Volkow ND, Wang GJ, Fowler JS, Telang F. Overlapping neuronal circuits in addiction and obesity: evidence of systems pathology. Philos Trans R Soc Lond B Biol Sci 363: 3191-3200

Abstract

Drugs and food exert their reinforcing effects in part by increasing dopamine (DA) in limbic regions, which has generated interest in understanding how drug abuse/addiction relates to obesity. Here, we integrate findings from positron emission tomography imaging studies on DA's role in drug abuse/addiction and in obesity and propose a common model for these two conditions. Both in abuse/addiction and in obesity, there is an enhanced value of one type of reinforcer (drugs and food, respectively) at the expense of other reinforcers, which is a consequence of conditioned learning and resetting of reward thresholds secondary to repeated stimulation by drugs (abuse/addiction) and by large quantities of palatable food (obesity) in vulnerable individuals (i.e. genetic factors). In this model, during exposure to the reinforcer or to conditioned cues, the expected reward (processed by memory circuits) overactivates the reward and motivation circuits while inhibiting the cognitive control circuit, resulting in an inability to inhibit the drive to consume the drug or food despite attempts to do so. These neuronal circuits, which are modulated by DA, interact with one another so that disruption in one circuit can be buffered by another, which highlights the need of multiprong approaches in the treatment of addiction and obesity.

Full text

Overlapping neuronal circuits in addiction
and obesity: evidence of systems pathology
Nora D. Volkow
1,2,
*, Gene-Jack Wang
3
, Joanna S. Fowler
3
and Frank Telang
2
1
National Institute on Drug Abuse, and
2
National Institute on Alcohol Abuse and Alcoholism,
Bethesda, MD 20892, USA
3
Medical Department, Brookhaven National Laborator y, Upton, NY 11973, USA
Drugs and food exert their reinforcing effects in part by increasing dopamine (DA) in limbic regions,
which has generated interest in understanding how drug abuse/addiction relates to obesity. Here, we
integrate findings from positron emission tomography imaging studies on DA’s role in drug
abuse/addiction and in obesity and propose a common model for these two conditions. Both in
abuse/addiction and in obesity, there is an enhanced value of one type of reinforcer (drugs and food,
respectively) at the expense of other reinforcers, which is a consequence of conditioned learning and
resetting of reward thresholds secondary to repeated stimulation by drugs (abuse/addiction) and by
large quantities of palatable food (obesity) in vulnerable individuals (i.e. genetic factors). In this
model, during exposure to the reinforcer or to conditioned cues, the expected reward (processed by
memory circuits) overactivates the reward and motivation circuits while inhibiting the cognitive
control circuit, resulting in an inability to inhibit the drive to consume the drug or food despite
attempts to do so. These neuronal circuits, which are modulated by DA, interact with one another so
that disruption in one circuit can be buffered by another, which highlights the need of multiprong
approaches in the treatment of addiction and obesity.
Keywords: dopamine; positron emission tomography; imaging; self-control; compulsion
1. INTRODUCTION
Drug abuse and addiction, and certain types of obesity
can be understood as resulting from habits that
strengthen with repetition of the behaviour and that
become increasingly harder for the individual to control
despite their potentially catastrophic consequences.
Consumption of food, other than eating from hunger,
and some drug use are initially driven by their rewarding
properties, which in both instances involves activation of
mesolimbic dopamine (DA) pathways. Food and drugs
of abuse activate DA pathways differently (table 1).
Food activates brain reward circuitry both through
palatability (involves endogenous opioids and cannabi-
noids) and through increases in glucose and insulin
concentrations (involves DA increases), whereas drugs
activate this same circuitry via their pharmacological
effects (via direct effects on DA cells or indirectly
through neurotransmitters that modulate DA cells such
as opiates, nicotine, g-aminobutyric acid or cannabi-
noids; Volkow & Wise 2005).
The repeated stimulation of DA reward pathways is
believed to trigger neurobiological adaptations in other
neurotransmitters and in downstream circuits that
may make the behaviour increasingly compulsive and
lead to the loss of control over food and drug intake. In the
case of drugs of abuse, repeated supraphysiological DA
stimulation from chronic use is believed to induce plastic
changes in brain (i.e. glutamatergic cortico-striatal
pathways), which result in enhanced emotional reactivity
to drugs or their cues, poor inhibitory control over drug
consumption and compulsive drug intake (Volkow & Li
2004). In parallel, dopaminergic stimulation during
intoxication facilitates conditioning to drugs and drug-
associated stimuli (drug cues), further strengthening
learned habits that then drive the behaviour to take drugs
when exposed to cues or to stressors. Similarly, repeated
exposure to certain foods (particularly, large quantities
of energy-dense food with high-fat and sugar contents;
Avena et al.2008) in vulnerable individuals can also
result in compulsive food consumption, poor food
intake control and conditioning to food stimuli. In
vulnerable individuals (i.e. those with genetic or
developmental predisposing factors), this can result in
obesity (for food) or in addiction (for drugs).
The neurobiological regulation of feeding is much
more complex than the regulation of drug abuse, since
food consumption is controlled not only by reward but
also by multiple peripheral, endocrinological and
central factors beyond those that participate in reward
(Levine et al. 2003). In this paper, we concentrate
solely on the neurocircuitry linked with the rewarding
properties of food, since it is likely to be a key
contributor in accounting for the massive increase in
obesity that has emerged over the past three decades.
Our hypothesis is that adaptation in the reward circuit
and also in the motivational, memory and control
circuits that occur with repeated exposure to large
quantities of highly palatable food is similar to that
which one observes with repeated drug exposures
(table 2). We also postulate that differences between
Phil. Trans. R. Soc. B (2008) 363, 3191–3200
doi:10.1098/rstb.2008.0107
Published online 24 July 2008
One contribution of 17 to a Discussion Meeting Issue ‘The
neurobiology of addiction: new vistas’.
*Author and address for correspondence: National Institute on
Drug Abuse, Bethesda, MD 20892, USA (nvolkow@nida.nih.gov).
3191 This journal is q2008 The Royal Society

individuals in the function of these circuits prior to
compulsive eating or drug abuse are likely to contribute
to the differences in vulnerability to food or drugs as the
preferred reinforcer. These include differences in
sensitivity to rewarding properties of food versus that
to drugs; differences in their ability to exert inhibitory
control over their intention to eat appealing food in the
face of its negative consequences (gain weight) or to
take an illicit drug (illegal act); and differences in the
propensity to develop conditioned responses when
exposed to food versus drugs.
2. REWARD/SALIENCY CIRCUITRY
IN ADDICTION AND OBESITY
Since DA underlies the rewarding properties of food
and many drugs, we postulate that differences in the
reactivity of the DA system to food or to drugs could
modulate the likelihood of their consumption. To test
this hypothesis, we have used positron emission
tomography (PET) and a multiple tracer approach to
assess the DA system in the human brain in healthy
controls as well as in subjects that are addicted to drugs
and in those that are morbidly obese. Of the synaptic
markers of DA neurotransmission, the availability of
DA D
2
receptors in striatum is recognized to modulate
the reinforcing responses to both drugs and food.
(a)Drug responses and vulnerability for drug
abuse/addiction
In healthy non-drug abusing controls, we showed that
D
2
receptor availability in the striatum modulated their
subjective responses to the stimulant drug methylphe-
nidate (MP). Subjects describing the experience as
pleasant had significantly lower levels of receptors
compared with those describing MP as unpleasant
( Volkow et al.1999a,2002a). This suggests that the
relationship between DA levels and reinforcing
responses follows an inverted U-shaped curve: too little
is not optimal for reinforcement but too much is
aversive. Thus, high D
2
receptor levels could protect
against drug self-administration. Support for this is
given by preclinical studies showing that upregulation of
D
2
receptors in nucleus accumbens (NAc; region in
striatum implicated in drug and food reward) dramati-
cally reduced alcohol intake in animals previously
trained to self-administer alcohol (Thanos et al.2001),
and by clinical studies showing that subjects who
despite having family histories of addiction were not
addicted had higher D
2
receptors in striatum than
individuals without such family histories (Mintun et al.
2003;Vo l k o w et al.2006a).
Using PETand the D
2
receptor radioligands, we and
other researchers have shown that subjects with a wide
variety of drug addictions (cocaine, heroin, alcohol and
Table 1. Comparison of food and drugs as reinforcers. (Modified from Volkow & Wise 2005.)
food drug
potency as a reinforcer
a
CC oral, CC snorted, CCC smoked, injected CCCC
delivery oral oral, snorted, smoked, injected
mechanisms reward somatosensory (palatability)
chemical (glucose)
chemical (drug)
relevance of kinetics not investigated the faster the stimulation the more powerful
its reinforcing effects
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 CCC CCC
a
Potency as reinforcer is estimated on the basis of the magnitude and the duration of the increases in DA induced by either food or drugs in
the NAc, and is an approximate comparison since the potency will be a function of the particular foodstuff as well as the particular drug and its
route of administration.
Table 2. Disrupted brain functions implicated in the behavioural phenotype of addiction and obesity and the brain regions
believed to underlie their disruption. (Modified from Volkow & O’Brien 2007.)
disrupted functions implicated brain region
impaired inhibitory control prefrontal cortex
to drug intake in addiction anterior cingulate gyrus
to food intake in obesity lateral orbitofrontal cortex
enhanced reward nucleus accumbens
to drugs in addiction ventral pallidum
to food in obesity hypothalamus
conditioning/habits amygdala
to drugs and drug cues in addiction hippocampus
to food and food cues in obesity dorsal striatum
Enhanced motivation/drive medial orbitofrontal cortex
to consume drugs in addiction mesencephalic dopamine nuclei
to consume food in obesity dorsal striatum
emotional reactivity amygdala
ventral cingulate gyrus
3192 N. D. Volkow et al. Neurocircuitry in addiction and obesity
Phil. Trans. R. Soc. B (2008)

methamphetamine) have significant reductions in D
2
receptor availability in striatum that persist months after
protracted detoxification (reviewed by Volkow et al.
2004). In addition, drug abusers (cocaine and alcohol)
also show decreased DA release, which is likely to reflect
reduced DA cell firing (Vo l k o w et al. 1997;Martinez
et al. 2005). DA release was measured using PET and
[
11
C]raclopride, which is a D
2
receptor radioligand that
competes with endogenous DA for binding to D
2
receptors and thus can be used to assess the changes
in DA induced by drugs. The striatal increases in DA
(seen as reductions in the specific binding of
[
11
C]raclopride) induced by the intravenous adminis-
tration of stimulant drugs (MP or amphetamine) in
cocaine abusers and alcoholics were markedly blunted
when compared with controls (more than 50% lower;
Vo l k ow et al. 1997,2007a; Martinez et al.2005,2007).
Since DA increases induced by MP are dependent on
DA release, a function of DA cell firing, we speculated
this difference probably reflected decreased DA cell
activity in the cocaine abusers and alcoholics.
These studies suggest two abnormalities in addicted
subjects that would result in decreased output of DA
reward circuits: decreases in DA D
2
receptors, and
DA release in striatum (including NAc). Each would
contribute to the decreased sensitivity in addicted
subjects to natural reinforcers. Indeed, drug-addicted
individuals appear to suffer from an overall reduction in
the sensitivity of their reward circuits to natural
reinforcers. For example, a functional magnetic reso-
nance imaging study showed reduced brain activation in
response to sexual cues in cocaine-addicted individuals
(Garavan et al. 2000). Similarly, a PET study found
evidence suggesting that the brains of smokers react in a
different way to monetary and non-monetary rewards
when compared with non-smokers (Martin-Solch et al.
2001). Since drugs are much more potent at stimulating
DA-regulated reward circuits than natural reinforcers,
they would still be able to activate these downregulated
reward circuits. Decreased sensitivity of reward circuits
would result in a decreased interest for environmental
stimuli, possibly predisposing subjects to seek drug
stimulation as a means to temporarily activate these
reward circuits.
(b)Eating behavioural patterns and
vulnerability for obesity
In healthy normal weight subjects, D
2
receptor
availability in the striatum modulated eating beha-
vioural patterns ( Volkow et al. 2003a). Specifically, the
tendency to eat when exposed to negative emotions was
negatively correlated with D
2
receptor availability (the
lower the D
2
receptors, the higher the likelihood that
the subject would eat if emotionally stressed).
In morbidly obese subjects (body mass index
(BMI)O40), we showed lower than normal D
2
receptor availability and these reductions were pro-
portional to their BMI ( Wang et al. 2001). That is,
subjects with the lower D
2
receptors had higher BMI.
Similar results of decreased D
2
receptors in obese
subjects were recently replicated (Haltia et al. 2007).
These findings led us to postulate that low D
2
receptor
availability could put an individual at risk for over-
eating. In fact, this is consistent with findings showing
that blocking D
2
receptors (antipsychotic medications)
increases food intake and raises the risk for obesity
(Allison et al. 1999). However, the mechanisms by
which low D
2
receptor availability would increase the
risk of overeating (or how they increase the risk for drug
abuse) are poorly understood.
3. INHIBITORY CONTROL/EMOTIONAL
REACTIVITY CIRCUIT IN ADDICTION
AND OBESITY
(a)Drug abuse and addiction
Drug availability markedly increases the likelihood of
experimentation and abuse ( Volkow & Wise 2005).
Thus, the ability to inhibit prepotent responses that are
likely to occur in an environment with easy access to
drugs is likely to contribute to the ability of the
individual to restrain from taking drugs. Similarly,
adverse environmental stressors (i.e. social stressors)
also facilitate drug experimentation and abuse. Since
not all subjects react the same to stress, differences in
emotional reactivity have also been implicated as a
factor that modulates the vulnerability for drug abuse
(Piazza et al. 1991).
In studies on drug abusers and those on subjects at
risk for addiction, we have assessed the relationships
between the availability of D
2
receptors and regional
brain glucose metabolism (marker of brain function) to
evaluate the brain regions that have reduced activity
when D
2
receptors are decreased. We have shown that
the reductions in striatal D
2
receptors in the detoxified
drug-addicted subjects were associated with decreased
metabolic activity in orbitofrontal cortex (OFC),
anterior cingulate gyrus (CG) and dorsolateral pre-
frontal cortex (DLPFC; figure 1; Volkow et al.1993,
2001,2007a). Since OFC, CG and DLPFC are
involved with inhibitory control (Goldstein & Volkow
2002) and with emotional processing (Phan et al.2002),
we had postulated that their improper regulation by DA
in addicted subjects could underlie their loss of control
over drug intake and their poor emotional self-
regulation. Indeed, in alcoholics, reductions in D
2
receptor availability in ventral striatum are associated
with craving severity and greater cue-induced acti-
vation of the medial prefrontal cortex and CG ( Heinz
et al. 2004). In addition, because damage to the OFC
results in perseverative behaviours (Rolls 2000)andin
humans impairments in OFC and CG are associated
with obsessive compulsive behaviours (Insel 1992), we
also postulated that DA impairment of these regions
could underlie the compulsive drug intake that
characterizes addiction (Volkow et al.2005).
However, the association could also be interpreted
to indicate that impaired activity in prefrontal regions
could put individuals at risk for drug abuse and then
the repeated drug use could result in the down-
regulation of D
2
receptors. Indeed, support for the
latter possibility is provided by our studies, in subjects
who despite having a high risk for alcoholism (owing
to a dense family history of alcoholism) were not
alcoholics: in these, we showed higher D
2
receptors in
striatum than in individuals without such family
histories ( Volkow et al. 2006a). In these subjects, the
higher the D
2
receptors, the higher the metabolism in
Neurocircuitry in addiction and obesity N. D. Volkow et al. 3193
Phil. Trans. R. Soc. B (2008)

OFC, CG and DLPFC. In addition, OFC metabolism
was also positively correlated with personality measures
of positive emotionality. Thus, we postulate that high
levels of D
2
receptors could protect against addiction
by modulating prefrontal regions involved in inhibitory
control and emotional regulation.
(b)Food intake and obesity
Since food availability and variety increase the
likelihood of eating ( Wardle 2007), the easy access to
appealing food requires the frequent need to inhibit the
desire to eat it (Berthoud 2007). The extent to which
individuals differ in their ability to inhibit these
responses and control how much they eat is likely to
modulate their risk for overeating in our current food-
rich environments (Berthoud 2007).
As described above, we had previously documented a
reduction in D
2
receptors in morbidly obese subjects.
This led us to postulate that low D
2
receptors could put
an individual at risk for overeating. The mechanisms by
which low D
2
receptors could increase the risk of
overeating is unclear but we postulated that, just as for
the case with drug abuse/addiction, this could be
mediated by D
2
receptor-mediated regulation of pre-
frontal regions.
To assess whether the reductions in D
2
receptors in
morbidly obese subjects were associated with activity
in prefrontal regions (CG, DLPFC and OFC), we
assessed the relationship between D
2
receptor avail-
ability in striatum and brain glucose metabolism. Both
SPM analysis (to assess correlations on a pixel-by-pixel
basis with no pre-selection of regions) as well as
independently drawn regions of interest revealed that
D
2
receptor availability was associated with metabolism
in dorsolateral prefrontal cortex (Brodmann areas (BA)
9 and 10), medial OFC (BA 11) and CG (BA 32 and
25; figure 2). The association with prefrontal metab-
olism suggests that decreases in D
2
receptors in obese
subjects contribute to overeating in part through
deregulation of prefrontal regions implicated in inhibi-
tory control and emotional regulation.
4. MOTIVATION/DRIVE IN DRUG
ABUSE/ADDICTION AND OBESITY
(a)Drug abuse and addiction
In contrast to the decreases in metabolic activity in
prefrontal regions in detoxified cocaine abusers, these
regions are hypermetabolic in active cocaine abusers
(Volkow et al. 1991). Thus, we postulate that during
cocaine intoxication or as the intoxication subsides, the
drug-induced DA increases in striatum activate OFC
and CG, which result in craving and compulsive drug
intake. Indeed, we have shown that intravenous MP
increased metabolism in OFC only in the cocaine
abusers in whom it induced intense craving ( Volkow
et al. 1999b). Activation of the OFC and the CG in
drug abusers has also been reported to occur during
craving elicited by viewing a cocaine-cue video (Grant
et al. 1996) and by recalling previous drug experiences
(Wang et al. 1999).
(b)Obesity
Imaging studies in obese subjects have documented
increased activation of prefrontal regions upon exposure
to a meal, which is greater in obese than lean subjects
(Gautier et al. 2000). When food-related stimuli are
given to obese subjects (as when drug-related stimuli are
given to addicts; Volkow & Fowler 2000), medial
striatum
CG
PreF
OFC
30
35
40
45
50
55
60
65
1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4
DA D2 receptors (ratio index)
r = 0.7, p < 0.001
30
40
50
60
70
80
90
2.9 3.0 3.1 3.2 3.3 3.4 3.5 3.6
DA D2 receptors (Bmax/Kd)
r = 0.7, p < 0.005
(a)(c)
(b)
OFC
mol (100 g) –1 min–1
OFC
mol (100 g) –1 min–1
(i)
(ii)
(i) (ii)
Figure 1. (a) Images of DA D
2
receptors (measured with [
11
C]raclopride in striatum) in (i) a control and (ii) a cocaine abuser.
(b) Diagram showing where glucose metabolism was associated with DA D
2
receptors in cocaine abusers, which included the
orbitofrontal cortex (OFC), the cingulate gyrus (CG) and the dorsolateral prefrontal cortex (PreF). (c) Regression
slopes between D
2
receptor availability and brain glucose metabolism in OFC in a group of detoxified (i) cocaine and
(ii) methamphetamine abusers. Modified from Volkow et al. (2007b).
3194 N. D. Volkow et al. Neurocircuitry in addiction and obesity
Phil. Trans. R. Soc. B (2008)

prefrontal cortex is activated and cravings are reported
(Gautier et al. 2000;Wan g et al. 2004;Miller et al.
2007). Several areas of the prefrontal cortex (including
OFC and CG) have been implicated in motivation to
feed (Rolls 2004). 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- or food-oriented
behaviour, depending on the sensitivity to the reward
and/or established habits of the subject.
5. MEMORY, CONDITIONING AND HABITS
TO DRUGS AND FOOD
(a)Drug abuse and addiction
Circuits underlying memory and learning, including
conditioned incentive learning, habit learning and
declarative memory (reviewed by Vanderschuren &
Everitt 2005), have been proposed to be involved in
drug addiction. The effects of drugs on memory
systems suggest ways that neutral stimuli can acquire
reinforcing properties and motivational salience, i.e.
through conditioned incentive learning. In research on
relapse, it is important to understand why drug-
addicted subjects experience an intense desire for the
drug when exposed to places where they have taken
the drug, to people with whom prior drug use occurred
and to paraphernalia used to administer the drug. This
is clinically relevant since exposure to conditioned cues
(stimuli associated with the drug) is a key contributor
to relapse. Since DA is involved with the prediction of
reward (reviewed by Schultz 2002), we hypothesized
that DA might underlie conditioned responses that
trigger craving. Studies in laboratory animals support
this hypothesis: when neutral stimuli are paired with a
drug they will, with repeated associations, acquire the
ability to increase DA in NAc and dorsal striatum
(becoming conditioned cues). Furthermore, these
neurochemical responses are associated with drug-
seeking behaviour (reviewed by Va n d e rs chure n &
Everitt 2005).
In humans, PET studies with [
11
C]raclopride
recently confirmed this hypothesis by showing that in
cocaine abusers drug cues (cocaine-cue video of scenes
of subjects taking cocaine) significantly increased DA
in dorsal striatum and these increases were associated
with cocaine craving (figure 3;Volkow et al. 2006b;
Wo n g et al. 2006). Because the dorsal striatum is
implicated in habit learning, this association is likely to
reflect the strengthening of habits as chronicity of
addiction progresses. This suggests that a basic neuro-
biological disruption in addiction might be DA-trig-
geredconditionedresponsesthatresultinhabits
leading to compulsive drug consumption. It is likely
that these conditioned responses involve adaptations in
cortico-striatal glutamatergic pathways that regulate
DA release (reviewed Kalivas et al. 2005). Thus, while
drugs (as well as food) may initially lead to DA release
in ventral striatum (signalling reward), with repeated
administration and as habits develop there appears
to be a shift in the DA increases occurring into the
dorsal striatum.
(b)Food and obesity
DA regulates food consumption not only through
modulation of its rewarding properties ( Martel &
Fantino 1996) but also by facilitating conditioning to
food stimuli that then drive the motivation to consume
the food (Kiyatkin & Gratton 1994;Mark et al. 1994).
One of the first descriptions of a conditioned response
was by Pavlov who showed that when dogs were
3.0 3.5 4.0 4.5 5.0
40
45
50
55
60
65
70
40
45
50
55
60
65
70
2
0
ml gm–1
6
5
4
3
2
1
0
mol (100 g)–1 min –1
(a)(c)
(b)
(i)
(i)
(ii)
(ii)
Figure 2. (a) Averaged images for DA D
2
receptors (measured with [
11
C]raclopride) in a group of (i) controls (nZ10) and
(ii) morbidly obese subjects (nZ10). (b) Results from SPM identifying the areas in the brain where D
2
receptors availability was
associated with brain glucose metabolism; these included the OFC, the CG and the DLPFC (region not shown in sagittal
plane). (c) Regression slopes between D
2
receptor availability (measured in striatum) and brain glucose metabolism in (i) CG
and (ii) OFC in obese subjects. Modified from Wang et al. (2001) and Volkow et al. (in press).
Neurocircuitry in addiction and obesity N. D. Volkow et al. 3195
Phil. Trans. R. Soc. B (2008)

exposed to repeated pairing of a tone with a piece of
meat the tone by itself would elicit salivation in these
animals. Since then, voltammetry studies have shown
that the presentation of a neutral stimulus that has been
conditioned to food results in increases in striatal DA
and that the DA increases are linked to the motoric
behaviour required to procure the food (lever pressing;
Roitman et al. 2004).
We have used PET to evaluate these conditioned
responses in healthy controls. We hypothesize that food
cues would increase extracellular DA in striatum and
that these increases would predict the desire for food.
Food-deprived subjects were studied while stimulated
with a neutral or food-related stimulus (conditioned
cues). To amplify the DA changes, we pretreated the
subjects with MP (20 mg orally), a stimulant drug that
blocks DA transporters (the main mechanism for the
removal of extracellular DA; Giros et al. 1996). Food
stimulation significantly increased DA in striatum and
these increases correlated with the increases in self-
reports of hunger and desire for food ( Volkow et al.
2002b;figure 4). Similar findings were reported when
food cues were presented to healthy controls without
pretreatment with MP. These findings corroborate the
involvement of striatal DA signalling in conditioned
responses to food and the participation of this pathway
in food motivation in humans. Since these responses
were obtained when subjects did not consume the food,
this identifies these responses as distinct from the role
of DA in regulating reward through NAc.
We are currently evaluating these conditioned
responses in obese subjects in whom we hypothesize
an accentuated increase in DA when exposed to cues
compared with those of normal weight individuals.
6. A SYSTEMS MODEL OF ABUSE/ADDICTION
AND OF OBESITY
As summarized previously, several common brain
circuits have been identified by imaging studies as
being relevant in the neurobiology of drug abuse/
addiction and obesity. Here, we highlight four of
these circuits: (i) reward/saliency, (ii) motivation/drive,
(iii) learning/conditioning, and (iv) inhibitory control/
emotional regulation/executive function. Note that the
two other circuits (emotion/mood regulation and inter-
oception) also participate in modulating the propensity
to eat or take drugs but for simplicity are notincorporated
into the model. We propose that a consequence of the
disruption of these four circuits is an enhanced value of
one type of reinforcer (drugs for the drug abuser and
high-density food for the obese individual) at the expense
of other reinforcers, which is a consequence of con-
ditioned learning and resetting of reward thresholds
secondary to repeated stimulation by drugs (drug
abuser/addict) and by large quantities of high-density
food (obese individual) in vulnerable individuals.
A consequence of the impairment in the reward/
saliency circuit (processes mediated in part through
NAc, ventral pallidum, medial OFC and hypothalamus),
percentage of change
Bmax/Kd
–0.5
0
0.5
1.0
1.5
2.0
2.5
–40–30–20–10
0102030
change in craving
2.00
2.50
3.00
3.50
Bmax/Kd
caudate putamen
(a)
(c)
(b)
control
video
cocaine-cue
video
Figure 3. (a) Averaged images of DA D
2
receptors (measured with [
11
C]raclopride) in a group of cocaine-addicted subjects
(nZ16) tested while viewing a neutral video and while viewing a cocaine-cue video. (b) Histogram showing the measures of DA
D
2
receptor availability (B
max
/K
d
) in caudate and putamen when viewing the neutral (blue bars) and cocaine-cue (red bars)
videos. (c) Regression slopes between DA changes (assessed as changes in B
max
/K
d
) induced by the cocaine video and the self-
reports of craving. Modified from Volkow et al. (2006b).
3196 N. D. Volkow et al. Neurocircuitry in addiction and obesity
Phil. Trans. R. Soc. B (2008)

which modulates our response to both positive and
negative reinforcers, is a decreased value to stimuli that
otherwise would motivate behaviours likely to result in
beneficial outcomes while avoiding behaviours that
could result in punishment. For the case of drug
abuse/addiction, one can predict that as a result of
dysfunction in this neurocircuit the person would be less
likely to be motivated to abstain from drug use because
alternative reinforcers (natural stimuli) are much less
exciting and negative consequences (e.g. incarceration,
divorce) are less salient. For the case of obesity, one can
predict that as a result of dysfunction in this neurocircuit
the person would be less likely to be motivated to abstain
from eating because alternative reinforcers (physical
activity and social interactions) are less exciting and
negative consequences (e.g. gaining weight, diabetes) are
less salient.
A consequence of disruption of the inhibitory
control/emotional regulation circuit is the impairment
of the individual to exert inhibitory control and
emotional regulation (processes mediated in part
through the DLPFC, CG and lateral OFC), which
are critical components of the substrates necessary to
inhibit prepotent responses such as the intense desire
to take the drug in an addicted subject or to eat
high-density food in an obese individual. As a result,
the person is less likely to succeed in inhibiting the
intentional actions and to regulate the emotional
reactions associated with the strong desires (either to
take the drug or to eat the food).
The consequences of the involvement of memory/
conditioning/habits circuit (mediated in part through
hippocampus, amygdala and dorsal striatum) are that
repeated use of drugs (drug abuser/addict) or repeated
consumption of large quantities of high-density food
(obese individual) results in the formation of new
linked memories (processes mediated in part through
hippocampus and amygdala), which condition the
individual to expect pleasurable responses, not only
when exposed to the drug (drug abuser/addict) or to
the food (obese individual) but also from exposure to
stimuli conditioned to the drug (i.e. smell of cigarettes)
or conditioned to the food (i.e. watching TV ). These
stimuli trigger automatic responses that frequently
drive relapse in the drug abuser/addict and food
bingeing, even in those who are motivated to stop
taking drugs or to lose weight.
The motivation/drive and action circuit (mediated in
part through OFC, dorsal striatum and supplementary
motor cortices) is involved both in executing the act
Bmax/Kd
2.5
3.0
3.5
4.0
neutral food
p < 0.005
–2
0
2
4
6
8
10
0 5 10 15 20 25 30
desire for food
percentage of change Bmax/Kd
neutral food cues
family
genealogy
(a)
(b)
(c)
Figure 4. (a) Averaged images of DA D
2
receptors (measured with [
11
C]raclopride) in a group of controls (nZ10) tested while
reporting on their family genealogy (neutral stimuli) or while being exposed to food. (b) Histogram showing the measures of DA
D
2
receptor availability (B
max
/K
d
) in striatum (average caudate and putamen) when viewing the neutral and cocaine-cue videos.
(c) Regression slopes between DA changes (assessed as changes in B
max
/K
d
) induced by the food stimuli and the self-reports of
desire for the food.
a
To enhance the DA signal, subjects were pretreated with oral MP to block DA transporters and so amplify
the DA signal. Modified from Volkow et al. (2002b).
Neurocircuitry in addiction and obesity N. D. Volkow et al. 3197
Phil. Trans. R. Soc. B (2008)

and in inhibiting it and its actions are dependent on the
information from the reward/saliency, memory/condi-
tioning and inhibitory control/emotional reactivity
circuits. When the value of a reward is enhanced
owing to its previous conditioning, it has greater
incentive motivation and if this occurs in parallel to a
disruption of the inhibitory control circuit this could
trigger the behaviour in a reflexive fashion (no cognitive
control; figure 5). This could explain why drug-
addicted subjects report taking drugs even when they
were not aware of doing so and why obese individuals
have such a difficult time in controlling their food
intake and why some individuals claim that they take
the drug or the food compulsively even when it is not
perceived per se as pleasurable.
In this model, during exposure to the reinforcer or to
the cues conditioned to the reinforcer, the expected
reward (processed by memory circuit) results in
overactivation of the reward and motivation circuits
while decreasing the activity in the cognitive control
circuit. This contributes to an inability to inhibit the
drive to seek and consume the drug (drug abuser/
addict) or the food (obese person) despite the attempt
to do so (figure 5). Because these neuronal circuits,
which are modulated by DA, interact with one another,
disruption on one circuit can be buffered by the activity
of another, which would explain why an individual may
be better able to exert control over their behaviour to
take drugs or food on some occasions but not on others.
7. CLINICAL SIGNIFICANCE
This model has therapeutic implications for it suggests
a multi-prong approach that targets strategies to:
decrease the rewarding properties of the problem
reinforcer (drug or food); enhance the rewarding
properties of alternative reinforcers (i.e. social interac-
tions, physical activity); interfere with conditioned-
learned associations (i.e. promoting new habits to
substitute for old ones); and strengthen inhibitory
control (i.e. biofeedback), in the treatment of drug
abuse/addiction and obesity Volkow et al. (2003b).
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NOT
GO
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