1998, Salamone, 1992, Schultz et al., 1997, Wise, 1988). Any neurotransmitter that directly or
indirectly stimulates DA cell bodies in the VTA reinforces 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 addictive drugs also act at DA terminals (Cheer et al.,
2004, Mifsud et al., 1989, Nisell et al., 1994, Westerink et al., 1987, Yoshimoto et al., 1992).
Thus, any substance that repeatedly causes the release of DA or reduces DA reuptake at
terminals via these circuits may be a candidate for abuse.
A variety of foods can release DA in the NAc, including lab chow, sugar, saccharin, and corn
oil (Bassareo and Di Chiara, 1997, Hajnal et al., 2004, Liang et al., 2006, Mark et al., 1991,
Rada et al., 2005b). The rise in extracellular DA can outlast the meal in food-deprived rats
(Hernandez and Hoebel, 1988). However, in satiated animals, this DA release appears to be
contingent on novelty since it wanes with repeated access, even when the food is palatable
(Bassareo and Di Chiara, 1997, Rada et al., 2005b). An exception, which is described below
(Section 5.C.), is when animals are food deprived and fed sugar intermittently.
Extracellular DA decreases in reaction to drug withdrawal (Acquas et al., 1991, Acquas and
Di Chiara, 1992, Rada et al., 2004, Rossetti et al., 1992). The symptoms of withdrawal from
dopaminergic drugs are less well-defined than those observed during withdrawal from opiates.
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Therefore, it may be easier to discern the signs of withdrawal when using foods that release
both DA and opioids. Sugar is one such food.
3.B. Opioids
Opioid peptides are heavily expressed throughout the limbic system and linked to DA systems
in many parts of the forebrain (Haber and Lu, 1995, Levine and Billington, 2004, Miller and
Pickel, 1980). The endogenous opioid systems exert some of their effects on reinforcement
processing by interacting with DA systems (Bozarth and Wise, 1986, Di Chiara and Imperato,
1986, Leibowitz and Hoebel, 2004). The opioid peptide enkephalin in the NAc has been related
to reward (Bals-Kubik et al., 1989, Bozarth and Wise, 1981, Olds, 1982, Spanagel et al.,
1990) and can activate both mu and delta receptors to increase the release of DA (Spanagel et
al., 1990). Morphine alters gene expression of endogenous opioid peptides while increasing
opioid peptide production in the NAc (Przewlocka et al., 1996, Spangler et al., 2003Turchan
et al., 1997). Opioids are also important components of this system as cotransmitters with
GABA in some accumbens and dorsal striatal outputs (Kelley et al., 2005).
Repeated use of opiates, or even some non-opiate drugs, can result in mu-opioid receptor
sensitization in several regions, including the NAc (Koob et al., 1992, Unterwald, 2001). A
mu-receptor antagonist injected into the NAc will attenuate the rewarding effects of heroin
(Vaccarino et al., 1985), and systemically such drugs have been used as a treatment for
alcoholism and heroin dependence (Deas et al., 2005, Foster et al., 2003, Martin, 1975, O’Brien,
2005, Volpicelli et al., 1992).
Ingestion of palatable foods has effects via endogenous opioids in a variety of sites (Dum et
al., 1983, Mercer and Holder, 1997, Tanda and Di Chiara, 1998), and the injection of 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 other hand, decrease ingestion of
sweet food and shorten meals of palatable, preferred foods, even at doses that have no effect
on standard chow intake (Glass et al., 1999). This opioid-palatability link is further
characterized by theories in which the reinforcing effect is dissociated into a dopaminergic
system for incentive motivation and an opioid “liking” or “pleasure” system for hedonic
responses (Berridge, 1996, Robinson and Berridge, 1993, Stein, 1978). Evidence that opioids
in the NAc influence hedonic reactions comes from data showing that morphine enhances rats’
positive facial taste reactivity for a sweet solution in the mouth (Pecina and Berridge, 1995).
The dissociation between the “wanting” and “liking” systems is also suggested by studies in
humans (Finlayson et al., 2007).
3.C. Acetylcholine
Several cholinergic systems in the brain have been implicated in both food and drug intake,
and related to DA and the opioids (Kelley et al., 2005, Rada et al., 2000, Yeomans, 1995).
Focusing on ACh interneurons in the NAc, systemic administration of morphine decreases
ACh turnover (Smith et al., 1984), a finding that was confirmed by in vivo microdialysis in
freely-behaving rats (Fiserova et al., 1999, Rada et al., 1991a, 1996). Cholinergic interneurons
in the NAc may selectively modulate enkephalin gene expression and peptide release (Kelley
et al., 2005). During morphine withdrawal, extracellular ACh increases in the NAc while DA
is low, suggesting that this neurochemical state could be involved in the aversive aspects of
withdrawal (Pothos et al., 1991, Rada et al., 1991b, 1996). Likewise, both nicotine and alcohol
withdrawal increase extracellular ACh, while decreasing DA in the NAc (De Witte et al.,
2003, Rada et al., 2001, 2004). This withdrawal state may involve behavioral depression,
because M1-receptor agonists injected in the NAc can cause depression in the forced-swim
test (Chau et al., 1999). The role of ACh in drug withdrawal has been further demonstrated
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with systemically administered acetylcholinesterase inhibitors, which can precipitate
withdrawal signs in non-dependent animals (Katz and Valentino, 1984, Turski et al., 1984).
ACh in the NAc has also been implicated in food intake. We theorize that its overall muscarinic
effect is to inhibit feeding at M1 receptors since local injection of the mixed muscarinic agonist
arecholine will inhibit feeding, and this effect can be blocked by the relatively specific M1
antagonist pirenzapine (Rada and Hoebel, unpublished). Feeding to satiety increases
extracellular ACh in the NAc (Avena et al., 2006, Mark et al., 1992). A conditioned taste
aversion also increases ACh in the NAc and simultaneously lowers DA (Mark et al., 1991,
1995). D-fenfluramine combined with phentermine (Fen-Phen) increases extracellular 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-lesioned rats (Hajnal et al., 2000).
DA/ACh balance is controlled in part by hypothalamic systems for feeding and satiety.
Norepinephrine and galanin, which induce eating when injected in the paraventricular nucleus
(PVN), lower accumbens ACh (Hajnal et al., 1997, Rada et al., 1998). An exception is
neuropeptide-Y, which fosters eating when injected into the PVN, 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 injection into the PVN increases accumbens ACh (Helm
et al., 2003).
It is very interesting that when DA is low and extracellular ACh is high, this apparently creates
not satiety, but instead an aversive state (Hoebel et al., 1999), as during behavioral depression
(Zangen et al., 2001, Rada et al., 2006), drug withdrawal (Rada et al., 1991b, 1996, 2001,
2004) and conditioned taste aversion (Mark et al., 1995). We conclude that when ACh acts as
a post-synaptic M1 agonist it has effects opposite to DA, and thus may act as a “brake” on
dopaminergic functions (Hoebel et al., 1999, Rada et al., 2007) causing satiety when DA is
high and behavioral depression when DA is relatively low.
4. BEHAVIORAL SIMILARITIES BETWEEN DRUG SELF-ADMINISTRATION
AND INTERMITTENT, EXCESSIVE SUGAR INTAKE
The concept of “sugar addiction” has been bandied about for many years. Clinical accounts of
“sugar addiction” have been the topic of many best-selling books and the focus for popular
diet programs (Appleton, 1996, DesMaisons, 2001, Katherine, 1996, Rufus, 2004). In these
accounts, people describe symptoms of withdrawal when they deprive themselves of sugar-
rich foods. They also describe food craving, particularly for carbohydrates, chocolate, and
sugar, which can trigger relapse and impulsive eating. This leads to a vicious cycle of self-
medication with sweet foods that may result in obesity or an eating disorder.
Although food addiction has been popular in the media and proposed to be based on brain
neurochemistry (Hoebel et al., 1989, Le Magnen, 1990), this phenomenon has only recently
been systematically studied in the laboratory.
As outlined in the overview in Section 1, we use a feeding schedule that induces rats to binge
on a sugar solution, then apply the criteria for drug dependence that are presented in Section
2 and test for the behavioral and neurochemical commonalties given in Section 3. Rats are
given 12-h daily access to an aqueous 10% sucrose solution (25% glucose in some experiments)
and lab chow, followed by 12 h of deprivation for three or more weeks (i.e., Daily Intermittent
Sugar and Chow). These rats are compared with control groups such as Ad libitum Sugar and
Chow, Ad libitum Chow, or Daily Intermittent Chow (12-h deprivation followed by 12-h access
to lab chow). For the intermittent access groups, availability is delayed 4 h into the animal’s
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active period in order to stimulate feeding, which normally ensues at the onset of the dark cycle.
Rats maintained on the Daily Intermittent Sugar and Chow regimen enter a state that resembles
drug dependence on several dimensions. These are divided into behavioral (Section 4) and
neurochemical (Section 5) similarities to drug dependence.
4.A. “Bingeing”: Escalation of daily sugar intake and large meals
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 same euphoric effects
(Koob and Le Moal, 2005), and sensitization, such as locomotor sensitization, in which the
substance produces enhanced behavioral activation (Vezina et al., 1989). Studies using drug
self-administration usually limit access to a few hours per day, during which animals will self-
administer in regular intervals that vary as a function of the dose received (Gerber and Wise,
1989) and in a manner that keeps extracellular DA elevated 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 self-administration behavior. For example, the most cocaine is
self-administered during the first 10 min of a session when access is at least 6 h per day (Ahmed
and Koob, 1998). Limited periods of access, to create “binges”, have been useful, because the
pattern of self-administration behavior that emerges is similar to that of a “compulsive” drug
user (Markou et al., 1993, Mutschler and Miczek, 1998, O’Brien et al., 1998). Even when
drugs, such as cocaine, are given with unlimited access, humans or laboratory animals will
self-administer them in repetitive episodes or “binges” (Bozarth and Wise, 1985, Deneau et
al., 1969). However, experimenter-imposed intermittent access is better than ad libitum access
for experimental purposes, since it becomes very likely that the animal will take at least one
large binge at the onset of the drug-availability period. Moreover, a period of food restriction
can enhance drug intake (Carr, 2006, Carroll, 1985) and has been shown to produce
compensatory neruoadaptations in the mesoaccumbens DA system (Pan et al., 2006).
The behavioral findings with sugar are similar to those observed with drugs of abuse. Rats fed
daily intermittent sugar and chow escalate their sugar intake and increase their intake during
the first hour of daily access, which we define as a “binge” (Colantuoni et al., 2001). The
animals with ad libitum access to a sugar solution tend to drink it throughout the day, including
their inactive period. Both groups increase their overall intake, but the limited-access animals
consume as much sugar in 12 h as ad libitum-fed animals do in 24 h. Detailed meal pattern
analysis using operant conditioning (fixed-ratio 1) reveals that the limited animals consume a
large meal of sugar at the onset of access, and larger, fewer meals of sugar throughout the
access period, compared with animals drinking sugar ad libitum (Fig. 1; Avena and Hoebel,
unpublished). Rats fed Daily Intermittent Sugar and Chow regulate their caloric intake by
decreasing their chow intake to compensate for the extra calories obtained from sugar, which
results in a normal body weight (Avena, Bocarsly, Rada, Kim and Hoebel, unpublished, Avena
et al., 2003b, Colantuoni et al., 2002).
4.B. “Withdrawal”: Anxiety and behavioral depression induced by an opioid-antagonist or
food deprivation
As described in Section 2, animals can show signs of opiate withdrawal after repeated exposure
when the substance of abuse is removed, or the appropriate synaptic receptor is blocked. For
example, an opioid antagonist can be used to precipitate withdrawal in the case of opiate
dependency (Espejo et al., 1994, Koob et al., 1992). In rats, opiate withdrawal causes severe
somatic signs (Martin et al., 1963, Way et al., 1969), decreases in body temperature (Ary et
al., 1976), aggression (Kantak and Miczek, 1986), and anxiety (Schulteis et al., 1998), as well
as a motivational syndrome characterized by dysphoria and depression (De Vries and
Shippenberg, 2002, Koob and Le Moal, 1997).
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These signs of opioid withdrawal have been noted after intermittent access 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 opioid antagonist 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 reduced
time spent on the exposed arm of an elevated plus-maze (Colantuoni et al., 2002) (Fig. 2).
Behavioral depression has also been found during naloxone-precipitated withdrawal in
intermittent sugar-fed rats. In this experiment, rats were given an initial 5-min forced-swim
test in which escape (swimming and climbing) and passive (floating) behaviors were measured.
Then the rats were divided into four groups that were fed Daily Intermittent Sucrose and Chow,
Daily Intermittent Chow, Ad libitum Sucrose and Chow, or Ad libitum Chow for 21 days. On
day 22, at the time that the intermittent-fed rats would normally receive their sugar and/or
chow, all rats were instead injected with naloxone (3 mg/kg, s.c.) to precipitate withdrawal and
were then placed in the water again for another test. In the group that had been fed Daily
Intermittent Sucrose and Chow, escape behaviors were significantly suppressed compared with
Ad libitum Sucrose and Chow and Ad libitum Chow controls (Fig. 3; Kim, Avena and Hoebel,
unpublished). This decrease in escape efforts that were replaced by passive floating suggests
the rats were experiencing behavioral depression during withdrawal.
Signs of opiate-withdrawal also emerge when all food is removed for 24 h. Again this includes
somatic signs such as teeth chattering, forepaw tremor and head shaking (Colantuoni et al.,
2002) and anxiety as measured with an elevated plus-maze (Avena, Bocarsly, Rada, Kim and
Hoebel, unpublished). Spontaneous withdrawal from the mere remove of sugar has been
reported using decreased body temperature as the criterion (Wideman et al., 2005). Also, signs
of aggressive behavior have been found during withdrawal of a diet that involves intermittent
sugar access (Galic and Persinger, 2002).
4.C. “Craving”: Enhanced responding for sugar following abstinence
As described in Section 2, “craving” in laboratory animals can be defined as enhanced
motivation to procure an abused substance (Koob and Le Moal, 2005). After self-administering
drugs of abuse and then being forced to abstain, animals often persist in unrewarded operant
responding (i.e., resistance to response extinction), and increase their responding for cues
previously associated with the drug that grows with time (i.e., incubation) (Bienkowski et al.,
2004, Grimm et al., 2001, Lu et al., 2004). Additionally, if the drug becomes available again,
animals will take more than they did prior to abstinence (i.e., the “deprivation effect”) (Sinclair
and Senter, 1968). This increase in motivation to procure a substance of abuse may contribute
to relapse. The power of “craving” is evidenced by results showing that animals will sometimes
face adverse consequences to obtain a substance of abuse such as cocaine or alcohol (Deroche-
Gamonet et al., 2004, Dickinson et al., 2002, Vanderschuren and Everitt, 2004). These signs
in laboratory animals mimic those observed with humans in which the presentation of stimuli
previously associated with a drug of abuse increases self-reports of craving and the likelihood
of relapse (O’Brien et al., 1977, 1998).
We used the “deprivation effect” paradigm to investigate consumption of sugar after abstinence
in rats that had been bingeing on sugar. Following 12-h daily access to sugar, rats lever press
for 23% more sugar in a test after 2 wks of abstinence than they ever did before (Fig. 4; Avena
et al., 2005). A group with 0.5-h daily access to sucrose did not show the effect. This provides
a cogent control group in which rats are familiar with the taste of sucrose, but have not
consumed it in a manner that leads to a deprivation effect. The results suggest a change in the
motivational impact of sugar that persists throughout two weeks of abstinence, leading to
enhanced intake.
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Additionally, like the drugs described above, the motivation to obtain sugar appears to
“incubate”, or grow, with the length of abstinence (Shalev et al., 2001). Using operant
conditioning, Grimm and colleagues (2005) find that sucrose seeking (lever pressing in
extinction and then for a sucrose-paired cue) increases during abstinence in rats after
intermittent sugar access for 10 days. Remarkably, responding for the cue was greater after 30
days of sugar abstinence compared with 1 week or 1 day. These results suggest the gradual
emergence of long-term changes in the neural circuitry underlying motivation as a result of
sugar self-administration and abstinence.
4.D. “Cross-sensitization”: Increased locomotor response to psychostimulants during sugar
abstinence
Drug-induced sensitization may play a role in the enhancement of drug self-administration and
is implicated as a factor contributing to drug addiction (Robinson and Berridge, 1993). In a
typical sensitization experiment, the animal receives a drug daily for about a week, then the
procedure stops. However, in the brain there are lasting, even growing, changes apparent a
week or more later when a low, challenge dose of the drug results in hyperlocomotion (Kalivas
et al., 1992). Additionally, cross-sensitization from one drug to another has been demonstrated
with several drugs of abuse, including amphetamine sensitizing rats 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 effect with non-drug substances.
Behavioral cross-sensitization between cocaine and stress has been demonstrated (Antelman
and Caggiula, 1977, Covington and Miczek, 2001, Prasad et al., 1998). Also, increases in food
intake (Bakshi and Kelley, 1994) or sexual behaviors (Fiorino and Phillips, 1999, Nocjar and
Panksepp, 2002) have been observed in animals with a history of drug sensitization.
We and others have found that Intermittent sugar intake cross-sensitizes with drugs of abuse.
Rats sensitized with daily amphetamine injections (3 mg/kg, i.p.) are hyperactive one week
later in response to tasting 10% sucrose (Avena and Hoebel, 2003a). Conversely, rats fed Daily
Intermittent Sugar and Chow show locomotor cross-sensitization to amphetamine.
Specifically, such animals are hyperactive in response to a low, challenge dose of amphetamine
(0.5 mg/kg, i.p.) that has no effect on naïve animals, even after 8 days of abstinence from sugar
(Fig. 5; Avena and Hoebel, 2003b). Rats maintained on this feeding schedule but administered
saline were not hyperactive, nor were rats in control groups (Daily Intermittent Chow, Ad
libitum Sugar and Chow, Ad libitum Chow) given the challenge dose of amphetamine.
Intermittent sucrose access also cross-sensitizes with cocaine (Gosnell, 2005) and facilitates
the development of sensitization to the DA agonist quinpirole (Foley et al., 2006). Thus, results
with three different DA agonists from three different laboratories support the theory that the
DA system is sensitized by intermittent sugar access, as evidenced by cross-sensitization. This
is important since enhanced mesolimbic dopaminergic neurotransmission plays a major role
in the behavioral effects of sensitization as well as cross-sensitization (Robinson and Berridge,
1993), and may contribute to addiction and comorbidity with poly-substance abuse.
4.E. “Gateway effect”: Increased alcohol intake during sugar abstinence
Numerous studies have found that sensitization to one drug can lead not only to hyperactivity,
but also to subsequent increased intake of another drug or substance (Ellgren et al., 2006,
Henningfield et al., 1990, Hubbell et al., 1993, Liguori et al., 1997, Nichols et al., 1991, Piazza
et al., 1989, Vezina, 2004, Vezina et al., 2002, Volpicelli et al., 1991). We refer to this
phenomenon as “consummatory cross-sensitization”. In the clinical literature, when one drug
leads to taking another, this is known as a “gateway effect”. It is particularly noteworthy when
a legal drug (e.g. nicotine) acts as a gateway to an illegal drug (e.g. cocaine) (Lai et al.,
2000).
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Rats maintained on intermittent sugar access and then forced to abstain, subsequently show
enhanced intake of 9% alcohol (Avena et al., 2004). This suggests that intermittent access to
sugar can be a gateway to alcohol use. Others have shown that animals that prefer sweet-taste
will self-administer cocaine at a higher rate (Carroll et al., 2006). As with the locomotor cross-
sensitization described above, underlying this behavior are presumably neurochemical
alterations in the brain, such as adaptations in DA and perhaps opioid functions.
5. NEUROCHEMICAL SIMILARITIES BETWEEN DRUG SELF-
ADMINISTRATION AND INTERMITTENT SUGAR INTAKE
The studies described above suggest that intermittent sugar access can produce numerous
behaviors that are similar to those observed in drug-dependent rats. In this section, we describe
neurochemical findings that may underlie sugar dependency. To the extent that these brain
alterations match the effects of drugs of abuse, it strengthens the case that sugar can resemble
a substance of abuse.
5.A. Intermittent sugar intake alters D1, D2 and mu-opioid receptor binding and mRNA
expression
Drugs of abuse can alter DA and opioid receptors in the mesolimbic regions of the brain.
Pharmacological studies with selective D1, D2 and D3 receptor antagonists and gene knockout
studies have revealed that all three receptor subtypes mediate the reinforcing effects drugs of
abuse. There is an up-regulation of D1 receptors (Unterwald et al., 1994) and increase in D1
receptor binding (Alburges et al., 1993, Unterwald et al., 2001) in response to cocaine.
Conversely, D2 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 gene expression of DA
receptors. Morphine and cocaine have been shown to decrease accumbens D2 receptor mRNA
(Georges et al., 1999, Turchan et al., 1997), and an increase in D3 receptor mRNA (Spangler
et al., 2003). These finding with laboratory animals support clinical studies, which have
revealed that D2 receptors are down-regulated in cocaine addicts (Volkow et al., 1996a,
1996b, 2006).
Similar changes have been reported with intermittent access to sugar. Autoradiography reveals
increased D1 in the NAc and decreased D2 receptor binding in the striatum (Fig. 6; Colantuoni
et al., 2001). This was relative to chow-fed rats, so it is not known whether ad libitum sugar
would also show this effect. Others have reported a decrease in D2 receptor binding in the NAc
of rats with restricted access to sucrose and chow compared with rats fed restriced chow only
(Bello et al., 2002). Rats with intermittent sugar and chow access also have decreases in D2
receptor mRNA in the NAc compared with ad libitum chow controls (Spangler et al., 2004).
mRNA levels of D3 receptor mRNA in the NAc are increased in the NAc and caudate-putamen.
Regarding the opioid receptors, mu-receptor binding is increased in response to cocaine and
morphine (Bailey et al., 2005, Unterwald et al., 2001, Vigano et al., 2003). Mu-opioid receptor
binding is also significantly enhanced after three weeks on the intermittent sugar diet, compared
with ad libitum chow. This effect was observed in the accumbens shell, cingulate, hippocampus
and locus coeruleus (Colantuoni et al., 2001).
5.B. Intermittent sugar intake alters enkephalin mRNA expression
Enkephalin mRNA in the striatum and the NAc is decreased 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 those observed in cocaine-dependent human subjects (Zubieta et
al., 1996).
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Rats with intermittent sugar access also display a significant decrease in enkephalin mRNA,
although it is difficult to judge its functional significance (Spangler et al., 2004). This decrease
in enkephalin mRNA is consistent with findings observed in rats with limited daily access to
a sweet-fat, liquid diet (Kelley et al., 2003). Assuming this decrease in mRNA results in less
enkephalin peptide being synthesized and released, it could account for a compensatory
increase in mu-opioid receptors, as cited above.
5.C. Daily intermittent sugar intake repeatedly releases dopamine in the accumbens
One of the strongest neurochemical commonalities between intermittent sugar access and drugs
of abuse has been found using in vivo microdialysis to measure extracellular DA. The repeated
increase in extracellular DA is a hallmark of drugs that are abused. Extracellular DA increases
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, Rada et al., 1991a) and drug-associated
stimuli (Ito et al., 2000). Unlike drugs of abuse, which exert their effects on DA release each
time they are administered (Pothos et al., 1991, Wise et al., 1995), the effect of eating palatable
food on DA release wanes with repeated access when the food is no longer novel, unless the
animal is food deprived (Bassareo and Di Chiara, 1999, Di Chiara and Tanda, 1997, Rada et
al., 2005b). Thus normally feeding is very different than taking drugs because the DA response
during feeding is phased out.
However, and this is very important, rats fed daily intermittent sugar and chow apparently
release DA every day as measured on days 1, 2 and 21 of access (Fig. 7; Rada et al., 2005b).
As controls, rats fed sugar or chow ad libitum, rats with intermittent access to just chow, or
rats that taste sugar only two times, develop a blunted DA response as is typical of a food that
looses it novelty. These results are supported by findings of alterations in accumbens DA
turnover and DA transporter in rats maintained on an intermittent sugar-feeding schedule
(Bello et al., 2003,Hajnal and Norgren, 2002). Together, these results suggest that intermittent
access to sugar and chow causes recurrent increases in extracellular DA in a manner that is
more like a drug of abuse than a food.
An interesting question is whether the neurochemical effects observed with intermittent sugar
access are due to its postingestive properties or whether the taste of sugar can be sufficient. To
investigate orosensory effects of sugar, we used the sham feeding preparation. Rats that are
sham feeding with an open gastric fistula can ingest foods but not fully digest them (Smith,
1998). Sham feeding does not completely eliminate post-ingestive effects (Berthoud and
Jeanrenaud, 1982, Sclafani and Nissenbaum, 1985), however it does allow the animals to taste
the sugar while retaining almost no calories.
The results of sham feeding sugar for the first hour of access each day show that DA is released
in the NAc, even after three weeks of daily bingeing, simply due to the taste of sucrose (Avena
et al., 2006). Sham feeding does not further enhance the typical sugar-induced DA release.
This supports other work showing that the amount of DA release in the NAc is proportional
to the sucrose concentration, not the volume consumed (Hajnal et al., 2004).
5.D. Accumbens acetylcholine release is delayed during sugar binges and eliminated during
sham feeding
Sham-feeding revealed interesting results with ACh. As described in Section 3.C., accumbens
ACh increases in the midst of a meal when feeding slows down and then stops (Mark et al.,
1992). One could predict that when an animal takes a very large meal, as with the first meal
of a sugar solution and chow, the release of ACh should be delayed until the satiation process
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begins as reflected in gradual termination of the meal. This is what was observed; ACh release
occurred when this initial “binge” meal was drawing to a close (Rada et al., 2005b).
Next we measured ACh release when the animal could take a large meal of sugar while sham
feeding. Purging the stomach contents drastically reduced the release of ACh (Avena et al.,
2006). This is predictable based on the theory that ACh is normally important for the satiation
process (Hoebel et al., 1999, Mark et al., 1992). It also suggests that by purging, one eliminates
the ACh response that opposes DA. Thus when “bingeing” on sugar is accompanied by purging,
the behavior is reinforced by DA without ACh, which is more like taking a drug and less like
normal eating.
5.E. Sugar withdrawal upsets dopamine/acetylcholine balance in the accumbens
Behavioral signs of drug withdrawal are usually accompanied by alterations in DA/ACh
balance in the NAc. During withdrawal, DA decreases while ACh is increased. This imbalance
has been shown during chemically-induced withdrawal with several drugs of abuse, including
morphine, nicotine and alcohol (Rada et al., 1996, 2001, 2004). Mere abstinence from an abused
substance is also sufficient to elicit neurochemical signs of withdrawal. For example, rats that
are forced to abstain from morphine or alcohol have decreased extracellular DA in the NAc
(Acquas and Di Chiara, 1992, Rossetti et al., 1992) and ACh increases during spontaneous
morphine withdrawal (Fiserova et al., 1999). While withdrawal from an anxyolitic drug
(diazepam) precipitated by a bendodiazepine-receptor antagonist does not lower extracellular
DA, it does release accumbens ACh, which may contribute to benzodiazepine dependency
(Rada and Hoebel, 2005)
Rats that have intermittent access to sugar and chow show the morphine-like neurochemical
imbalance in DA/ACh during withdrawal. This was produced two ways. As shown in Fig. 8,
when they are given naloxone to precipitate opioid withdrawal, there is a decrease in accumbens
DA release coupled with an increase in ACh release (Colantuoni et al., 2002). The same thing
occurs after 36 h of food deprivation (Avena, Bocarsly, Rada, Kim, Hoebel, unpublished). One
way to interpret deprivation-induced withdrawal is to suggest that without food to release
opioids, the animal suffers the same type of withdrawal 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, but intermittent bingeing and deprivation
changes that. Based on the observed behavioral and neurochemical similarities between the
effects of intermittent sugar access and drugs of abuse, we suggest that sugar, as common as
it is, nonetheless meets the criteria for a substance of abuse and may be “addictive” for some
individuals when consumed in a “binge-like” manner. This conclusion is reinforced by the
changes in limbic system neurochemistry that are similar for the drugs and for sugar. The effects
we observe are smaller in magnitude than those produced by drug of abuse such as cocaine or
morphine; however, the fact that these behaviors and neurochemical changes can be elicited
with a natural reinforcer is interesting. It is not clear from this animal model if intermittent
sugar access can result in neglect of social activities as required by the definition of dependency
in the DSM-IV-TR (American Psychiatric Association, 2000). Nor is it known whether rats
will continue to self-administer sugar despite physical obstacles, such as enduring pain to obtain
sugar, as some rats do for cocaine (Deroche-Gamonet et al., 2004). Nonetheless, the extensive
series of experiments revealing similarities between sugar-induced and drug-induced behavior
and neurochemistry, as chronicled in Sections 4 and 5, lends credence to the concept of “sugar
addiction”, gives precision to its definition, and provides a testable model.
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6.A. Bulimia nervosa
The feeding regimen of Daily Intermittent Sugar and Chow shares some aspects of the
behavioral pattern of people diagnosed with binge-eating disorder or bulimia. Bulimics often
restrict intake early in the day and then binge later in the evening, usually on palatable foods
(Drewnowski et al., 1992, Gendall et al., 1997). These patients later purge the food, either by
vomiting or laxative use, or in some cases by strenuous exercise (American Psychiatric
Association, 2000). Bulimic patients have low β-endorphin levels (Brewerton et al., 1992,
Waller et al., 1986), which might foster eating with a preference or craving for sweets. They
also have decreased mu-opioid receptor binding in the insula compared with controls, which
correlates with recent fasting behavior (Bencherif et al., 2005). This contrasts with the increase
observed in rats following a binge. Cyclic bingeing and food deprivation may produce
alterations in mu-opioid receptors, which help perpetuate bingeing behavior.
We used the sham feeding preparation to mimic the purging associated with bulimia. The
finding described in Section 5.C., that intermittent sugar access repeatedly releases DA in
response to the taste of sugar, may be important for understanding the bingeing behaviors
associated with bulimia. DA has been implicated in bulimia by comparing it to hypothalamic
self-stimulation, which also releases DA without calories (Hoebel et al., 1992). Bulimic
patients have low central DA activity as reflected in analysis of DA metabolites in the spinal
fluid, which also indicates a role for DA in their abnormal responses to food (Jimerson et al.,
1992).
The overall similarlites in behavior and brain adaptations with sugar bingeing and drug intake
described above support the theory that obesity and eating disorders, such as bulimia and
anorexia, may have properties of an “addiction” in some individuals (Davis and Claridge,
1998, Gillman and Lichtigfeld, 1986, Marrazzi and Luby, 1986, Mercer and Holder, 1997,
Riva et al., 2006). The auto-addiction theory proposed that some eating disorders can be an
addiction to endogenous opioids (Heubner, 1993, Marrazzi and Luby, 1986, 1990). In support,
appetite dysfunctions in the form of binge eating and self-starvation can stimulate endogenous
opioid activity (Aravich et al., 1993).
Bulimic patients will binge on excessive amounts of non-caloric sweeteners (Klein et al.,
2006), suggesting that they derive benefits from sweet orosensory stimulation. We have shown
that purging leaves DA unopposed by satiety-associated ACh in the accumbens (Section 5.D.).
This neurochemical state may be conducive to exaggerated binge eating. Moreover, the
findings that intermittent sugar intake cross-sensitizes with amphetamine and fosters alcohol
intake (Sections 4.D. and 4.E.) may be related to the comorbidity between bulimia and
substance abuse (Holderness et al., 1994).
6.B. Obesity
Sugar and obesity—Obesity is one of the leading preventable causes of death in the US
(Mokdad et al., 2004). Several studies have correlated the rise in the incidence of obesity with
an increase in sugar consumption (Bray et al., 1992, Elliott et al., 2002, Howard and Wylie-
Rosett, 2002, Ludwig et al., 2001). The US Department of Agriculture has reported that per
capita soft-drink consumption has increased by almost 500% in the past 50 years (Putnam and
Allhouse, 1999). Sugar intake may lead to an increased number of and/or affinity for opioid
receptors, which in turn leads to further ingestion of sugar and may contribute to obesity
(Fullerton et al., 1985). Indeed, rats maintained on the diet of intermittent sugar access show
opioid receptor changes (Section 5.A.); however, after one month on the diet using 10% sucrose
or 25% glucose, these animals do not become overweight (Colantuoni et al., 2001, Avena and
Hoebel, 2003b), although others have reported a metabolic syndrome (Toida et al., 1996), a
loss of fuel efficiency (Levine et al., 2003) and an increase in body weight in rats fed sucrose
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(Bock et al., 1995, Kawasaki et al., 2005) and glucose (Wideman et al., 2005). Most studies
of sugar intake and body weight do not use a binge-inducing diet, and the translation to human
obesity is complex (Levine et al., 2003). As described in Section 4.A., it appears that rats in
our model compensate for sucrose or glucose calories by decreasing chow intake (Avena,
Bocarsly, Rada, Kim and Hoebel, unpublished). They gain weight at a normal rate (Colantuoni
et al., 2002). This may not be true of all sugars.
Fructose is a unique sweetener that has different metabolic effects on the body than glucose or
sucrose. Fructose is absorbed further down the intestine, and whereas circulating glucose
releases insulin from the pancreas (Sato et al., 1996, Vilsboll et al., 2003), fructose stimulates
insulin synthesis but does not release it (Curry, 1989, Le and Tappy, 2006, Sato et al., 1996).
Insulin modifies food intake by inhibiting eating (Schwartz et al., 2000) and by increasing
leptin release (Saad et al., 1998), which also can inhibit food intake. Meals of high-fructose
corn 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 corn
syrup has become a major constituent in the American diet (Bray et al., 2004) and lacks some
effects on insulin and leptin, it may be a potential agent for producing obesity when given
intermittently to rats. Whether or not signs of dependency on fructose are apparent when it is
offered intermittently has yet to be determined. However, based on our results showing that
sweet taste is sufficient to elicit the repeated release of DA in the NAc (see Section 5.C.), we
hypothesize that any sweet taste consumed in a binge-like manner is a candidate for producing
signs of dependence.
Fat and obesity—While we have chosen to focus on sugar, the question arises as to whether
non-sweet, palatable foods could produce signs or dependence. The evidence is mixed. It
appears that some signs of dependence are apparent with fat, while others have not been shown.
Fat bingeing in rats occurs with intermittent access to pure fat (vegetable shortening), sweet-
fat cookies (Boggiano et al., 2005, Corwin, 2006), or sweet-fat chow (Berner, Avena and
Hoebel, unpublished). Repeated, intermittent access to oil releases DA in the NAc (Liang et
al., 2006). Like sugar, bingeing on a fat-rich diet is known to affect the opioid system in the
accumbens by decreasing enkephalin mRNA, an effect that is not observed with acute access
(Kelley et al., 2003). Also, treatment with baclofen (GABA-B agonist), which reduces drug
intake, also reduces binge eating of fat (Buda-Levin et al., 2005).
This all implies that fat dependency is a real possibility, but withdrawal from fat-bingeing is
not as apparent as it is with sugar. Le Magnen (1990) noted naloxone could precipitate
withdrawal in rats on a cafeteria-style diet, which contains a variety of fat- and sugar-rich foods
(e.g., cheese, cookies, chocolate chips). However, we have not observed signs of naloxone-
precipitated or spontaneous withdrawal in rats fed pure fat (vegetable shortening) or a sugar-
fat combination, nor has such a result been published by others. Further studies are needed to
fully understand the differences between sugar and fat bingeing and their subsequent effects
on behavior. Just as different classes of drugs (e.g., dopamine agonists vs. opiates) have specific
behavioral and physiological withdrawal signs, it may be that different macronutrients may
also produce specific withdrawal signs. Since craving of fat or cross-sensitization between fat
intake and drugs of abuse has yet to be documented in animals, sugar is currently the only
palatable substance for which bingeing, withdrawal, abstinence-induced enhanced motivation
and cross-sensitization have all been demonstrated (Sections 4 and 5).
Brain imaging—Recent findings using positron emission tomography (PET) and functional
magnetic resonance imaging (fMRI) in humans have supported the idea that aberrant eating
behaviors, including those observed in obesity, may have similarities to drug dependence.
Craving-related changes in fMRI signal have been identified in response to palatable foods,
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similar to drug craving. This overlap occurred in the hippocampus, insula, and caudate (Pelchat
et al., 2004). Similarly, PET scans reveal that obese subjects show a reduction in striatal D2
receptor availability that is associated with the body weight of the subject (Wang et al.,
2004b). This decrease in D2 receptors in obese subjects is similar in magnitude to the reductions
reported in drug-addicted subjects (Wang et al., 2001). The involvement of the DA system in
reward and reinforcement has led to the hypothesis that alterations in DA activity in obese
subjects dispose them to excessive use of food. Exposure to especially palatable foods, such
as cake and ice cream, activates the several brain regions including the anterior insula and right
orbitofrontal cortex (Wang et al., 2004a), which may underlie the motivation to procure food
(Rolls, 2006).
7. CONCLUSION
From an evolutionary perspective, it is in the best interest of humans to have an inherent desire
for food for survival. However, this desire may go awry, and certain people, including some
obese and bulimic patients in particular, may develop an unhealthy dependence on palatable
food that interferes with well-being. The concept of “food addiction” materialized in the diet
industry on the basis of subjective reports, clinical accounts and case studies described in self-
help books. The rise in obesity, coupled with the emergence of scientific findings of parallels
between drugs of abuse and palatable foods has given credibility to this idea. The reviewed
evidence supports the theory that, in some circumstances, intermittent access to sugar can lead
to behavior and neurochemical changes that resemble the effects of a substance of abuse.
According to the evidence in rats, intermittent access to sugar and chow is capable of producing
a “dependency”. This was operationally defined by tests for bingeing, withdrawal, craving and
cross-sensitization to amphetamine and alcohol. The correspondence to some people with
binge eating disorder or bulimia is striking, but whether or not it is a good idea to call this a
“food addiction” in people is both a scientific and societal question that has yet to be answered.
What this review demonstrates is that rats with intermittent access to food and a sugar solution
can show both a constellation of behaviors and parallel brain changes that are characteristic of
rats that voluntarily self-administer addictive drugs. In the aggregrate, this is evidence that
sugar can be addictive.
Acknowledgements
This reseach was supported by USPHS grant MH-65024 (B.G.H.), DA-10608 (B.G.H.), DA-16458 (fellowship to
N.M.A) and the Lane Foundation.
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Figure 1.
Meal analysis of two representative rats living in operant chambers. The one maintained on
Daily Intermittent Sucrose and Chow (black lines) had an increased intake of sugar compared
with one given Ad libitum Sucrose and Chow (grey lines). Hour 0 is 4 h into the dark phase.
Each lever press delivers 0.1 mL of 10% sucrose. A sugar meal is defined as ending when the
rat does not press for 2 min. Both rats consume several meals of about equal size on day 1 (top
panel). Note that the rat with sugar available 24 h also drinks during the inactive (light) phase.
By day 21 (bottom panel), the rat with sucrose and chow available for only 12 h consumes an
initial “binge” of sucrose (indicated by the first arrow), followed by fewer, but larger meals,
than the rat with sucrose and chow ad libitum. Sugar-bingeing rats are the ones that show signs
of dependency in a battery of tests.
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Figure 2.
Time spent on the open arms of an elevated plus-maze. Four groups of rats were maintained
on their respective diets for one month and then received naloxone (3 mg/kg, s.c.). The Daily
Intermittent Glucose and Chow group spent less time on the open arms of the maze. *p<0.05
compared with the Ad libitum Chow group. From Colantuoni et al., 2002.
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Figure 3.
Rats that have been maintained on Daily Intermittent Sucrose and Chow are more immobile
than control groups in a forced-swim test during naloxone-precipitated withdrawal. *p<0.05
compared with Ad libitum Sugar and Chow and Ad libitum Chow groups.
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Figure 4.
After 14 days of abstinence from sugar, rats that previously had 12-h daily access significantly
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 after abstinence. **p<0.01. From Avena et al., 2004.
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Figure 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 specified diets regimens. Rats maintained on Daily
Intermittent Sucrose and Chow were hyperactive nine days later in response to a low dose of
amphetamine, compared with control diet groups. **p<0.01. From Avena and Hoebel, 2003.
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Figure 6.
Intermittent sugar access alters DA receptor binding at the level of the striatum. D1 receptor
binding (top panel) increases in the NAc core and shell of animals exposed to Daily Intermittent
Glucose and Chow (black bars) for 30 days compared with control animals fed chow ad
libitum (white bars). D2 receptor binding (bottom panel) decreases in the dorsal striatum in
sections from taken the same animals. *p<0.05. From Colantuoni et al., 2001.
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Figure 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 vivo microdialysis, increases for the Daily Intermittent
Sucrose and Chow rats (open circles) on days 1, 2 and 21; in contrast, DA release was attenuated
on day 21 in four control groups as follows: a group that only had 1-h access to sucrose on day
1 and 21 with ad libitum chow in the interim (Sucrose Twice), Ad libitum Sucrose and Chow
group, and Daily Intermittent Chow group (bottom panel). The bar on the ordinate indicates
the hour (0-60 min) that sucrose or chow was available for the tests. *p<0.05. From Rada et
al., 2005.
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Figure 8.
Extracellular DA (upper graph) decreased to 81% of baseline after naloxone injection (3 mg/
kg, s.c.) in rats with a history of Daily Intermittent Sucrose and Chow. Acetylcholine (lower
graph) increased to 157% in the same intermittent sugar-access rats. No effects were seen in a
control group with Ad libitum Chow followed by a naloxone injection. *p<0.05, **p<0.01.
From Colantuoni et al., 2002.
Avena et al. Page 35
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