REVIEW ARTICLE

Natural Addiction
A Behavioral and Circuit Model Based on Sugar Addiction in Rats
Bartley G. Hoebel, PhD, Nicole M. Avena, PhD, Miriam E. Bocarsly, BA, and Pedro Rada, MD

making addiction a moral condition.1 Later, addiction was

Abstract: The distinction between natural addiction and drug ad-
diction is interesting from many points of view, including scientific
described in modern terms of neuropsychopharmacology as a
and medical perspectives. “Natural addictions” are those based on
“disease” caused by drug-induced chronic adaptations in
activation of a physiobehavioral system, such as the one that
brain function that change a voluntary behavior into an
controls metabolism, foraging, and eating to achieve energy balance. uncontrollable habit.2 This view of drug addiction as a dis-
“Drug addictions” activate many systems based on their pharmacol- ease-state partially shifts the blame from the person to the
ogy. This review discusses the following questions: (1) When does drug; however, both views depict the end result in terms of
food produce a natural addiction? Sugar causes signs of addiction if compulsive behavior and loss of control. Recently, there has
the scheduling conditions are appropriate to cause binge eating. (2) been a move in the direction of deemphasizing drugs and
Why does addictive-like behavior result? Bingeing on a 10% su- suggesting that addiction, including addiction to activities
crose solution repeatedly releases dopamine in the nucleus accum- such as eating or sexual behavior, be framed as unusually
bens, and it delays the release of acetylcholine, thereby postponing strong, desires for pleasure.3–7 The Diagnostic and Statistical
satiety. Opioid involvement is shown by withdrawal caused by Manual of Mental Disorders sidestepped the issue of addic-
naloxone or food deprivation. Bingeing, withdrawal, and abstinence- tion, per se, and focused on the criteria for “dependence,”
induced motivation are described as the basis for a vicious cycle with continued, life-disruptive, substance abuse as the bench-
leading to excessive eating. (3) Which foods can lead to natural mark for diagnosis.8 Disruptive behavior is continued despite
addiction? A variety of sugars, saccharin, and sham feeding are knowledge of persistent physical or psychological problems,
compared with bingeing on high-fat diets, which seem to lack which are likely caused or exacerbated by the substance of
sugar’s opioid-withdrawal characteristic. (4) How does natural food abuse.9 Debates are now appearing in anticipation of the next
addiction relate to obesity? Low basal dopamine may be a common diagnostic manual.10 Our view, based largely on evidence
factor, leading to “eating for dopamine.” (5) In a neural model, the from laboratory animal research, is that addiction to sugar
accumbens is depicted as having separate GABA output pathways for could be a problem and can involve the same neural adapta-
approach and avoidance, both controlled by dopamine and acetylcho- tions and behavioral alterations as addiction to drugs.11,12
line. These outputs, in turn, control lateral hypothalamic glutamate These changes are observed in instances of aberrant feeding,
release, which starts a meal, and GABA release, which stops it. which can be modeled in the laboratory. The closest human
condition to our laboratory animal model would be binge
Key Words: dopamine, acetylcholine, accumbens, binge, bulimia
eating disorder or bulimia nervosa. Evidence for addiction in
(J Addict Med 2009;3: 33–41) patients with eating disorders has been presented.13,14 Brain
imaging studies have focused attention on addiction-like
changes in the obese population, where the psychological
risks of dependency are compounded by medical risks, in-
NATURAL AND DRUG ADDICTIONS cluding cardiovascular impairment and type-2 diabetes.15,16
The definition of addiction is open to debate. An early view To understand “addiction,” one must identify the neural
described drug addiction as being due to a lack of will power, systems that cause it. Addictive drugs act, in part, via systems
that evolved for ingestive and perhaps reproductive behav-
From the Department of Psychology and Princeton Neuroscience Institute iors. This means that addiction to specific behavior patterns
(BGH, NMA, MEB), Princeton University, Princeton, NJ; The Rock- may have evolved through genetic benefits that selected
efeller University (NMA), New York, NY; Department of Psychology animals with innately programmed addictive processes. If so,
(MEB), Princeton University, Princeton, NJ; and Department of Physi- there are 2 major kinds of addiction, both of which can
ology (PR), University of Los Andes, Merida, Venezuela.
Received for publication October 31, 2008; accepted December 31, 2008. become compulsive and sometimes dangerous: (1) survival
Send correspondence and reprint requests to Dr. Bartley G. Hoebel, Prince- behavior, such as that which leads to risky behavior for eating
ton University, Department of Psychology, Washington Road, Princeton, and mating and (2) maladaptive behavior that bypasses the
NJ 08540. e-mail: [email protected] normal inhibitory sensory signals and artificially stimulates
Supported by USPHS Grants DA10608, MH65024, and AA12882 (to BGH)
and fellowship DK-079793 (to NMA).
the reward systems, as in the case of drugs of abuse.
Copyright © 2009 American Society of Addiction Medicine In summary, natural addiction can occur when environ-
ISSN: 1921-0621/09/0301-0033 mental stimuli act via designated, normal receptor systems,

J Addict Med • Volume 3, Number 1, March 2009 33

Hoebel et al J Addict Med • Volume 3, Number 1, March 2009

such as sugar acting via glucoreceptors. In this case, the

“system” involved is one that evolved with energy regulation
as the survival benefit. Drug addiction can result from com-
pounds that can bypass sensory inputs and act within a system
that is characterized by its neurochemical function. Thus,
drugs such as psychostimulants or opiates may activate mul-
tiple systems with diverse physiobehavioral functions. It
would be illogical to claim that only drugs can be addictive,
if it could be proven that natural stimulation, such as activa-
tion of the energy control system, can be sufficient for the
addictive process to occur.

WHEN DOES SUGAR PRODUCE A NATURAL FIGURE 1. Schematic representation of some criteria used
ADDICTION? EATING IN BINGES CAN to classify substances of abuse as described by Koob and Le
FACILITATE ADDICTION Moal.42 We have applied these criteria to the study of food
After 10 years of research on sugar addiction,11,17,18 we addiction. Limited daily access to a sugar solution leads to
still use the same basic technique to obtain clear signs of food bingeing and ensuing opiate-like withdrawal when animals
dependency by imposing a feeding schedule that repeatedly are administered naloxone or food deprived. After a period
induces sugar bingeing after a period of fasting. In our animal of sugar abstinence, these animals show signs of craving, as
measured by increased responding for sugar or sugar-associ-
model of sugar bingeing, a “binge” is defined simply as an
ated cues. Cross-sensitization between sugar and drugs of
unusually large meal, compared with animals eating the same abuse is shown by hyperactivity in response to a low dose of
diet ad libitum. Periodic, 12-hour food restriction is used to a psychostimulant and by avidity for alcohol.
create hunger and anticipation of eating. Then the animals are
offered 25% glucose (or 10% sucrose to simulate the sugar
concentration of a soft drink) along with their rodent chow.
one (3 mg/kg s.c.), which proves opioid involvement and
The opportunity to begin the first meal of the day is delayed
suggests opioid “dependency.”21 Withdrawal is also seen
4 hours beyond the time they would have normally started
eating at dark onset.19 Over the course of 3 weeks, this daily without naloxone, when both food and sugar are denied for
24 hours.11,21,24 Our quantitative polymerase chain reaction
food restriction and delayed feeding results in 32% of the
(qPCR) and autoradiographic evidence in sugar-bingeing rats
rat’s caloric intake coming from sugar. Rats on this daily
shows downregulated enkephalin mRNA22 and upregulated mu-
12-hour schedule of sugar and chow escalate their total daily
receptor binding in the nucleus accumbens (NAc).23 This is
sugar intake during the weeks of access. It is interesting to
interpreted to mean that repeated sugar bingeing releases
note that some rats with 12-hour access to sugar take not only
opioids, such as enkephalin or beta-endorphin, and the brain
a large meal at the onset of access but they also binge
compensates by expressing less of these opioid peptides in
spontaneously throughout the feeding period.11
certain regions. Perhaps the postsynaptic cells respond to less
Rats with ad libitum access to the sugar solution are a
of these peptides by expressing or exposing more mu-opioid
valuable control group. They drink sugar even during the
receptors. If the receptors are then blocked by naloxone, or
inactive, light phase. These animals consume the same large
the rats are food deprived, the animals display anxiety in an
quantities of sugar solution as bingeing rats; however, it is
elevated plus-maze24,21 and depression in a swim test (Kim et
spread out over the course of 24 hours. We do not see
al, unpublished). These behavioral and neurochemical alter-
evidence of binge-eating behavior with ad libitum sugar
ations are accepted indications of opiate-like “withdrawal” in
access.11 As a result, they do not show signs of dependency.
Thus, it is the intermittent feeding schedule that seems to be animal models.25
critical for inducing bingeing and the subsequent signs of Dopaminergic Adaptation and Signs of
dependency. In Figure 1, bingeing is indicated as the first Sensitization
stage in route to addiction. An opioid system in the ventral midbrain is partially
responsible for stimulating DA cells during the consumption
WHY DOES SUGAR BINGEING RESULT IN of highly palatable foods.26,27 In various parts of the striatum,
ADDICTIVE-LIKE BEHAVIORS? sugar bingeing results in an increase in DA binding to D1
Bingeing causes repeated, excessive dopamine (DA) re- receptors coupled with a decrease in D2-receptor binding.23
lease and opioid stimulation that is followed, during abstinence, This may occur because each binge releases DA sufficiently
by progressive changes that enhance the likelihood of relapse. to raise extracellular levels to about 123% of baseline.28,29
Unlike typical feeding patterns, DA release in response to
Opioid Adaptations and Signs of Withdrawal binge eating does not diminish with repeated meals, as
The comparison of sugar addiction with drug addiction normally seen with food that is no longer novel.30,27 As seen
has been reviewed in detail.20,11 In just a few weeks on the in Figure 2, the restriction-refeeding conditions imposed by
intermittent, 12-hour sugar-chow feeding schedule, rats will our laboratory model of binge eating cause a surge of DA,
show signs of opiate-like “withdrawal” in response to nalox- even after 21 days of daily exposure. Repeated surges of DA

34 © 2009 American Society of Addiction Medicine

J Addict Med • Volume 3, Number 1, March 2009 Sugar Addiction

FIGURE 2. Rats with intermittent access to sugar release DA in response to drinking sucrose for 60 minutes on day 21. DA,
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 3 control groups as follows: a group that only had 1-hour access
to sucrose on days 1 and 21 with ad libitum chow in the interim (sucrose twice, filled circles), ad libitum sucrose and chow
group (filled squares), and the 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 ⬍ 0.05.29

may alter the gene production and intracellular signaling can be viewed as signs of enhanced motivation, which is
mechanisms of postsynaptic neurons, presumably leading to integral to relapse to substance abuse.15,42,43
neural adaptations that compensate for excessive DA stimu- In summary, sugar has the addictive-like properties of
lation.31 both a psychostimulant and an opiate. Cross-sensitization
Repeated psychostimulant activation of the mesolimbic with amphetamine is clearly dopaminergic and important in
DA system causes behavioral sensitization.32–36 Evidence some stages of addiction. The naloxone-induced withdrawal21
suggests that the mesolimbic DA system is also altered by and abstinence-induced incubation of responding for sugar-
sugar bingeing. An amphetamine challenge causes locomotor associated cues have opioid components.44 This leads to the
hyperactivity in rats with a history of bingeing on sugar.37 suggestion that sugar bingeing results in behavioral and
The effect occurred 9 days after the rats stopped bingeing, neurochemical signs of excessive dopaminergic and opioid
suggesting that changes in DA function are long lasting. stimulation, which contribute to long-term changes in moti-
Conversely, when rats are sensitized by daily injections of vational behavior (Fig. 1).
amphetamine, they show hyperactivity 10 days later when Compulsion and life-disruptive consequences are evident
they drink sugar.38 We interpret this to mean that sugar in some people who suffer from binge eating disorder, bulimia
bingeing and amphetamine injections sensitize the same DA nervosa, or obesity; thus, some people may be “dependent” by
system, resulting in behavioral cross-sensitization. Diagnostic and Statistical Manual of Mental Disorders criteria.
This raises the obvious question: do they have a food addiction?
Abstinence-induced Signs of Increased Motivation The animal model discussed above suggests it is possible that
Other long-lasting effects of sugar bingeing include some binge eaters and bulimics could be addicted to sugar, but
a) enhanced lever pressing for sugar after 2 weeks of absti- this does not explain all eating disorders or obesity although
nence,39 b) enhanced voluntary alcohol intake in rats with a much has been published on this highly speculative topic.45–50
history of sugar-bingeing,40 and c) enhanced responding for
sugar-associated cues.41 These phenomena are referred to as WHICH FOODS ARE POTENTIALLY ADDICTIVE?
the sugar “deprivation effect,” the alcohol “gateway effect,” THERE IS SOMETHING SPECIAL ABOUT SUGAR
and cue “incubation effect,” respectively. They all occur
during abstinence, weeks after daily sugar bingeing stopped. Sugar
Because they are seen during abstinence, it is tempting to There is more to food addiction than food restriction
categorize them as signs of “craving.” Conservatively, they and bingeing. The type of nutrient that the animal ingests is

© 2009 American Society of Addiction Medicine 35

Hoebel et al J Addict Med • Volume 3, Number 1, March 2009

also important. Our studies of food addiction have largely of high-sucrose, high-fat pellets. Both the pure vegetable fat
focused on sugar (sucrose or glucose). The positive results and the high-fat pellets were consumed avidly on a binge-
may relate to sugar as a special nutrient. It has its own receptor inducing schedule.68 Either the animals were not dependent
system in the tongue,51,52 the intestines,53,54 the liver,55 pan- on the fat or it was a type of addiction that does not cause
creas,55 and brain.56 Glucoreceptors provide life-saving infor- opiate-like withdrawal. In terms of withdrawal, fat may be to
mation to the ingestive behavior system and its associated sugar as cocaine is to heroin; that is to say, there are fewer
learning, emotion, and motivational systems. In all probabil- observable behavioral manifestation of withdrawal with co-
ity, sugar addiction in rats is engendered by excessive, re- caine compared with heroin and similarly, fat compared with
peated activation of this pervasive sugar sensory system. sugar. Because of this, we have been biased toward looking
for signs of opiate-like withdrawal in rats bingeing on sugar.
Saccharin and Sweet-taste If the opioid system is not perturbed to a significant degree in
It would be interesting to test artificial sweeteners to see rats bingeing on fat, then opiate-like withdrawal signs will
whether the oral component of sweetness is sufficient to not emerge. Although it is clear that sugar releases opioids
produce dependency. We used 12-hour intermittent access to that prolong a meal,69,70 fat might not be effective in this way.
chow and 0.1% saccharin solution to simulate the taste of a Fat is less satiating than carbohydrate, calorie for calorie, but
“diet soft drink.” After 8 days of this dietary regimen, animals sugar may actually suppresses satiety, just as it can suppress
were deprived of food and saccharin for 36 hours, with somatic pain and discomfort in general.71,72 We have also speculated
signs related to anxiety scored every 12 hours. Depriving the that fat-stimulated peptides such as galanin, which show
rats of food and saccharin led to increased instances of teeth increased mRNA expression in response to a high-fat meal
chattering, head shakes, and forepaw tremors over the 36- and also inhibit some opioid systems,73 might thus reduce
hour period. This aversive state was readily counteracted by sugar-stimulated opioid-based withdrawal.68 Thus, although
5 mg/kg of morphine or access to a saccharin solution fat does not seem to produce opioid-based dependence, it
(Hoebel and McCarthy, unpublished). Thus, we suspect that may still be addictive, but in a way that we have not yet
scheduled saccharin binges may stimulate dopamine and measured.
opioid-induced dependency, much like the case with sucrose.
This is not surprising, given extensive research in the Carroll
laboratory suggesting that saccharin can be a substitute for
IS THERE A LINK BETWEEN BINGE EATING
cocaine, and saccharin preference is a marker for addiction AND OBESITY? IT DEPENDS ON THE DIET
liability.57,58 Further support for the extreme reinforcing
value of saccharin, and its relation to addiction, comes from Sucrose or Glucose Bingeing, Alone, Does Not
Ahmed and coworkers,59 who have shown that some rats Cause Obesity
prefer saccharin to cocaine self-administration. In terms of overall body weight, some studies have
Another way to test the power of the sweetness of sugar found that bingeing on fat or sugar does not result in weight
without the concomitant calories is to purge the stomach by dysregulation,23,74 –76 whereas others have shown an increase
opening a gastric fistula while rats drink 10% sucrose. As one in body weight.77–79 In our laboratory, rats that binge on
would expect, sham drinkers consume excessive amounts of glucose or sucrose show many of the same signs as animals
sugar because of the relative lack of satiety signals.60 After 3 taking drugs of abuse, as described above, and serve as
weeks of sham-binge eating, the taste of a sham-meal of sucrose animal models of sugar addiction, but they compensate for
will still increase extracellular DA to 131% of baseline.61 the sugar calories by eating less chow and thus control their
body weight.24,21 A control group with ad libitum access to
Postingestive Carbohydrates sugar also compensates for their caloric intake such that they
Real sucrose intake is probably more addictive than do not become obese.
either saccharin or sham intake, because extensive evidence
shows that intestinal glucose receptors and other postinges- Sweet-fat Bingeing Does Increase Body Weight
tional factors are important for the sugar reward that is Although animals bingeing on a 10% sugar solution
manifested in conditioned taste preference.62 Flavors associ- demonstrate an ability to regulate their body weight, those
ated with intragastric feeding are preferred,63 and they release that are maintained on a similar bingeing diet, but with a
accumbens DA.64 – 67 We conclude on the basis of these sweet, high-fat food source, do show weight gain.80 Animals
conditioning studies that carbohydrate postingestive cues that were given 2-hour access to this palatable diet showed
could contribute to the DA or opioid release that is triggered bingeing patterns, even though they had ad libitum access to
by sugar during acquisition, maintenance, and reinstatement a nutritionally complete diet for the remainder of the day.
of a binge. Body weight increased because of the large binge meals, and
then it decreased between binges as a result of self-restricted
A Surprising Feature of Fat intake of standard chow. However, despite these daily fluc-
We were surprised by our inability to obtain naloxone- tuations in body weight, the animals with access to sweet-fat
induced anxiety using the plus-maze test as an indication of chow every day gained significantly more weight than the
a withdrawal state in rats on a high-fat diet. Withdrawal failed control group with ad libitum access to standard chow. This
to emerge in rats given vegetable fat (Crisco) along with could lend insight to the connection between binge eating and
standard chow pellets, or given a nutritionally complete diet obesity.81

36 © 2009 American Society of Addiction Medicine

J Addict Med • Volume 3, Number 1, March 2009 Sugar Addiction

Low Basal Dopamine

To test the theory that some obese people are food
addicts, we need obese rats. Extensive work in the Pothos
laboratory shows that inbred obesity-prone rats and obese
cafeteria-diet rats have low basal DA and impaired DA
release.82 This is thought to have underlying causes related, in
part, to weight-related changes in insulin and leptin sensitiv-
ity in the control of DA cell firing.83,84 We know that
underweight rats on a restricted diet also have low basal
DA.85 Thus, it seems that both high- and low-weight animals
may be hyperphagic as a means of restoring their extracellu- FIGURE 3. Simplified diagram showing opposing DA and
lar DA level. This is analogous to rats self-administering ACh influences on dual GABA outputs that are theoretically
cocaine in a manner that keeps their DA elevated.86 In fact, associated with approach behavior and avoidance behavior.
sugar-bingeing rats that are food restricted to the point of The left side of the diagram represents the nucleus accum-
weight loss release more DA than usual when allowed to bens. Note that the DA input on the right is depicted as act-
binge again, and thus they would raise their own DA level.28 ing at D1 receptors to stimulate (plus sign) medium spiny
output neurons (containing GABA, dynorphin, and SP) for
approach and appetitive behavior. DA also acts at D2 recep-
A SIMPLIFIED NEURAL CIRCUIT MODEL OF tors, which inhibit (minus sign) the output path (GABA-
ACCUMBENS FUNCTION enkphalin neurons) labeled for avoidance and aversion.
Given that sugar dependency, like obesity, is related both Acetylcholine from interneurons shown at the far left, may
to basal DA levels and to food-induced release of DA, we need act at muscarinic M2 receptors to inhibit the approach
system, and also act via M1 receptors to stimulate avoid-
a model depicting the role of DA circuitry in behavioral moti-
ance and aversion.
vation. One would expect this circuit to interact with opioid
systems. We have proposed a model in which the NAc has
separate GABA outputs for motivation that are similar to the
well-documented outputs in the dorsal striatum for locomo- “avoidance” neurons. Indeed, local D2 stimulation can induce
tion.87 Just as neurotransmitter imbalance in the motor system signs of aversion, such as gaping and chin rubbing.97 DA
leads to Huntington Chorea and Parkinson disease,88,89 neu- acting via D2 receptors reduces GABA striatal-pallidum
rotransmitter imbalance in the accumbens may be related to neuron responsiveness to glutamate and promotes long-term
general motivational hyperactivity and depression. Specific depression of glutamatergic transmission.98 D1 receptors are
instances may be manifest as hyperphagia and anorexia. reported to promote responses to strong-coordinated gluta-
Taking our clues from the extensive Parkinson disease liter- mate input and long-term potentiation, at least in the GABA
ature,90 we propose that there is an accumbens GABA output neurons that project to the nigra.99,100 D1 receptors in the
pathway that is specialized for positive, “go” motivation caudate potentiated reward-related eye movements, and
(“approach”), including learned approach and appetitive be- again, D2-receptor function was the opposite.101 This pro-
havior, and another for negative, “no-go” motivation (“avoid- vides support for the schema shown in Figure 3 to the extent
ance”), including learned aversion.91,87 Focusing on the shell, that the accumbens shell is organized along lines similar to
the approach pathway would be the “direct path” with dynor- the dorsal striatum. There are different views expressed in the
phin and Substance P as cotransmitters. The avoidance path literature describing the paths from the accumbens to the
presumably uses enkephalin as a cotransmitter and takes an pallidum, nigra, and the hypothalamus. Each may have dif-
“indirect path” to the thalamus and ventral midbrain. Cortex- ferent functions with regard to acquisition and expression of
striatal-pallidum-thalamus-cortex loops may circle around conditioned responses and instrumental performance.102–104
several times in a spiral, leading from cognitive processes to Within the accumbens, the shell and core must be distin-
motor activity.92 Striatal-midbrain pathways have also been guished, in terms of both their functions and their action
described as a spiral, with the shell influencing the core, sequence.105–109 Moreover, subsecond measurements by in
which influences the medial striatum and then the dorsal- vivo voltammetry show DA release within “microenviron-
lateral striatum.93 This brings the ventral midbrain with its ments” of the accumbens may vary with functionally specific
ascending DA and GABA neurons into the schema for cognition subpopulations of DA inputs.110
to be transformed into action. Directly or indirectly the accum- DA surges in response to drugs of abuse cause down-
bens outputs also reach the hypothalamus.94 In the lateral hypo- stream changes, such as postsynaptic, intracellular accumu-
thalamus, glutamate inputs initiate eating and GABA stops it. lation of Delta FosB, which could alter gene production for
This was shown by both microinjection and our microdialysis receptors and other cellular components as a form of com-
studies.95,96 pensation; this could then foster restorative reinstatement of
As shown in Figure 3, DA input from the midbrain to drug taking during abstinence.31 We suggest that if this
the NAc may act to stimulate approach and inhibit avoidance, cascade of intracellular changes can occur in response to
thus fostering behavior repetition. Excitation is envisioned drugs of abuse, it might also occur when repeated surges of
via D1 receptors on the GABA-dynorphin “approach” neu- DA are caused by sugar bingeing.11,61 This hypothesis is
rons and inhibition via D2 types on the GABA-enkephalin supported by recent evidence showing that natural reinforc-

© 2009 American Society of Addiction Medicine 37

Hoebel et al J Addict Med • Volume 3, Number 1, March 2009

ers, such as sucrose and sexual behavior, alter Delta FosB CONCLUSIONS
expression in the NAc.111 This article summarizes data suggesting that, repeated,
Acetylcholine interneurons may act as an opponent excessive sugar intake can lead to changes in brain and
process to halt behavior by doing the opposite of DA at some behavior that are remarkably similar to the effects of drugs of
accumbens synapses as suggested in Figure 3. ACh theoret- abuse. Thus, sugar may be addictive under special circum-
ically inhibits appetitive approach and stimulates the aver- stances. On the other hand, bingeing on fat, or even sweet-fat,
sion-avoidance path; this could be due to synaptic effects at has given negative results as far as withdrawal is concerned,
muscarinic M2 and M1 receptors, respectively (Fig. 3). Nu- suggesting that different neural systems are involved. A
merous studies in the rat support the view that accumbens high-fat diet, if rats binge on it every day, can lead to extra
ACh interneurons inhibit behavior, including the inhibition of weight gain. Rats prone to obesity on a high-fat diet show
feeding behavior and cocaine intake.61,91,112,113 A muscarinic low-basal DA levels in the NAc, as do underweight rats,
agonist applied locally to the accumbens can cause behavioral suggesting that both may overeat opportunistically in a man-
depression in the swim test and a relatively specific M1 ner that restores DA levels. Surges of binge-induced DA may
antagonist alleviates depression.114 Dynorphin and other be partially responsible for the neural adaptations manifest as
transmitters also enter into the control of this system with locomotor sensitization and abstinence-induced enhancement
depression as one of the outcomes.115 A conditioned taste of motivation for the food. Opioids are another important part
aversion releases ACh116 and neostigmine, used to raise local of the picture, but the exact system is not known, because
ACh levels, is sufficient to engender an aversion to a flavor opioids can induce feeding in many brain regions. It seems
that was previously paired with the cholinergic injection.117 that opioids may be responsible for the withdrawal signs and
This suggests that excessive ACh can cause an aversive state for abstinence-induced incubation of cue-induced relapse.
that is manifest as a conditioned taste aversion. The possible ACh in the NAc is one of the countervailing forces in this
actions of other muscarinic and nicotinic drugs in the accum- process. Sugar bingeing seems to postpone ACh release, and
bens do not fit our model94,118,119 and are discussed elsewhere sham feeding greatly attenuates it. This is all consistent with
in light of the possibility that some muscarinic agonists a model in which DA stimulates approach and inhibits avoid-
release DA and some muscarinic antagonists may act via M2 ance outputs in the NAc. ACh does the opposite, unless it is
receptors to release ACh.87,120 ACh interneurons may be circumvented by drugs of abuse, sugar bingeing, or purging.
inhibited by DA via D2 receptors, as reviewed by Surmeier et
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