Article

Volkow ND, Wise RA. How can drug addiction help us understand obesity? Nat Neurosci 8: 555-560

National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature Neuroscience (Impact Factor: 16.1). 06/2005; 8(5):555-60. DOI: 10.1038/nn1452
Source: PubMed
ABSTRACT
To the degree that drugs and food activate common reward circuitry in the brain, drugs offer powerful tools for understanding the neural circuitry that mediates food-motivated habits and how this circuitry may be hijacked to cause appetitive behaviors to go awry.

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FEEDING REGULATION AND OBESITY
How can drug addiction help us
understand obesity?
Nora D Volkow & Roy A Wise
To the degree that drugs and food activate common reward circuitry in the brain, drugs offer powerful tools for understanding the
neural circuitry that mediates food-motivated habits and how this circuitry may be hijacked to cause appetitive behaviors to go awry.
Until recently in our evolutionary history,
addictive agents have been ingested in foods.
Many are secondary plant metabolites that
evolved because they discourage ingestion by
animals
1
. The hungers that arise from bodily
needs are non-directive; they merely encourage
us to put things in our mouth. The more acute
the hunger, the greater the range of substances
we will ingest
2
. We learn to return to the yellow
banana, the purple fig, the pink peach. We also
learn to chew the tobacco leaf and drink the
nectar of fermented fruits and grains. Because
of the need for the nutrients in plants con-
taining addictive substances, many species
have learned to accept mildly intoxicating
amounts of these compounds. Paradoxically,
some of the poisons that evolved in plants to
discourage animals from returning are—like
the nutrients that the plants offer—habit-
forming in their own right.
Addiction and obesity each results from
foraging and ingestion habits that persist
and strengthen despite the threat of cata-
strophic consequences. Feeding and drug use
involve learned habits and preferences that
are stamped in by the reinforcing properties
of powerful and repetitive rewards. Palatable
food activates brain reward circuitry through
fast sensory inputs and through slow post-
ingestive consequences (such as raising glucose
concentration in blood and brain), whereas
drugs activate these same pathways mostly
through their direct pharmacological effects
on the reward circuitry. The repeated supra-
physiological stimulation of reward pathways
by drugs not only stamps in response habits
and stimulus preferences, but also triggers
neurobiological adaptations that may make
the behavior increasingly compulsive and lead
to further loss of control over intake.
Not all humans who are exposed to habit-
forming drugs become addicted, just as not
all humans who are exposed to high-fat, high-
calorie foods become obese. Although some
classes of obesity can be linked to known
genetic polymorphisms, the recent epidemics
of obesity and of certain addictions are more
clearly correlated with the increased avail-
ability of ‘comfort foods’ and of drugs or drug
forms such as methamphetamine and crack’
cocaine than to drift in the genome. Thus
obesity, like addiction, is linked strongly with
exposure to powerful reinforcers.
Genetic factors in obesity and addiction
Individuals suffering from addiction or from
obesity are stigmatized in part by the belief
that the decision to overeat or to take drugs is
completely under voluntary control. Yet addic-
tion and obesity are multifactorial disorders
that have significant genetic components.
As much as 40–60% of the vulnerability
to addiction
3,4
and 50–70% of the variability
in body mass index
5
might be attributed to
genetic differences under the specific circum-
stances of the studies. However, estimates of
heritability under one set of circumstances are
not necessarily valid for others. The contribu-
tions of genetic and environmental factors are
not simply additive; rather, they interact in
complex and sometimes counterintuitive ways.
For example, the contribution of genotype to
variability in the body mass of sheep is greater
in September than in June
6
and the genetic
contribution to the variability of smoking in
women is greater now than in earlier decades
when social restrictions on females were
stronger and fewer women tried cigarettes
3
.
Just as the genetic influences in addiction vary
between cultures with differential availability
of alcohol, so too is the genetic contribution
to obesity likely to differ between societies
that differ in the acceptance and availability
of high-calorie, high-fat foods.
Genetic studies have revealed point muta-
tions that are of importance for obesity
7
and
for addiction
8
. However, addiction and obesity
are also thought to be under polygenetic con-
trol. Addiction-prone and addiction-resistant
rat phenotypes are associated with differing
sensitivity to the various stressors in the envi-
ronment
9,10
, and stress has a potential role
in obesity
11
as well as addiction
12
. Moreover,
broad-based factors such as gender affect both
feeding
13
and drug taking
14
. Thus, it is very
possible that there are polygenic genotypes that
confer risk for both obesity and addiction.
Environmental factors
Of the environmental factors that influence
obesity and addiction, the availability of
seductive foods and drugs is the most obvious.
For the greater part of human evolution, sweet
taste was associated with fruits that afforded
quick energy. However, genes that were favored
under conditions of food scarcity have become
a liability in societies where high-energy,
highly refined foods are prevalent and read-
ily affordable. Indeed, the recent escalation in
the prevalence of obesity has developed over a
period when the genome has changed little but
the availability of low-cost, high-fat, high-car-
bohydrate foods has changed dramatically (for
instance, in vending machines, convenience
Nora D. Volkow and Roy A. Wise are at the National
Institute on Drug Abuse, National Institutes of
Health, Bethesda, Maryland 20892, USA.
e-mail: nvolkow@nida.nih.gov
Published online 26 April 2005; doi:10.1038/nn1452
© 2005 Nature Publishing Group http://www.nature.com/natureneuroscience
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stores and fast food restaurants). Similarly,
recent epidemics of addiction to cocaine and
heroin have accompanied increased availabil-
ity and lower cost of these drugs.
The quality of the reinforcer is another
factor of importance for addiction and obe-
sity (Table 1). In addiction, the strength of a
drug as a reinforcer depends on its route of
administration (intravenous and smoking
routes are more reinforcing than snorting or
oral administration) and dose. This is partly
because smoked or injected drugs reach the
brain more quickly and partly because they
reach the brain in higher concentration
15
. In
addition, drugs of abuse are not equally addic-
tive. When animals are given unlimited access
to intravenous amphetamine or cocaine
16
,
they self-administer the drug to the point of
death, whereas animals given unlimited access
to intravenous nicotine
17
do not.
Just as different drugs establish different
levels of compulsive behavior, so do different
foods. Individuals in a high-fat, high-carbohy-
drate environment are at considerably greater
risk than those in a vegetarian environment.
Notably, low-carbohydrate and low-fat diets
have each been recommended as methods for
weight loss, and each is effective for the time
it is practiced. The common denominator of
such diets is that neither allows consumption
of the very caloric and seductive foods that
combine high fat with high carbohydrates.
Another important environmental factor
is stress. Acute as well as chronic stress influ-
ences both food intake and the propensity to
take drugs. For example, childhood stress has
been associated with elevated risk for problems
with weight during adolescence or early adult-
hood
18
and also with a higher risk of substance
abuse and addiction
19
. The role of stress is
mediated in part by the corticotropin-releas-
ing factor (CRF) and related peptides
20
. CRF
not only controls the pituitary-adrenal axis
but also serves as a neuropeptide cotransmit-
ter in neurons orchestrating the central effects
of stress
21
. CRF is well-known to be involved
in the regulation of energy balance and food
intake
22
. Similarly, in addiction, CRF is rec-
ognized for its involvement in stress-induced
reinstatement of drug taking and vulnerability
to relapse
20
and in the responses to acute drug
withdrawal
12
.
Developmental factors
Developmental processes also seem to influ-
ence the behaviors associated with food con-
sumption and drug taking. Experimentation
with drugs often starts in early adolescence
23
.
Behaviors such as risk-taking, novelty-seek-
ing and response to peer pressure increase
the propensity to experiment with drugs. The
adolescent onset of these behaviors may reflect
delayed maturation of the prefrontal cortex,
a brain region involved with judgment and
inhibitory control
24
. In addition, drug expo-
sure during adolescence can result in different
neuroadaptations from those that occur during
adulthood. For example, in rodents, exposure
to nicotine during the period corresponding to
adolescence, but not during adulthood, leads
to significant changes in nicotine receptors and
an increased reinforcement value for nicotine
later in life
25
. Exposure to drugs during fetal
development may also increase the vulnerabil-
ity to drug use later in life. Indeed, smoking
during pregnancy increases the risk of nicotine
dependence in the offspring
26
. Interestingly, it
also increases their risk for obesity
27
. Similarly,
early exposure to certain diets during fetal
life and the immediate postnatal period can
influence the food preferences of an individual
later in life
28
. Moreover, the marked increases
in childhood and youth obesity in the United
States (which has tripled in the past 30 years)
highlights the importance of investigating the
interactions between developmental variables
and the environment in this disorder.
Neurobiological mechanisms
The biological mechanisms of feeding and
addiction have overlapped throughout our
evolutionary history. The opiate antagonist
naloxone inhibits feeding in mammals
29
, in
slugs and snails
30
and even in amoebae
31
.
The most clearly established commonality
of the mechanisms of food and drug intake
is their ability to activate the dopamine-
Table 1 Comparison of food and drugs as reinforcers
Food Drug
Potency as a reinforcer* ++ Oral: ++
Snorted: +++
Smoked, injected: ++++
Delivery Oral Oral, snorted, smoked,
injected
Mechanism of reward Somatosensory (palatability), Chemical (drug)
chemical (glucose)
Regulation of intake Peripheral and central factors Mostly central factors
Adaptations Physiologic Supraphysiologic
Physiological role Necessary for survival Unnecessary
Learning Habits, conditioned responses Habits, conditioned
responses
Role of stress +++ +++
*Potency as reinforcer is estimated based on the magnitude and duration of increases in dopamine induced by either
food or drugs in the nucleus accumbens, and is an approximate comparison, as potency will be a function of the
particular foodstuff or of the particular drug and its route of administration.
Figure 1 Dopaminergic pathways. (a) Dopaminergic pathways. PFC, prefrontal cortex; CG, cingulate
gyrus; OFC, orbitofrontal cortex; NAcc, nucleus accumbens; Amyg, amygdala; STR, striatum;
TH, thalamus; PIT, pituitary; HIP, hippocampus; VTA, ventral tegmental area; SN, substantia nigra.
(b) Increases in dopamine in nucleus accumbens induced by food and by amphetamine as assessed by
microdialysis in rodents. Graphs modified from ref. 60.
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containing link in brain reward circuitry
32
(Fig. 1). Pharmacological blockade of, or exper-
imental damage to, forebrain dopamine systems
attenuates free feeding and lever-pressing for
food reward, as well as the rewarding effects of
cocaine, amphetamine, nicotine and alcohol
33
.
Although the mesolimbic dopamine projection
from the ventral tegmental area to the nucleus
accumbens is most frequently implicated in
reward function, other forebrain dopamine
projections are almost certainly involved
34
.
Endogenous opioid systems interact at each
end of the forebrain dopamine systems. In the
midbrain, µ opioid receptors are localized on
GABAergic neurons that normally inhibit the
dopamine systems; µ opioids inhibit this input,
thus disinhibiting the dopamine system and
causing dopamine release in nucleus accum-
bens and related target regions. In nucleus
accumbens, µ opioid receptors are localized on
GABAergic neurons that receive input from the
mesolimbic dopamine system. Injections of µ
opioids into each of these regions is rewarding
in its own right
35
, and injections into each of
these regions potentiate feeding
36
. The role of
opiates in these areas seems to be to augment
the intake of high-fat, high-sugar foods rather
than to mimic the effects of nutritive deficit on
bland food
37
. Indeed, the endogenous opioid
system seems to underlie the rewarding prop-
erties of palatable foods
38
.
Thus the mesolimbic dopamine system
and its afferents and efferents contribute
to the rewarding effects of various addic-
tive drugs and of foods. These systems also
seem to be modulated by substrates of energy
regulation that are the topic of other papers
in this issue. Not only does food deprivation
potentiate the rewarding effects of food
39
,
chronic food restriction also potentiates the
rewarding effects of lateral hypothalamic
brain stimulation
40
and of most addictive
drugs
41
. The adipocyte hormone leptin,
which is lacking in obese ob/ob mice, not
only suppresses food intake, but also reverses
the effects of food restriction on brain stimu-
lation reward thresholds
40
and on the rein-
statement of drug-seeking
42
in an animal
model of addiction relapse.
Thus, in broad sketch, there is considerable
overlap between brain circuitry that evolved
in the service of body-weight regulation and
brain circuitry that is usurped by exogenous
drugs of abuse. As the finer details of the brain
mechanisms of addiction and feeding are
worked out—such as the role of GABAergic
and cholinergic modulation of the ventral
tegmental area and medium spiny neurons in
feeding and reward—considerable cross-fer-
tilization between the two literatures can be
expected to occur.
Neurobiological adaptations
The regulation of food consumption is much
more complex than that of drug consumption
because food intake is modulated by multiple
peripheral and central signals, whereas drugs
are modulated mostly by the drug’s central
effects. However, addictive drugs, like addic-
tive foods, activate brain circuitry involved in
reward, motivation and decision-making
43
.
In addiction, it seems almost as if the brain
responds to the drug as it would respond to
food under conditions of severe deprivation.
What leads to the increasing desire for the
drug as addiction progresses? Researchers have
postulated that neurobiological adaptations
initiated by chronic and intermittent supra-
physiological perturbations in the dopamine
system by a drug trigger changes in some of
the regions and neurotransmitter systems
modulated by dopamine
44
. Advances in neu-
roscience have begun to provide insight into
the nature of these adaptations.
Figure 2 Relationship between dopamine (DA) D2 receptors in the brains of cocaine abusers and methamphetamine abusers, and metabolic activity in
orbitofrontal cortex.
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Neurotransmitter adaptations are docu-
mented not only for dopamine but also for
glutamate, GABA, opiates and CRF, among
others
45
. Some of these changes disrupt brain
function. For example, in cocaine-addicted
subjects, imaging studies show that changes in
dopamine brain activity (reductions in dopa-
mine D2 receptors and in dopamine release
in striatum) are associated with disruption in
the activity of the prefrontal cortex
46
(Fig. 2).
Disrupted function of the orbitofrontal cor-
tex (OFC) and the anterior cingulate gyrus,
regions of the prefrontal cortex involved
with salience attribution and with inhibitory
control, are particularly informative for the
understanding of addiction, as their disrup-
tion is linked to compulsive behaviors and
poor impulse control
46
. In preclinical studies,
drug-related adaptations in the prefrontal cor-
tex specifically enhance activity of the cortico-
striatal glutamatergic pathway that regulates
dopamine release in the nucleus accumbens
47
.
Adaptations in this pathway have been linked
to drug- and cue-induced relapse into drug-
seeking in animal models. The extent to which
the prefrontal abnormalities in addicted sub-
jects (reported by imaging studies) result in
disruption of corticostriatal glutamatergic
pathways (reported in preclinical studies)
requires further investigation.
In addition to the adaptations in the targets
of the dopamine mesocortical pathway, there
is also evidence of adaptations in the targets of
the dopamine mesolimbic circuit (including
neurons of the nucleus accumbens, amygdala
and hippocampus), which may underlie the
enhanced motivation for the drug and condi-
tioned responses. Adaptations may also occur
in the targets of the dopamine nigrostriatal cir-
cuit (including the dorsal striatum)
48
, which
might underlie habits that are linked with the
rituals of drug consumption. The search for
neuroadaptations associated with addiction
is largely a search within the brain circuitry
through which drugs exert their reinforcing
effects. To the degree that the same circuitry is
important for the reinforcing effects of food,
neuroadaptations in this circuitry should
affect food intake as well as drug intake.
The relevance of dopamine to obesity has
also been documented by both preclinical and
clinical studies. In animal models of obesity
(including leptin-deficient ob/ob mice, obese
Zucker rats, obesity-prone Sprague-Dawley
rats and seasonally obese animals), dopamine
activity is reduced in the tuberoinfundibular
pathway that projects to the hypothalamus
49
.
In these animals, treatment with dopamine
agonists reverses the obesity, presumably by
activating dopamine D2 and D1 receptors
49
.
In humans, brain imaging studies show reduc-
tions in dopamine D2 receptors in the stria-
tum of obese individuals that are similar in
magnitude to the reductions reported in drug-
addicted subjects
50
(Fig. 3a). In obese subjects,
but not in controls, dopamine D2 receptor
abundance is inversely related to body mass
index, suggesting that the dopamine system is
involved in compulsive food intake (Fig. 3b).
Further support for this idea is provided by
clinical studies showing that chronic treatment
with drugs that block dopamine D2 receptors
(antipsychotics) is associated with a higher risk
of obesity
51
. Though decreases in dopamine
D2 receptors have been documented across a
wide variety of drug addictions and in obesity,
by themselves they are insufficient to account
for these disorders, and their role is likely to be
one of modulating vulnerability.
Similarly, imaging studies in obese subjects
document abnormalities in prefrontal cor-
tex
52
. When food-related stimuli are given to
obese subjects (as when drug-related stimuli
are given to addicts
46
), the OFC is activated
and cravings are reported
53
. Several areas of
the prefrontal cortex (including the OFC and
cingulate gyrus) are implicated in motiva-
tion to feed
54
. These prefrontal regions could
reflect a neurobiological substrate common
to the drive to eat or the drive to take drugs.
Abnormalities of these regions could enhance
either drug-oriented or food-oriented behav-
iors, depending on the established habits of
the subject.
Neuroadaptations are also documented in
the opioid system in cocaine abusers
55
and
in alcoholics
56
. Though there are no pub-
lished studies in humans, preclinical studies
show adaptations in the opioid system after
administration of palatable foods (reviewed
in ref. 57). The neuroadaptations resulting
from chronic food intake are likely to be more
complex than those observed with drugs and
are known to include changes in neuronal cir-
cuitry that modify the motivation to eat, as
well as neuroadaptations that modify energy
efficiency and metabolic thresholds
57
.
Prevention
One of the most successful prevention inter-
ventions in public health in the last century
was in promoting smoking cessation. Over a
period of 30 years, the prevalence of smoking
in adults in the United States dropped from
42.4% in 1965 to 24.7% in 1995 (ref. 58). The
success of this intervention can be linked to
an effective educational campaign based on
solid scientific information about the deleteri-
ous health effects of smoking. Policy changes
that made cigarettes more expensive, selling of
cigarettes to minors illegal and smoking much
more restricted in public spaces also contrib-
uted to its success. The campaign also alerted
the medical community to the importance of
evaluating and treating smokers. All of these
factors were effective in producing dramatic
changes in the attitude of the public toward
smoking.
The success of this intervention for an addic-
tion (to nicotine) can be used to suggest and
design an effective campaign to reduce obesity.
As for the antismoking campaign, this should
include education regarding healthy eating
and exercising (as sedentary lifestyles have
also contributed to the increase in obesity).
Interventions should be initiated in early child-
hood, because this is when children develop
life-long eating habits and start to become
overweight. It should also involve the medi-
cal community, which should be prepared to
evaluate and treat obesity, along with the food
industry, which should be encouraged to make
healthy foods more attractive, palatable and
less expensive, and policy makers, who should
consider incentives to facilitate these changes.
Finally, a campaign to reduce obesity should
involve institutions such as schools, with
Figure 3 Role of dopamine D2 receptors in obesity. (a) Dopamine D2 receptors in controls and in obese
individuals. (b) Relationship between D2 receptors and body mass index (BMI).
© 2005 Nature Publishing Group http://www.nature.com/natureneuroscience
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efforts to remove junk foods from dispensing
machines and cafeterias where they help to
seduce young people into obesity, just as read-
ily available cigarettes helped, until recently,
seduce them into addiction.
One unique challenge for the prevention
of obesity arises because food, unlike drugs,
is indispensable to survival. Thus, it will be
much harder for a society to implement regu-
lations to constrain the easy access to food that
can facilitate compulsive eating. What can be
hoped for, however, is more restricted access to
high-fat, high-calorie foods that are seductive
and unnecessary for good health, particularly
in public places such as schools.
Treatment
As in the treatment of drug addiction, scientific
knowledge about the involvement of multiple
brain circuits (reward, motivation, learning,
cortical inhibitory control) would suggest
a multimodal approach to the treatment of
obesity. For obesity as well as for addiction,
promising pharmacological interventions
may be those that interfere with various pro-
cesses, including the reinforcing value of the
substance (food or drug); with conditioned
responses to these processes; and with stress-
induced relapse after temporary successes are
achieved. Indeed, in some instances the same
medications that are effective in interfer-
ing with (or reducing) food consumption in
animal models of obesity are also effective in
interfering with (or reducing) drug consump-
tion by self-administration in animal models
of drug abuse (for example, cannabinoid CB
1
antagonists).
In a similar fashion, some of the behav-
ioral interventions that are beneficial in the
treatment of addiction are also helpful in the
treatment of obesity. These include incentive
motivation, cognitive-behavioral therapy and
12-step programs. However, the interventions
for obesity are complicated by the impossibil-
ity of completely refraining from eating, as is
frequently recommended for drug addiction.
For example, we know that for relapse to drug-
seeking, the priming effects of the drug are very
potent
59
; thus 12-step programs stress absolute
abstinence, a strategy that avoids the danger
of priming. Alcoholics note that it is easier to
draw a line between zero drinks and one drink
than between the first and second or the sixth
and seventh. In the case of food, a similar effect
is more difficult to achieve because food con-
sumption is essential and long periods of total
abstinence are not feasible. However, strategies
that avoid food rich in carbohydrates or fats,
or their combination, should help at-risk indi-
viduals to sidestep priming effects that trigger
compulsive eating.
Like addiction, obesity is a chronic condi-
tion with periods of protracted abstinence
(restriction of seductive foods) and periods of
relapse (compulsive eating). Thus, treatment
will in most cases require continuous care.
Large-scale prevention and treatment pro-
grams for obesity (like those for addiction)
will require the participation of the medical
community. The engagement of pediatricians
and family physicians might facilitate early
detection and treatment of obesity in child-
hood and adolescence. Unfortunately, as with
addiction, physicians, nurses and psycholo-
gists receive little training in the management
of obesity.
Conclusion
Obesity and addiction are special cases of the
consequences of ingestive behavior gone awry.
Each develops in some but not all individuals,
and each is subject to genetic predispositions
and the availability of a powerful reinforcer.
In each case, there appear to be periods of
developmental vulnerability. Although each
condition has its own interface with brain
mechanisms of motivation, the motivational
mechanisms themselves largely overlap. In
each case, neuroadaptations resulting from
excessive intake may make the ingestive behav-
ior more compulsive. The guidelines for pre-
vention and treatment of the two disorders
are remarkably similar, and some of the same
pharmacological interventions that are prom-
ising for the control of drug intake are also
promising for controlling the intake of food.
Few fields seem to offer as much potential for
cross-fertilization as the fields of addiction
and obesity research.
ACKNOWLEDGMENTS
The authors thank C. Kassed for her assistance in
preparing the manuscript.
COMPETEING INTEREST STATEMENT
The authors declare that they have no competing
financial interests.
1. Fraenkel, G.S. The raison d’etre of secondary plant
substances: these odd chemicals arose as a means of
protecting plants from insects and now guide insects
to food. Science 129, 1466–1470 (1959).
2. Rozin, P. Adaptive food sampling patterns in vitamin
deficient rats. J. Comp. Physiol. Psychol. 69, 126–132
(1969).
3. Kendler, K.S., Thornton, L.M. & Pedersen, N.L.
Tobacco consumption in Swedish twins reared apart
and reared together. Arch. Gen. Psychiatry 57, 886–
892 (2000).
4. Uhl, G.R., Liu, Q.R. & Naiman, D. Substance abuse
vulnerability loci: converging genome scanning data.
Trends Genet. 18, 420–425 (2002).
5. Baessler, A. et al. Genetic linkage and association of
the growth hormone secretagogue receptor (ghrelin
receptor) gene in human obesity. Diabetes 54, 259–
267 (2005).
6. Reale, D., Festa-Bianchet, M. & Jorgenson, J.T.
Heritability of body mass varies with age and sea-
son in wild bighorn sheep. Heredity 83, 526–532
(1999).
7. Friedman, J.M. & Leibel, R.L. Tackling a weighty prob-
lem. Cell 69, 217–220 (1992).
8. Volkow, N.D. & Li, T.K. Drug addiction: the neurobiol-
ogy of behaviour gone awry. Nat. Rev. Neurosci. 5,
963–970 (2004).
9. Kosten, T.A. et al. Acquisition and maintenance of
intravenous cocaine self-administration in Lewis and
Fischer inbred rat strains. Brain Res. 778, 418–429
(1997).
10. Ranaldi, R., Bauco, P., McCormick, S., Cools, A.R.
& Wise, R.A. Equal sensitivity to cocaine reward in
addiction-prone and addiction-resistant rat genotypes.
Behav. Pharmacol. 12, 527–534 (2001).
11. Dallman, M.F., Pecoraro, N.C. & la Fleur, S.E. Chronic
stress and comfort foods: self-medication and abdomi-
nal obesity. Brain Behav. Immunity (in the press).
12. Kreek, M.J. & Koob, G.F. Drug dependence: stress and
dysregulation of brain reward pathways. Drug Alcohol
Depend. 51, 23–47 (1998).
13. Geary, N. Is the control of fat ingestion sexually dif-
ferentiated? Physiol. Behav. 83, 659–671 (2004).
14. Hu, M., Crombag, H.S., Robinson, T.E. & Becker, J.B.
Biological basis of sex differences in the propensity
to self-administer cocaine. Neuropsychopharmacology
29, 81–85 (2004).
15. Volkow, N.D. et al. Effects of route of administration
on cocaine induced dopamine transporter blockade in
the human brain. Life Sci. 67, 1507–1515 (2000).
16. Johanson, C.E., Balster, R.L. & Bonese, K. Self-admin-
istration of psychomotor stimulant drugs: the effects
of unlimited access. Pharmacol. Biochem. Behav. 4,
45–51 (1976).
17. Corrigall, W.A. & Coen, K.M. Nicotine maintains
robust self-administration in rats on a limited-access
schedule. Psychopharmacology (Berl.) 99, 473–478
(1989).
18. Johnson, J.G., Cohen, P., Kasen, S. & Brook, J.S.
Childhood adversities associated with risk for eating
disorders or weight problems during adolescence or
early adulthood. Am. J. Psychiatry 159, 394–400
(2002).
19. Dube, S.R. et al. Childhood abuse, neglect, and house-
hold dysfunction and the risk of illicit drug use: the
adverse childhood experiences study. Pediatrics 111,
564–572 (2003).
20. Sarnyai, Z., Shaham, Y. & Heinrichs, S.C. The role
of corticotropin-releasing factor in drug addiction.
Pharmacol. Rev. 53, 209–243 (2001).
21. Swanson, L.W., Sawchenko, P.E., Rivier, J. & Vale,
W.W. Organization of ovine corticotropin-releasing fac-
tor immunoreactive cells and fibers in the rat brain: an
immunohistochemical study. Neuroendocrinology 36,
165–186 (1983).
22. Richard, D., Lin, Q. & Timofeeva, E. The corticotropin-
releasing factor family of peptides and CRF receptors:
their roles in the regulation of energy balance. Eur. J.
Pharmacol. 440, 189–197 (2002).
23. Wagner, F.A. & Anthony, J.C. From first drug use to
drug dependence; developmental periods of risk for
dependence upon marijuana, cocaine, and alcohol.
Neuropsychopharmacology 26, 479–488 (2002).
24. Sowell, E.R. et al. Mapping cortical change across
the human life span. Nat. Neurosci. 6, 309–315
(2003).
25. Adriani, W. et al. Evidence for enhanced neurobehav-
ioral vulnerability to nicotine during periadolescence
in rats. J. Neurosci. 23, 4712–4716 (2003).
26. Buka, S.L., Shenassa, E.D. & Niaura, R. Elevated risk
of tobacco dependence among offspring of mothers
who smoked during pregnancy: a 30-year prospective
study. Am. J. Psychiatry 160, 1978–1984 (2003).
27. Toschke, A.M., Ehlin, A.G., von Kries, R., Ekbom, A. &
Montgomery, S.M. Maternal smoking during pregnancy
and appetite control in offspring. J. Perinat. Med. 31,
251–256 (2003).
28. Mennella, J.A., Griffin, C.E. & Beauchamp, G.K. Flavor
programming during infancy. Pediatrics 113, 840–845
(2004).
29. Wise, R.A. & Raptis, L. Effects of naloxone and pimo-
zide on initiation and maintenance measures of free
feeding. Brain Res. 368, 62–68 (1986).
30. Kavaliers, M. & Hirst, M. Slugs and snails and opiate
tales: opioids and feeding behavior in invertebrates.
Fed. Proc. 46, 168–172 (1987).
© 2005 Nature Publishing Group http://www.nature.com/natureneuroscience
Page 5
COMMENTARY
560 VOLUME 8
|
NUMBER 5
|
MAY 2005 NATURE NEUROSCIENCE
31. Josefsson, J.O. & Johansson, P. Naloxone-reversible
effect of opioids on pinocytosis in Amoeba proteus.
Nature 282, 78–80 (1979).
32. Di Chiara, G. & Imperato, A. Drugs abused by humans
preferentially increase synaptic dopamine concentra-
tions in the mesolimbic system of freely moving rats.
Proc. Natl Acad. Sci. USA 85, 5274–5278 (1988).
33. Wise, R.A. & Rompre, P.P. Brain dopamine and reward.
Annu. Rev. Psychol. 40, 191–225 (1989).
34. Wise, R.A. Dopamine, learning and motivation. Nat.
Rev. Neurosci. 5, 483–494 (2004).
35. Bozarth, M.A. & Wise, R.A. Intracranial self-adminis-
tration of morphine into the ventral tegmental area in
rats. Life Sci. 28, 551–555 (1981).
36. MacDonald, A.F., Billington, C.J. & Levine, A.S.
Alterations in food intake by opioid and dopamine sig-
naling pathways between the ventral tegmental area
and the shell of the nucleus accumbens. Brain Res.
1018, 78–85 (2004).
37. Zhang, M., Gosnell, B.A. & Kelley, A.E. Intake of
high-fat food is selectively enhanced by mu opioid
receptor stimulation within the nucleus accumbens.
J. Pharmacol. Exp. Ther. 285, 908–914 (1998).
38. Yeomans, M.R. & Gray, R.W. Opioid peptides and
the control of human ingestive behaviour. Neurosci.
Biobehav. Rev. 26, 713–728 (2002).
39. Cabanac, M. Physiological role of pleasure. Science
173, 1103–1107 (1971).
40. Fulton, S., Woodside, B. & Shizgal, P. Modulation of
brain reward circuitry by leptin. Science 287, 125–128
(2000).
41. Carroll, M.E. in Drugs of Abuse and Addiction:
Neurobehavioral Toxicology (eds. Niesink, R.J.M.,
Jaspers, R.M.A., Kornet, L.M.W. & vanRee, J.M.) 286–
311 (CRC Press, Boca Raton, Florida, USA, 1999).
42. Shalev, U., Yap, J. & Shaham, Y. Leptin attenuates
acute food deprivation-induced relapse to heroin seek-
ing. J. Neurosci. 21, RC129-1–RC129-5 (2001).
43. Volkow, N.D., Fowler, J.S. & Wang, G.J. The addicted
human brain: insights from imaging studies. J. Clin.
Invest. 111, 1444–1451 (2003).
44. Volkow, N.D., Fowler, J.S., Wang, G.J. & Swanson,
J.M. Dopamine in drug abuse and addiction: results
from imaging studies and treatment implications. Mol.
Psychiatry 9, 557–569 (2004).
45. Koob, G.F. et al. Neurobiological mechanisms in the
transition from drug use to drug dependence. Neurosci.
Biobehav. Rev. 27, 739–749 (2004).
46. Volkow, N.D. & Fowler, J.S. Addiction, a disease of
compulsion and drive: involvement of the orbitofrontal
cortex. Cereb. Cortex 10, 318–325 (2000).
47. McFarland, K., Davidge, S.B., Lapish, C.C. & Kalivas,
P.W. Limbic and motor circuitry underlying footshock-
induced reinstatement of cocaine-seeking behavior. J.
Neurosci. 24, 1551–1560 (2004).
48. Porrino, L.J., Lyons, D., Smith, H.R., Daunais, J.B.
& Nader, M.A. Cocaine self-administration produces
a progressive involvement of limbic, association, and
sensorimotor striatal domains. J. Neurosci. 24, 3554–
3562 (2004).
49. Pijl, H. Reduced dopaminergic tone in hypothalamic
neural circuits: expression of a “thrifty” genotype
underlying the metabolic syndrome? Eur. J. Pharmacol.
480, 125–131 (2003).
50. Wang, G.J. et al. Brain dopamine and obesity. Lancet
357, 354–357 (2001).
51. American Diabetes Association et al. Consensus develop-
ment conference on antipsychotic drugs and obesity and
diabetes. J. Clin. Psychiatry 65, 267–272 (2004).
52. Gautier, J.F. et al. Differential brain responses to satia-
tion in obese and lean men. Diabetes 49, 838–846
(2000).
53. Wang, G.J. et al. Exposure to appetitive food stimuli
markedly activates the human brain. Neuroimage 21,
1790–1797 (2004).
54. Rolls, E.T. The functions of the orbitofrontal cortex.
Brain Cogn. 55, 11–29 (2004).
55. Zubieta, J.K. et al. Increased mu opioid receptor bind-
ing detected by PET in cocaine-dependent men is asso-
ciated with cocaine craving. Nat. Med. 2, 1225–1229
(1996).
56. Heinz, A. et al. Correlation of stable elevations in stria-
tal µ-opioid receptor availability in detoxified alcoholic
patients with alcohol craving: a positron emission
tomography study using carbon 11-labeled carfentanil.
Arch. Gen. Psychiatry 62, 57–64 (2005).
57. Levine, A.S., Kotz, C.M. & Gosnell, B.A. Sugars:
hedonic aspects, neuroregulation, and energy balance.
Am. J. Clin. Nutr. 78, 834S–842S (2003).
58. National Center for Health Statistics. FASTATS A to Z
(2004) <http://www.cdc.gov/nchs/fastats/>.
59. Shaham, Y., Shalev, U., Lu, L., De Wit, H. & Stewart,
J. The reinstatement model of drug relapse: history,
methodology and major findings. Psychopharmacology
(Berl.) 168, 3–20 (2003).
60. Bassareo, V. & Di Chiara, G. Differential responsiveness
of dopamine transmission to food-stimuli in nucleus
accumbens shell/core compartments. Neuroscience
89, 637–641 (1999).
© 2005 Nature Publishing Group http://www.nature.com/natureneuroscience
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  • Source
    • "HFHS foods and drugs are used to regulate emotional states and cope with stress (Epel, Lapidus, McEwen, & Brownell, 2001; Sinha, 2007). Individuals with substance use disorders and those who overconsume HFHS foods report increased craving in response to relevant cues (Volkow & Wise, 2005) and display hyperactivity of the limbic system in response to environmental cues and consumption of both HFHS foods and drugs (Gearhardt et al., 2011; Volkow & Wise, 2005). Therefore, applying paradigms used in drug addiction research to the study of HFHS food consumption has the potential to inform our understanding of the motivational processes that influence consumption. "
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    Full-text · Article · May 2015 · Appetite
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    • "High impulsivity predicts food addiction C Velázquez-Sánchez et al (Davis et al, 2011; Gearhardt et al, 2009; Smith and Robbins, 2013; Volkow and Wise, 2005). Remarkably, our results reveal that high trait impulsivity is a risk factor, which can predict the individual susceptibility to the addictive properties of highly palatable foods. "
    Full-text · Dataset · Apr 2015
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    • "It is still unclear whether these neural features could serve as vulnerability factors for BD in individuals with metabolic disorders and/or high BMI. Thus far the dysregulation of the reward system circuits and dopaminergic receptor activity in obesity may be the most compelling piece of evidence linking food intake and mood regulation in obese individuals at risk of developing BD [52] [53] [54] "
    [Show abstract] [Hide abstract] ABSTRACT: Recent evidence shows an important relationship between metabolic disturbances and bipolar disorder (BD). However, it is still unclear whether such metabolic disturbances are only a consequence or to some extent the precipitating factors for health problems and maladaptive behaviors observed in BD. Because both metabolic disturbances and BD are medical conditions sharing common alterations in multiple biomarkers, it is plausible to hypothesize that metabolic disturbances may be considered to some extent as a major vulnerability factor in the latent phase of BD for some young adults. In line with this hypothesis , obesity may be regarded as a major driving force for prevalent cardio-metabolic disorders encountered within the early stages of BD. Likewise, premorbid metabolic disturbances as a whole may be considered as a potential source for vulnerability to develop BD. In addition, a synergistic relationship between obesity and metabolic disturbances associated with a premorbid disruption of biological rhythms may also lead to BD. Therefore, we postulate that metabolic disturbances may serve as a specific marker of premorbid illness activity in some people at risk for BD. Future prospective studies should focus on validating metabolic disturbances as vulnerability factors within the staging model of BD.
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