REVIEW – Evidence For Sugar Addiction: Behavioral and Neurochemical Effects of Intermittent Excessive Sugar Intake (2008)

Nicole M. Avena, Pedro Rada, and Bartley G. Hoebel^*

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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.

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 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.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. 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., 2003,Turchan 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 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.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).

 

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 …

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).

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).

 

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 …

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.

 

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. …

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.

 

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 …

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.

 

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 …

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).

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.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.

 

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 …

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).

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.

 

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, …

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 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.

 

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. …

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

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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