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Is sugar more addictive than cocaine?

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Is Sugar as Addictive as Cocaine?
Serge H. Ahmed
In contemporary affluent societies, people report consuming sugar-sweetened foods and
beverages not only to get calories but also to experience pleasant sensations, to cope with stress
or fatigue, to enhance cognition, and/or to ameliorate mood (e.g., relief of negative affect). As a
result, sweetened foods and drinks have often been metaphorically likened to certain drugs of
abuse, including psychostimulants and opiates. However, it is not until recently after having
taken full measure of the rapid “sweetening of the world’s diet”[1] and the associated obesity
epidemic that serious concerns have begun to emerge about the real addictive potential of sugar-
sweetened goods.[2-5] There is also a rapidly rising issue about the potential long-term impact of
overconsumption of sugar-sweetened diets during infant and adolescent development on
subsequent adult psychosocial functioning (e.g., impulse control, motivation).[6, 7]
Most, though not all, of the satisfaction or gratification that is derived from sugar-
sweetened foods and drinks comes from the sense of taste. In virtually all mammals, including
humans, the taste of sweet is unique in being an innately and intensely rewarding primary
sensory modality that is hardwired to the brain reward system.[8] There is now compelling
evidence that sweet taste, along other primary taste modalities, is mediated by a “distinct and
strictly segregated population of taste receptor cells.”[8] Thus, for instance, if a non-taste-
receptor is ectopically expressed in sweet cells in the taste buds of mutant mice, they will drink a
solution containing a normally tasteless ligand.[9] More strikingly, in fruit flies, feeding behavior
can be initiated by a light stimulus when their sweet receptor neurons have been genetically
engineered to express a light-sensitive ionic channel.[10] At a more central level, sweet taste
587
activates brain systems that are also targeted by drugs of abuse. For instance, consumption of
sweetened water activates midbrain dopamine neurons,[11] which then release dopamine in the
ventral striatum[12]—a neurochemical event that plays a major role in reinforcement learning
and associated functions, including decision making and action selection. Sweet taste also
activates other components of the brain reward circuitry that is affected by drugs of abuse, such
as the ventral striatum,[13] the ventral pallidum,[14] and the orbitofrontal cortex.[15, 16] The
orbitofrontal cortex—which is anatomically and functionally linked to the insular gustatory
cortex—is currently conceptualized as a general valuation system that allows a subject to
represent and to compare the values of different kinds of rewards to determine choice.[17] It is
intriguing to note that the valuation system of the brain—that is also recruited during moral
judgments—is probably evolutionarily and functionally related to the gustatory cortex.
Thus, there exist clear behavioral, psychological, and neurobiological commonalities
between sweet diets and drugs of abuse. Little is known, however, about the relative rewarding
and addictive potential of the former compared to the latter. For instance, is sweetness as
addictive as cocaine, the current prototypical drug of abuse? This information will be useful in
updating the hierarchy of addictive substances and activities and to prioritize public health
action. In the recent past the direct comparison of nicotine—which was initially thought to be
nonaddictive—with cocaine contributed substantially to change public awareness about its
addictive potential.[18, 19] In light of the difficulties inherent in conducting direct comparisons
between sweet goods and drugs of abuse in humans, we began to address this question in
laboratory rats. Rats are, by far, the most frequently used animal model in experimental research
on addiction. Like humans, rats have a sweet tooth, and they self-administer most major drugs of
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abuse (e.g., cocaine, heroin). Finally, most breakthrough advances in the neurobiology of drugs
of abuse have been initially obtained through research using rats.[20]
To assess the relative rewarding and addictive value of sweet taste, rats that were not
hungry or thirsty were allowed to choose between drinking water sweetened with a near optimal
concentration of saccharin (0.2%) or taking an intravenous bolus of cocaine (0.25 mg per
injection).[21] Saccharin—a nonnutritive sweetener—was chosen to study the unique
contribution of taste sweetness on preference. However, similar findings have been obtained with
sucrose[21]—a natural sugar that is more rewarding than saccharin.[22] Cocaine, especially
when it is delivered rapidly to the brain following smoking or intravenous injection, induces
intense rewarding sensations that are thought to contribute to its addictive liability. At the
neurobiological level, cocaine boosts dopamine signaling in the ventral striatum by inhibiting the
dopamine transporter[23] and also by activating midbrain dopamine neurons through an as-yet-
undetermined interoceptive conditioning mechanism.[24] In addition to these acute effects,
extended use of cocaine also induces long-lasting structural and functional changes in several
brain regions[20, 25, 26] that may explain some of the behavioral symptoms of addiction,
including escalation of cocaine use,[27] increased effort to obtain cocaine,[28] and continued
cocaine use despite potential negative consequences.[29]
To make their choice, rats had to press one of two levers, one associated with sweetened
water, the other with cocaine. Each daily choice session consisted of several discrete, spaced
trials and was divided into two successive phases: sampling and choice.[21] During sampling,
each lever was presented alternatively, thereby allowing rats to separately learn the value of each
reward before making their choice. In contrast, during choice, the cocaine- and sweet-associated
levers were presented simultaneously and rats were free to respond on either lever to obtain the
589
corresponding reward. When one reward was selected, the two levers retracted simultaneously
until the next trial. As a result, selecting one reward excluded the alternative reward, thereby
allowing rats to express their preference (i.e., choice was mutually exclusive or either/or). Naïve
rats were initially tested in the choice procedure under three reward conditions. The first two
reward conditions were control conditions aimed at separately measuring the effectiveness of
each type of reward. In those control conditions, only responding on one lever was rewarded by
the corresponding reward (cocaine or saccharin); responding on the other lever remained
unrewarded. In the third, experimental condition, responding on one lever was rewarded by
cocaine and responding on the alternate lever was rewarded by sweetened water.
As expected, when only one response was rewarded by either cocaine or sweet water, rats
developed a significant preference for it and ignored the nonrewarded lever (Fig. 35.1a). This
result demonstrates that when presented alone, each type of reward effectively and selectively
reinforced and maintained responding. Surprisingly, however, the rate of preference acquisition
(i.e., number of days to reach a stable preference) was slower when behavior was rewarded with
cocaine than with sweetened water (Fig. 35.1b), suggesting that the former reward is probably
less efficacious than the latter. This interpretation is confirmed by the outcome of the
experimental condition. When responding on either lever was rewarded, rats developed a rapid
and marked preference for sweetened water and almost completely ignored cocaine (Fig.
35.1a,b), a finding that is consistent with previous research in rats with concurrent access to
cocaine and saccharin.[30, 31] Interestingly, sweet preference was acquired and persisted despite
near maximal sampling of the cocaine lever.[21] Finally, the latency to choose sweet water was
shorter than the latency to choose cocaine (Fig. 35.1c). Since the latency to respond is generally
inversely related to the magnitude of the upcoming reward (i.e., the more intense the reward, the
590
shorter the latency), this outcome provides additional, independent confirmation that the reward
value of cocaine is weaker than that of sweetened water in rats.
<insert Figure 35.1 about here>
The preference for sweetened water was not surmountable by increasing the dose of
cocaine (i.e., up to the subconvulsive dose of 1.5 mg), suggesting that the reward value of sweet
water is higher than the maximal reward value of cocaine.[21] In addition, once acquired,
preference for sweet taste did not persist because of some sort of behavioral inertia, unrelated to
the reward value of sweetness. For instance, it could be argued that since rats rapidly learned to
choose sweet water almost exclusively, they would subsequently have little opportunity to
change their preference in favor of cocaine. To address this important issue, rats were first
trained in the choice procedure with no alternative to cocaine. Once they developed a stable
preference for the cocaine lever, they were then offered the choice between cocaine and
sweetened water. Subjects rapidly shifted their preference away from cocaine toward sweetened
water (Fig. 35.2a), suggesting that behavioral inertia is unlikely a significant factor in sweet
preference.[21] To further address this issue, other rats were first trained on alternate days to
lever press to self-administer either cocaine or saccharin. The number of rewards was limited to
30 per session to equal the number of pairings of each lever with its corresponding reward. After
acquisition and stabilization of cocaine and saccharin self-administration, rats were then trained
in the choice procedure. Surprisingly, prior FR training accelerated, rather than retarded, the
expression of sweet preference.[32] In fact, rats presented a significant preference for sweet
water on the first day of testing (Fig. 35.2b). This outcome shows that during FR training, rats
had independently attributed a higher value to the saccharin lever compared to the cocaine lever,
a process that does not support a role for behavioral inertia in sweet preference. Finally, to
definitively rule out behavioral inertia, rats were trained in a modified choice procedure. Briefly,
591
the sampling period was replaced by 1 h of continuous access to cocaine. Thus, every day before
choice testing, rats were allowed to self-administer cocaine continuously. If behavioral inertia
played a significant role in choice performance, then one should expect that rats will continue—
at least transiently—to respond on the cocaine lever during choice. Contrary to this prediction,
however, rats normally self-administered cocaine during the first hour, but they almost
immediately shifted their response to the lever associated with sweet water during choice.[21]
The fact that rats quickly reoriented their behavior away from cocaine to sweet water clearly
demonstrates that the persistence of sweet preference is not attributable to behavioral inertia.
<insert Figure 35.2 about here>
Overall, the research reviewed earlier demonstrates that the reward value of sweet taste is
greater than that of intravenous cocaine. But what is exactly the magnitude of this difference in
reward value? To address this question, the number of responses or amount of effort required to
earn sweetened water was gradually increased above that of cocaine until a reversal of preference
and thus identification of the indifference point (or point of subjective equality). The latter
provides a quantitative estimation of the relative value of cocaine compared to sweet water. As
one would expect, when the amount of effort for sweetened water increased, rats progressively
shifted their preference to cocaine.[32] At the highest amount of effort (i.e., 16 times that for
cocaine), virtually all rats shifted their preference to cocaine. Importantly, the point of
indifference was reached when the effort demanded for sweetened water was about 8 times that
for cocaine.[32] This large ratio of effort suggests that the reward value of sweet water is about
one order of magnitude higher than that of cocaine.
Preference for sweet water was observed in either initially cocaine-naïve rats or in rats
with a limited experience with cocaine. As mentioned earlier, following extended access to
cocaine, most rats escalate their consumption of cocaine and work harder for and take more risk
592
to obtain the drug, suggesting an increased drug value.[32] Thus, a key issue is whether sweet
preference can be overridden by this increase in cocaine value. To answer this question, rats
were first allowed to have daily extended access to cocaine self-administration during several
weeks before choice testing (i.e., 6 hours per day, 6 days a week). As expected, following
extended access to cocaine self-administration, most rats escalated their consumption of cocaine
(Fig. 35.3a). Surprisingly, however, when offered a choice between cocaine and sweet water,
most rats rapidly acquired a strong preference for the latter regardless of the cocaine dose
available (Fig. 35.3b). In fact, sweet preference reached statistical significance as early as the
second day of testing, a rate of acquisition that was comparable to that seen in initially naïve
rats.[21] Thus, although the value of cocaine definitively increases during extended drug self-
administration, this increase was apparently not sufficient to override sweet preference, at least
in the majority of individuals.
<insert Figure 35.3 about here>
In summary, in nonhungry, nonthirsty rats, the taste sensation associated with the
ingestion of sweetened water is clearly more rewarding than the artificial sensations of
intravenous cocaine, independent of prior cocaine history. Recently, this conclusion was
generalized to intravenous heroin, with one notable difference[33, 34]: heroin was more potent
than cocaine in competing with sweet taste, especially following extended heroin use.[34] This
difference is consistent with epidemiological research in humans suggesting that heroin is more
addictive than cocaine.[35] Nevertheless, when offered a choice, most heroin-dependent rats
eventually cut down heroin use to drink more sweet water.[34] This observation further
underscores the importance of sweet taste reward in driving and controlling preference. Other
recent research has also uncovered a major role of other palatability factors (i.e., other than taste
quality) in determining preference. For instance, Kippin and colleagues have recently shown
593
using a similar choice procedure to that described here that hungry rats rapidly stop using
cocaine to prefer standard food pellets (nonsweet, nonfat), an effect that is partially sex
dependent.[36] Similarly, using a behavioral economic approach, it was recently estimated that
the reward value of standard food pellets or sucrose is much greater than that of intravenous
cocaine in hungry rats from different strains.[37-39] This difference in value persists even
following chronic cocaine self-administration and evidence for escalated cocaine use.[40] These
observations are also consistent with older, though often overlooked, experiments showing that
under some circumstances, palatable food or sweetened water can compete with direct electrical
stimulation of the brain reward circuit.[41-44] More recently, it was found using optogenetic
methods that mice largely prefer drinking sucrose over direct stimulation of midbrain
dopamine cells.[45] This finding reminds us that sucrose intake activates more than
dopamine neurons in the brain which may explain why it is such a compelling stimulus
even when compared to cocaine. Finally, though little is known about the neural correlates
of sugar preference over cocaine, clues are beginning to emerge. A recent in vivo
electrophysiological recording study in rats self-administering cocaine or sucrose found
that sucrose-selective neurons outnumber by a large margin cocaine-selective neurons in
the ventral striatum (70% versus 5%)[46] – a finding that corroborates previous research
in monkeys.[47] This predominance of sugar-selective cells in the ventral striatum may
represent the neural correlate of rats’ preference for sugar over cocaine. All together these
different findings suggest that palatable diets, in general, and sweet diets, in particular, can
clearly be more rewarding—and thus potentially more addictive—than intravenous cocaine and
heroin in laboratory rats. Though one cannot, of course, directly extrapolate these findings to
humans, they should nevertheless contribute to prompt a serious reconsideration of the hierarchy
594
of potentially addictive substances and activities, with certain foods and drinks possibly taking
precedence over major drugs of abuse.
Acknowledgments
This work was supported by grants from the French Research Council (CNRS), Université
Victor-Segalen Bordeaux 2, the National Research Agency (ANR), the Mission Interministérielle
de Lutte contre la Drogue et la Toxicomaine (MILDT), and the Fondation pour la Recherche
Médicale (FRM). I thank Dr. Kelly Clemens for her comments on a previous draft of this book
chapter.
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cocaine in Fischer and Lewis rats. Behav Neurosci 2009;123(1):165–171.
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Figure 35.1.
The effects of choice on cocaine self-administration.
(a) Choice (mean ± SEM) between the saccharin-associated lever (S) and the cocaine-associated
lever (C) across reward conditions (S+/C–: only responses on lever S are rewarded; S–/C+: only
responses on lever C are rewarded; S+/C+: responses on both levers are rewarded). Preference
scores were normalized as described previously.[21] The horizontal dotted line at 0 indicates the
indifference level. Scores above 0 indicate a preference for sweet water, while values below 0
indicate a preference for cocaine. Asterisk indicates difference from the indifference level (p <
.05). (b) Number of days (mean ± SEM) before stabilization of preference scores (i.e., at least
three consecutive sessions of stable preference). Asterisk indicates differences from the other
two reward conditions. (c) Latency (mean ± SEM) of choice making in seconds (p < .05).
Asterisk indicates difference from the other two reward conditions (p < .05).
Source: Adapted from Lenoir et al., 2007.
Figure 35.2.
Sweet preference is not due to behavioral inertia.
(a) Reversal of preference in rats that had first acquired a preference for lever C under the S–/C+
condition. The first 3 days (–3 to –1) correspond to baseline choice under the S–/C+ condition.
The next 10 days correspond to choice after the shift to the S+/C+ reward condition. (b)
Immediate expression of sweet preference in rats previously trained to stably self-administer
cocaine and sweet water on alternate days under a continuous reinforcement schedule. Asterisk
indicates difference from the indifference level (p < .05).
Source: Panel (a) was adapted from Lenoir et al 2007); Panel (b) was adapted from Cantin et al., 2010.
Figure 35.3.
Sweet preference following extended cocaine self-administration.
600
(a) Escalation of cocaine self-administration during extended access to a high dose of cocaine
(0.75 mg per injection). Data corresponding to the 12th day are missing due to a computer
failure. Asterisk indicates difference from the first day (p < .05). (b) Choice between cocaine and
sweet water (mean ± SEM) after cocaine intake escalation. Asterisk indicates difference from the
indifference level (p < .05).
Source: Adapted from Lenoir et al., 2007.
1. Popkin BM, Nielsen SJ (2003) The sweetening of the world's diet. Obes Res 11: 1325-1332.
2. Ifland JR et al. (2009) Refined food addiction: a classic substance use disorder. Med Hypotheses 72: 518-
526.
3. Gearhardt AN, Corbin WR, Brownell KD (2009) Preliminary validation of the Yale Food Addiction Scale.
Appetite 52: 430-436.
4. Corwin RL, Grigson PS (2009) Symposium overview--Food addiction: fact or fiction? J Nutr 139: 617-
619.
5. Avena NM, Rada P, Hoebel BG (2008) Evidence for sugar addiction: behavioral and neurochemical effects
of intermittent, excessive sugar intake. Neurosci Biobehav Rev 32: 20-39.
6. Moore SC, Carter LM, van Goozen S (2009) Confectionery consumption in childhood and adult violence.
Br J Psychiatry 195: 366-367.
7. Frazier CR, Mason P, Zhuang X, Beeler JA (2008) Sucrose exposure in early life alters adult motivation
and weight gain. PLoS One 3: e3221.
8. Yarmolinsky DA, Zuker CS, Ryba NJ (2009) Common sense about taste: from mammals to insects. Cell
139: 234-244.
9. Zhao GQ et al. (2003) The receptors for mammalian sweet and umami taste. Cell 115: 255-266.
10. Gordon MD, Scott K (2009) Motor control in a Drosophila taste circuit. Neuron 61: 373-384.
11. Mirenowicz J, Schultz W (1996) Preferential activation of midbrain dopamine neurons by appetitive rather
than aversive stimuli. Nature 379: 449-451.
12. Hajnal A, Norgren R (2001) Accumbens dopamine mechanisms in sucrose intake. Brain Res 904: 76-84.
13. Roitman MF, Wheeler RA, Carelli RM (2005) Nucleus accumbens neurons are innately tuned for
rewarding and aversive taste stimuli, encode their predictors, and are linked to motor output. Neuron 45:
587-597.
14. Tindell AJ, Smith KS, Pecina S, Berridge KC, Aldridge JW (2006) Ventral pallidum firing codes hedonic
reward: when a bad taste turns good. J Neurophysiol 96: 2399-2409.
15. Kravitz AV, Peoples LL (2008) Background firing rates of orbitofrontal neurons reflect specific
characteristics of operant sessions and modulate phasic responses to reward-associated cues and behavior. J
Neurosci 28: 1009-1018.
16. Critchley HD, Rolls ET (1996) Olfactory neuronal responses in the primate orbitofrontal cortex: analysis in
an olfactory discrimination task. J Neurophysiol 75: 1659-1672.
17. Kable JW, Glimcher PW (2009) The neurobiology of decision: consensus and controversy. Neuron 63:
733-745.
18. Stolerman IP, Jarvis MJ (1995) The scientific case that nicotine is addictive. Psychopharmacology (Berl)
117: 2-10; discussion 14-20.
19. Pich EM et al. (1997) Common neural substrates for the addictive properties of nicotine and cocaine.
Science 275: 83-86.
20. Koob GF, Le Moal M (2006) Neurobiology of addiction (Academic Press, San Diego) p 490.
21. Lenoir M, Serre F, Cantin L, Ahmed SH (2007) Intense sweetness surpasses cocaine reward. PLoS One 2:
e698.
22. Smith JC, Sclafani A (2002) Saccharin as a sugar surrogate revisited. Appetite 38: 155-160.
601
23. Giros B, Jaber M, Jones SR, Wightman RM, Caron MG (1996) Hyperlocomotion and indifference to
cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379: 606-612.
24. Wise RA, Wang B, You ZB (2008) Cocaine serves as a peripheral interoceptive conditioned stimulus for
central glutamate and dopamine release. PLoS One 3: e2846.
25. Nestler EJ (2005) Is there a common molecular pathway for addiction? Nat Neurosci 8: 1445-1449.
26. Robinson TE, Kolb B (2004) Structural plasticity associated with exposure to drugs of abuse.
Neuropharmacology 47 Suppl 1: 33-46.
27. Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set
point. Science 282: 298-300.
28. Paterson NE, Markou A (2003) Increased motivation for self-administered cocaine after escalated cocaine
intake. Neuroreport 14: 2229-2232.
29. Vanderschuren LJ, Everitt BJ (2004) Drug seeking becomes compulsive after prolonged cocaine self-
administration. Science 305: 1017-1019.
30. Carroll ME, Lac ST, Nygaard SL (1989) A concurrently available nondrug reinforcer prevents the
acquisition or decreases the maintenance of cocaine-reinforced behavior. Psychopharmacology (Berl) 97:
23-29.
31. Carroll ME, Lac ST (1993) Autoshaping i.v. cocaine self-administration in rats: effects of nondrug
alternative reinforcers on acquisition. Psychopharmacology (Berl) 110: 5-12.
32. Cantin L et al. (2010) Cocaine is low on the value ladder of rats: possible evidence for resilience to
addiction. PLoS One 5: e11592.
33. Ahmed SH (2005) Imbalance between drug and non-drug reward availability: a major risk factor for
addiction. Eur J Pharmacol 526: 9-20.
34. Lenoir M, Cantin L, Serre F, S.H. A (2008) The value of heroin increases with extended use but not above
the value of a non-essential alternative reward. in 38th annual meeting of the Society for Neuroscience
(Washington DC, USA).
35. SubstanceAbuseandMentalHealthServicesAdministration (2003) Results from the 2002 National Survey on
Drug Use and Health: National findings. in NHSDUA Series H-22, DHHS Publication No. SMA 03-3836
(Office of Apllied Studies, Rockville, MD).
36. Kerstetter KA, Wade MA, Gonzalez SG, Kneib JB, Kippin TE (2009) Selecting Between Food and
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