stimuli in human subjects addicted to cocaine and whether this is associated with drug craving. We tested eighteen cocaine-addicted
subjects using positron emission tomography and [11C]raclopride (dopamine D2receptor radioligand sensitive to competition with
habit learning and in action initiation) is involved with craving and is a fundamental component of addiction. Because craving is a key
contributor to relapse, strategies aimed at inhibiting dopamine increases from conditioned responses are likely to be therapeutically
Drugs of abuse increase dopamine (DA) in the nucleus accum-
bens (NAc), which is an effect that is believed to underlie their
reinforcing effects (Di Chiara and Imperato, 1988; Koob and
Bloom, 1988). However, this acute effect does not explain the
intense desire for the drug and the compulsive use that occurs
when addicted subjects are exposed to drug cues such as places
use occurred, and paraphernalia used to administer the drug.
Cue-elicited craving is critical in the cycle of relapse in addiction
(O’Brien et al., 1998). However, after more than a decade of
imaging studies in cue-elicited craving, its underlying brain neu-
is a neurotransmitter involved with reward and with prediction
of reward (Wise and Rompre, 1989; Schultz et al., 1997), DA
release by drug cues is a strong candidate substrate for cue-
elicited craving. Studies in laboratory animals support this hy-
pothesis: when neutral stimuli are paired with a rewarding drug
they will, with repeated associations, acquire the ability to in-
crease DA in NAc and in dorsal striatum (becoming conditioned
cues), and these neurochemical responses are associated with
drug-seeking behavior in rodents (Di Ciano and Everitt, 2004;
Kiyatkin and Stein, 1996; Phillips et al., 2003; Vanderschuren et
al., 2005; Weiss et al., 2000). The extent to which conditioned
stimuli can lead to DA increases in the brain and correlated in-
creases in subjective experiences of drug craving have not been
into the experience of human drug-addicted subjects when ex-
posed to drug cues.
Here we investigate the hypothesis that increases in DA un-
to drug-related cues. We hypothesized that cocaine cues would
increase extracellular DA in striatum in proportion to the in-
creases in cocaine craving and that subjects with more severe
addiction would have larger DA increases in response to condi-
hypothesis, we studied 18 cocaine-addicted subjects with
Institute on Drug Abuse Grant DA06278-15. We thank David Schlyer, David Alexoff, Paul Vaska, Colleen Shea,
Correspondence should be addressed to Dr. Nora D Volkow, National Institute on Drug Abuse, 6001 Executive
TheJournalofNeuroscience,June14,2006 • 26(24):6583–6588 • 6583
(Volkow et al., 1994). Subjects were tested on 2 separate days
under two counterbalanced conditions: during presentation of a
neutral video (natural scenery) and during presentation of a
smoking of crack cocaine) (Childress et al., 1999). [11C]raclo-
pride binding is highly reproducible (Volkow et al., 1993), and it
has been shown that differences in specific binding between two
conditions predominantly reflect drug-induced or behavioral-
induced changes in extracellular DA (Breier et al., 1997).
Subjects. Eighteen active cocaine-addicted subjects who responded to an
advertisement were studied. Subjects fulfilled DSM-IV (Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition) criteria for co-
(free-base or crack, at least “four grams” a week). Exclusion criteria in-
cluded current or past psychiatric disease other than cocaine depen-
dence; past or present history of neurological, cardiovascular, or endo-
crinological disease; history of head trauma with loss of consciousness
?30 min; and current medical illness and drug dependence other than
tion on the subjects. Written informed consent was obtained in all
Behavioral scales. To assess cocaine craving, we used a brief version of
the Cocaine Craving Questionnaire (CCQ) (Tiffany et al., 1993), which
evaluates current cocaine craving (desire to use, intention and planning
to use, anticipation of positive outcome, anticipation of relief from with-
drawal or distressing symptoms, and lack of control over drug use) on a
seven-point visual analog scale. The average score was used as measure of
To assess severity of cocaine addiction we used the Addiction Severity
Index (ASI) (McLellan et al., 1992) and the Cocaine Selective Severity
Assessment Scale (CSSA) (Kampman et al., 1998). The ASI evaluates
severity across seven domains (drug, alcohol, psychiatric, family, legal,
average interviewer’s rating on these seven domains was used as a mea-
sure of addiction severity. The CSSA measures 18 symptoms of early
cocaine abstinence that are rated on an analog scale from 0 to 7. The
CSSA was obtained before each scan.
PET scan. We used a high resolution ? tomograph (resolution 4.5 ?
4.5 ? 4.5 mm full-width half-maximum, 63 slices) with [11C]raclopride
using methods described previously (Volkow et al., 1993). Briefly, emis-
sion scans were started immediately after injection of 4–8 mCi (specific
activity 0.5–1.5 Ci/?M at end of bombardment). Twenty dynamic emis-
sion scans were obtained from time of injection up to 54 min. Arterial
sampling was used to quantify total carbon-11 and unchanged [11C]ra-
clopride in plasma. Subjects were scanned on 2 different days with
[11C]raclopride under randomly ordered conditions (1) while watching
a video of nature scenes (neutral condition) and (2) while watching a
video that portrayed subjects smoking cocaine
(cocaine-cue condition). Videos were started
10 min before injection of [11C]raclopride and
were continued for 30 min after radiotracer in-
jection. The neutral video featured nonrepeat-
cue video featured nonrepeating segments
portraying scenes that simulated purchase,
preparation, and smoking of cocaine.
Image analysis. For region identification, we
summed the time frames from images taken
from 10–54 min and resliced them along the
intercommisural plane. Planes were added in
groups of two to obtain 12 planes encompass-
the cerebellum, which were measured on four,
three, one, and two planes, respectively. Right
and left regions were averaged. These regions were projected to the dy-
namic scans to obtain concentrations of C-11 versus time. These time–
activity curves for tissue concentration, along with the time–activity
constant of [11C]raclopride from plasma to brain (K1) and the distribu-
tion volumes (DVs), which corresponds to the equilibrium measure-
ment of the ratio of tissue concentration to plasma concentration, in
ible systems (Logan et al., 1990). The ratio of DV in striatum to that in
cerebellum corresponds to [receptor concentration (Bmax)/affinity
(Kd)] ? 1 and is insensitive to changes in cerebral blood flow (Logan et
al., 1994). The effect of the cocaine-cue video on DA was quantified as
percentage change in Bmax/Kd with respect to the neutral video.
To corroborate the location within the striatum, in which the DA
changes occurred we also analyzed the DV images using statistical para-
metric mapping (SPM) (Friston et al., 1995). Paired t tests were per-
uncorrected, threshold ?100 voxels).
Statistical analysis. Differences between conditions on the behavioral
and the PET measures were evaluated with paired t tests (two-tailed).
Product moment correlations were used to assess the correlation be-
tween the DA changes and the behavioral measures (CCQ, ASI, and
Because there were no differences between left and right regions,
we report the results for the average scores in the left and right
striatal and cerebellar regions. The K1measure did not differ
between conditions for any of the brain regions (Table 2). This
indicates that the tracer delivery was not affected by the cocaine-
The DV was significantly lower in the cocaine cue than in the
in cerebellum (Table 2). SPM analysis corroborated the signifi-
cant DV reduction in dorsal (caudate and putamen) but not in
ventral striatum (Fig. 1).
6584 • J.Neurosci.,June14,2006 • 26(24):6583–6588Volkowetal.•TheRoleofDopamineinCocaineCraving
The Bmax/Kd measures, which reflect D2receptors that are
not occupied by endogenous DA, were significantly lower in the
0.05) and in putamen (t ? 2.2; p ? 0.05) but did not differ in
cocaine cues induced DA release in the dorsal striatum.
The cocaine-cue video significantly increased the craving scores
neutral video did not; scores before the video were 2.8 ? 1.6 and
after the video were 3.0 ? 1.7 (t ? 1.1; p ? 0.30) (Fig. 2B). The
correlations between the changes in craving and the DA changes
did not differ for left and right regions and thus we report on the
correlations for the average measures. These correlations were
significant in putamen (r ? 0.69; p ? 0.002) and in caudate (r ?
0.54; p ? 0.03) but not in ventral striatum (r ? 0.36; p ? 0.14)
Correlation analysis between the DA changes and the clinical
DA changes in caudate (r ? 0.55; p ? 0.01) and a trend in puta-
men (r ? 0.40; p ? 0.10). Similarly, the scores on the ASI were
significantly correlated with DA changes in right putamen (r ?
and a trend in left caudate (r ? 0.41; p ? 0.09). The greater the
severity on the CSSA and the ASI the larger the DA changes.
The correlation between the measures of D2receptor avail-
ability obtained during the neutral video and the clinical scales
(CCQ, CSSA, and ASI) were not significant.
Here we show increases in DA in the dorsal striatum in cocaine-
addicted subjects watching a video that showed cocaine cues.
These results are in agreement with microdialysis studies docu-
menting increases in extracellular DA in the dorsal striatum in
rodents responding to cocaine cues (Ito et al., 2002). However,
the microdialysis studies reported DA increases in dorsal stria-
Volkowetal.•TheRoleofDopamineinCocaineCravingJ.Neurosci.,June14,2006 • 26(24):6583–6588 • 6585
et al., 2002), whereas noncontingent presentation increased DA
instead in the NAc (Neisewander et al., 1996). In our study, the
cocaine cues were noncontingent because the subjects were not
cues elicited significant DA increases in dorsal striatum and not
in ventral striatum (in which NAc is located). This is likely to
reflect differences between preclinical and clinical paradigms;
specifically, rodents are trained that responding to the cues pre-
dicts drug delivery, whereas for the cocaine-addicted subjects,
exposure to scenes with “cocaine cues” does not predict drug
delivery but instead primes them to engage in the behaviors re-
quired to procure the drug. That is, the delivery of cocaine will
not occur automatically but, as would be the case for contingent
DA activation of the dorsal striatum by cocaine cues appears to
occur when behavioral responses are necessary to procure the
less of the behavioral response emitted (Vanderschuren et al.,
selection and initiation of actions (Graybiel et al., 1994).
In this study, we show an association between cocaine craving
and DA increases in dorsal striatum (caudate and putamen). Be-
from the substantia nigra (Haber and Fudge, 1997), this impli-
that activation of the putamen in cocaine abusers was associated
oxygenation level-dependent (BOLD) changes with functional
magnetic resonance imaging (fMRI) [negative association (Bre-
iter et al., 1997) as well as positive association (Risinger et al.,
2005)] or by intravenous methylphenidate administration as as-
association (Volkow et al., 1999)]. Craving triggered by stress in
cocaine abusers was also associated with activation of the dorsal
striatum (including caudate) as assessed with fMRI (Sinha et al.,
2005). Similarly, an fMRI study that compared responses be-
tween a neutral and a cocaine video related the enhanced BOLD
signaling in dorsal striatum during the cocaine video to the crav-
ing induced by the video (Garavan et al., 2000).
The dorsal striatum is involved with the selection and initia-
tion of actions (Graybiel et al., 1994), and recent studies now
implicate it in mediating stimulus-response (habit) learning, in-
cluding that which occurs with chronic drug administration
(White and McDonald, 2002). Thus, the association between
dorsal striatal dopaminergic activity and cue-induced cocaine
craving could reflect the habit-based (automatized) nature of
craving in addiction (Tiffany, 1990). Several preclinical and clin-
with chronic exposure to cocaine (Letchworth et al., 2001; Por-
rino et al., 2004; Volkow et al., 2004). In fact, in laboratory ani-
mals, the dorsal regions of the striatum become progressively
al., 2001; Porrino et al., 2004). Indeed, it is hypothesized that the
dorsal striatum mediates the habitual nature of compulsive drug
prediction of reward) (Wise and Rompre, 1989; Schultz et al.,
a strong “reward predictor” (by its long conditioning history),
but subjects in the study were aware that drug reward (actual
similar to those in studies of healthy subjects shown food cues
the dorsal striatum that were associated with the “desire for the
food.” Although the DA increases were smaller after exposure to
food stimuli than after exposure to cocaine cues, the direction of
the correlation was similar: the greater the DA increases, the
greater the desire (Volkow et al., 2002). It would appear as if DA
activation of dorsal striatum is involved with the “desire” (want-
ing), which would result in the readiness to engage in the behav-
iors necessary to procure the desired object. These parallel find-
ings suggest the intriguing hypothesis that in the human brain,
drug addiction may engage the same neurobiological processes
The cue-elicited DA changes were also associated with estimates
the addiction severity, the larger the DA increases. Because the
dorsal striatum is implicated in habit learning, this association
Because the CSSA is a measure that has been shown to predict
treatment outcomes in cocaine-addicted subjects (Kampman et
al., 2002), this suggests that the reactivity of the DA system to
drug cues may be a biomarker for negative outcomes in cocaine-
addicted subjects. It also suggests that basic neurobiological dis-
ruptions in addiction are the conditioned neurobiological re-
sponses that result in activation of DA pathways that trigger the
6586 • J.Neurosci.,June14,2006 • 26(24):6583–6588 Volkowetal.•TheRoleofDopamineinCocaineCraving
behavioral habits leading to compulsive drug seeking and con-
sumption. It is likely that these conditioned neurobiological re-
sponses reflect corticostriatal and corticomesencephalic gluta-
matergic adaptations (Kalivas and Volkow, 2005).
This study did not find an association between craving and DA
changes in ventral striatum (in which the NAc is located). This
was unexpected because studies in laboratory animals have
shown that the NAc is part of the neural circuitry that mediates
cue-induced relapse to cocaine seeking (Fuchs et al., 2004). This
could imply that the involvement of the NAc in craving is non-
dopaminergic. Indeed, glutamatergic projections into the NAc
have been directly implicated in cue-associated drug-seeking be-
havior, which is an effect that is not blocked by DA antagonists
ton and Wise, 1994; Kiyatkin and Stein, 1996; Duvauchelle et al.,
2000; Ito et al., 2000; Weiss et al., 2000), although not all (Brown
and Fibiger, 1992; Bradberry et al., 2000), have shown DA in-
creases in NAc with presentation of cocaine cues. As discussed,
this could reflect the conditions under which the cues were pre-
sented (contingent vs noncontingent). Also, the stimuli in the
preclinical studies serve a different function from those in the
act as a discriminative stimulus, whereas if they are paired or
associated with cocaine presentation (as the cues were in the
present study), they are conditioned stimuli. However, they
could also reflect differences in species (humans vs rodents), ex-
perimental paradigms (videos showing cues vs physical presence
of cues), and methods for measuring DA (PET vs microdialysis
The limited spatial resolution of the PET methodology con-
relatively poor temporal resolution allowed us to detect DA
changes over a 20–30 min period, limiting our ability to detect
short-lasting DA increases as reported for cocaine cues with vol-
tammetry (Phillips et al., 2003). In addition, the [11C]raclopride
method is best suited to detect DA release in regions of high D2
receptor density such as striatum, but not low receptor density
such as extrastriatal regions, which could explain why we did not
show DA changes in amygdala, in which animals studies have
shown cue-elicited DA increases (Weiss et al., 2000).
Although we show that the variability in the magnitude of the
DA changes induced by the cocaine cue is associated with the
severity of the addiction process, it could also reflect differences
in reactivity of DA cells that may have preceded the abuse of
substances. In this study, 17 of the 18 subjects were males and
thus future studies are needed to examine gender differences.
Because the DA increases in dorsal striatum elicited by drug cues
predicted addiction severity, this provides evidence of a funda-
mental involvement of the nigrostriatal DA pathway in craving
and in cocaine addiction in humans. It also suggests that com-
pounds that could inhibit cue-induced striatal DA increases
would be logical targets for the development of pharmacological
interventions to treat cocaine addiction.
Note added in proof.
as preliminary data by Wong et al. (2003).
Similar findings of increases in dopa-
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