Reviews
Compulsive use of dopamine replacement
therapy in Parkinson’s disease: reward systems
gone awry?
Andrew D Lawrence, Andrew H Evans, and Andrew J Lees
Dopamine replacement therapy (DRT) is the most
effective treatment for Parkinson’s disease (PD); it
provides substantial benefit for most patients, extends
independence, and increases survival. A few patients with
PD, however, take increasing quantities of medication far
beyond those required to treat their motor disabilities.
These patients demand rapid drug escalation and continue
to request more DRT despite the emergence of increasingly
severe drug-induced motor complications and harmful
behavioural consequences. In this article we detail the
features of compulsive DRT-seeking and intake in PD, in
relation to theories of compulsive drug use.
Dorsal
striatum
Substantia
nigra
Accumbens
Hypothalamus
Ventral
tegmental
area
Lancet Neurol 2003; 2: 595–604
Parkinson’s disease (PD) is characterised by the presence of
cytoplasmic proteinaceous aggregates (Lewy bodies and
neurites), together with cell loss in dopaminergic neural
populations.1,2 Different dopamine projection fields are not
equally susceptible to PD.1–5 The most striking cell loss is in
the ventrolateral tier of the substantia nigra pars compacta,4
from which the dorsolateral putamen—the region most
affected in PD3—receives dopaminergic input.5 A variable,
less pronounced loss of neurons also occurs in the dorsal
tier of the nigra (projecting to the caudate), in the
retrorubral region (projecting to the hypothalamus), and in
the ventral tegmental area (projecting to the nucleus
accumbens, amygdala, hippocampus, and motor,
premotor, rhinal, cingulate, and prefrontal cortices;
figure).1,4,5
Striatal dopamine replacement—with the dopamine
precursor levodopa or synthetic dopamine agonists—is the
commonest treatment for the symptoms of PD.6 The precise
mechanisms of action of levodopa are still unknown, but
are probably not simply due to the replenishment of striatal
dopamine.7
Long-term dopamine replacement therapy (DRT) is
commonly associated with a series of motor complications,
which include hyperkinetic adventitious movements and
capricious diurnal fluctuations (the on-off phenomenon).7,8
DRT also induces psychomotor activation (eg, restlessness
and insomnia), aggression, hypomania, hypersexuality,
impulsivity, and vivid dreaming.9,10 These complications are
similar to those seen after excessive use of psychomotor
stimulants, such as amphetamines and cocaine.11
Surprisingly, not many studies have been done on the
addictive potential of DRT, and some authors have argued
that levodopa is not addictive,12 despite several case reports
of apparent “DRT addiction” (table).13–28
THE LANCET Neurology Vol 2 October 2003
Dopaminergic projection fields in the human brain, in which the caudate
and putamen form the striatum.
We have described a few patients with PD (about 4% of
patients attending a specialist tertiary referral clinic) who take
amounts of DRT far beyond those needed to treat their motor
disabilities.28 These patients are insistent on a rapid increase of
DRT and complain of intolerable motor and affective
symptoms, and many of them ignore the warnings given to
them by their physicians (panel 1).
A pattern of compulsive DRT-seeking and intake soon
develops, leading to the intake of very large total daily doses of
levodopa (1–4 g a day; table). Attempts at dose reduction are
met with strong resistance and most are unsuccessful. Patients
ignore advised dose schedules and “self-medicate” by use of
idiosyncratic cues. Their perception of the “on” state is
affected so that they only feel “on” and “mobile” when notably
dyskinetic. Many patients hoard the drug and seek out
alternative providers (eg, internet purchasing, visits to
multiple physicians) if the prescribing physician starts strict
rationing of levodopa. Compulsive DRT use may become
evident only when attempts are made to restrict the supply of
DRT (eg, during periods of hospitalisation) when additional
rescue doses are constantly demanded or when exaggerated
“off” states occur. Patients begin to deny symptoms and the
ADL is at the MRC Cognition and Brain Sciences Unit, Cambridge,
UK. AHE and AJL are at the Reta Lila Weston Institute of
Neurological Studies, Royal Free and University College London
Medical School, London, UK.
Correspondence: Dr Andrew D Lawrence, MRC Cognition and
Brain Sciences Unit, 15 Chaucer Rd, Cambridge CB2 2EF, UK.
Tel +44 (0)1223 355294; fax +44 (0)1223 359062;
email [email protected]
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
595
Review
Dopamine dysregulation syndrome in PD
Case reports of compulsive DRT use in PD
Reference
Patients
Mean age at
onset of PD
(range)
Mean age at
onset of
compulsive DRT
use (range)
Daily DRT
dose (range)
in levodopa
equivalent units
Previous drug
use
Past or family
history of
psychiatric
disorder
Dyskinesias
Quinn et al13
One man
44
47
4 g; D
··
··
Yes
Vogel et al14
One man
46
49
2 g; D, B
··
Unknown (suicide Yes
Priebe et al15
One woman
49
60
5 g; D
No
No
Nausieda et al16
Five men
50 (41–55)
54 (46–50)
1·9 g (1·5–2·5 g); D
··
No
Yes (five)
Tack et al17
One woman
18
25
2·5 g; D
··
Schizophrenia
Yes
··
by mother)
Yes
Uitti et al18
One man
37
64
0·75 g; D
··
No
Soyka et al19
One man
44
··
1·8 g; D
Alcoholism
Alcoholism
Yes
Weinman et al20
One man
53
63
3·5 g ; D
No
No
Yes
Spigset et al21
Two men
55 (51–58)
59 (52–66)
1·7 g (1·5–2 g); D
No (one);
No
Yes (two)
unknown (one)
Courty et al22
Four men
50 (46–57)
59 (50–65)
1·6 g (1·1–1·9 g); A
Alcoholism (one)
Depression (one)
··
Merims et al23
One man
60
78
2·2 g; D
··
No
Yes
Geschwandtner
Two men
51 (43–59)
56 (50–62)
1·6 g (1–2·2 g);
No
Depression (one)
Yes (one)
··
No
Yes (three)
D (two), R (one)
et al24
Serrano-Duenas25
Three men,
56 (49–62)
66 (59–71)
one woman
2·6 g (2·4– 2·9 g);
D (four), B (four)
Muller et al26
One man
27
35
1·4 g; D, R
Nicotine
No
Yes
Houeto et al27
Two men
45
59 (58–61)
1·4 g; D (two);
Alcohol (one);
Bipolar (one)
Yes (two)
DBS (one)
illegal drugs (one)
Giovannoni et al28
Three men,
one woman
39 (36–42)
··
3·3 g (2–5·5 g);
Alcohol (one);
Depression (three); Yes (four)
D (four), A (four)
nicotine (one)
panic (one)
D=levodopa; A=apomorphine; B=bromocriptine; R=ropinirole; P=pergolide; DBS=subthalamic nucleus deep brain stimulation; S=hypersexuality; E=eating; G=gambling; H=buying.
lack of insight to the harm caused to themselves and those
around them grows.28
A review of case reports reveals that compulsive use of
DRT is more common in patients with young-onset PD and in
men (table). Past heavy alcohol consumption or illegal drug
use, in addition to a history of affective disorder may be
predisposing factors in some patients (table). Social isolation
before or after the onset of the disorder may exacerbate the
syndrome. Compulsive DRT use is not limited to levodopa,
and may occur with all forms of DRT—including ergot and
non-ergot derived dopamine agonists (table). However, many
case reports highlight the use of acute “rescue” drugs, such as
dispersible oral formulations of levodopa and subcutaneous
apomorphine. The addition of intermittent apomorphine
injections to the therapeutic regimen can unmask or trigger
overuse of DRT.28 Compulsive use of dopamine agonists
(other than apomorphine) can occur, which is usually,
although not excusively, associated with the compulsive use of
levodopa (table). Although there are no reports of its
compulsive use, treatment with the monoamine oxidase-B
inhibitor selegiline can induce hypomania, compulsive
spending, and transvestic fetishism.29–31 There are also reports
of compulsive use of implanted subthalamic nucleus deepbrain stimulators with constant demands for increases in
stimulation parameters.27 The behavioural disturbances linked
to compulsive DRT use in PD can have devastating social
consequences resulting in divorce, bankruptcy, and prison
sentences (panel 2).
596
Is this syndrome a substance dependence
disorder or an addiction?
It can be difficult to diagnose a DSM-IV “substance
dependence disorder”44 in a patient with a progressive
incurable neurological disease. Development of tolerance is
difficult to detect when a symptomatic treatment relieves
the incapacitating physical symptoms. DRT requirements
increase as motor disability progresses. Pharmacological
tolerance to the motor effects of DRT has been described,
but is not a major management problem.45,46 Patients also
experience adverse effects if withdrawn from DRT.47
Under DSM-IV criteria,44 substance dependence
involves a maladaptive pattern of substance use. The correct
use of DRT in PD is to treat the motor symptoms of the
disease. In a study of 10 patients with PD thought to be
misusing DRT and a group of age-matched patients with
PD from the same clinic who were not thought to be
misusing DRT, we found that a significantly larger
proportion of misusers reported anxiety and depression
when unmedicated.131 Avoiding being unmedicated was the
reason given by most misusers for taking more DRT. In
addition, a significant number of misusers reported that
DRT had a negative impact on their quality of life. A past
history of alcohol use was greater in the misusing group,
and previous illicit drug use was reported in a small number
of patients. The use of DRT appears maladaptive in some
PD patients, and thus they meet DSM-IV criteria for
dependence.
THE LANCET Neurology Vol 2 October 2003
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
Review
Dopamine dysregulation syndrome in PD
(continued)
Reference
Stereotypies Other
or punding behavioural
addictions
Euphoria,
Delusions,
hypomania paranoia
Aggression Social or
Hoarding,
Withdrawal
relationship seeking,
symptoms
breakdown craving DRT
Relapse
after
attempted
dose reduction
Quinn et al13
Yes
S
··
··
Yes
Yes
Yes
No
··
Vogel et al14
··
S
··
Yes
Yes
Yes
··
··
Yes
Priebe et al15
··
··
··
Yes
Nausieda et al16 ··
··
No
Yes
··
··
S (one) H (one) Yes (three)
Yes (two)
Yes (three)
Yes (five)
Yes (four)
Yes (three)
Yes (five)
Tack et al17
··
H
··
Yes
Yes
Yes
Yes
··
Yes
Uitti et al18
··
S
Yes
Yes
··
Yes
··
··
No
Soyka et al19
··
··
Yes
··
··
··
··
Yes
··
Weinman et al20 ··
S
··
··
Yes
Yes
··
··
Yes
Spigset et al21
··
··
Yes (two)
Yes (one)
··
Yes (two)
··
No
Yes (one)
Courty et al22
··
S (four)
··
Yes (two)
Yes (four)
Yes (four)
··
Yes (two)
Yes (two)
Merims et al23
··
··
··
Yes
··
No
Yes
Yes
··
Geschwandtner ··
G
··
··
··
Yes
··
··
No
Yes (two)
G (four)
Yes (two)
Yes (two)
··
Yes (four)
··
Yes (two)
··
Muller et al26
··
E, H
··
Yes
Yes
Yes
Yes
Yes
No
Houeto et al27
··
S (two); G (two) Yes (one)
No
Yes (two)
Yes (two)
Yes (one)
Yes (one)
Yes (one)
Giovannoni
··
S (three)
Yes (three)
··
Yes (three)
··
Yes (one);
··
et al24
SerranoDuenas25
Yes (three)
unknown (three)
et al28
Unless otherwise stated the numbers in parentheses are the number of patients.
The ICD-10 criteria for “addiction”48 differ from
DSM-IV criteria for “dependence”, but present similar
difficulties when applied to PD. Nevertheless, it is clear that
the individuals in the above study 131 would meet ICD-10
criteria: they show difficulties in controlling their
substance-taking behaviour, have a strong compulsion to
take the substance, and continue to use the substance
despite clear evidence of harmful consequences.
The terms dependence and addiction, however, may be
unnecessarily stigmatising and inappropriate given an
inexorably progressive neurodegenerative disorder. The
label: “dopamine dysregulation syndrome” reflects the
disorder’s salient features, and indicates compulsive and
dysregulated drug use beyond that needed to achieve relief
of motor symptoms, resulting in harmful consequences.
Do models of psychostimulant addiction help
to understand compulsive DRT use in PD?
Current theories of addiction incorporate the idea that
drugs activate and, via neuroadaptive processes, change
dopaminergic neurotransmission in the nucleus accumbens
and related circuitry, altering important reward-related
processes (although different theories posit different
processes).49
Does DRT activate brain “reward” pathways?
There are few data on the activation of accumbens-related
reward pathways by DRT. Conditioned place-preference is
THE LANCET Neurology Vol 2 October 2003
used as one index of reward. In the learning phase of this
procedure, animals receive a stimulus in one compartment
of the place-conditioning chamber, and receive a control
stimulus in another. In the test phase, animals do not
receive a stimulus and are free to go to either compartment.
Rewards such as food, sexual stimuli, and psychostimulant
drugs cause conditioned place preferences to occur: animals
spend more time in the compartment previously paired
with reward.50
In rats, levodopa combined with the catechol-Omethyltransferase inhibitor entacapone induces a
conditioned place preference similar to that induced by
psychostimulants such as amphetamine.51 This effect is also
produced by the dopamine agonists apomorphine52,53 and
bromocriptine,54 suggesting they are “rewarding”. Such
conditioned place preference is accompanied by increased
dopamine turnover in the accumbens, and lesions to the
accumbens
disrupt
apomorphine-induced
place
preference52 and self-administration.55 Pramipexole
increases activity in accumbens-related circuitry.56 DRT
seems to share at least some of the properties of potentially
addictive drugs.
Theories of compulsive psychostimulant use
Pleasure models
The oldest explanation for addictions is that they are driven
by feelings of pleasure.57 Contemporary variants of pleasure
theories—such as Wise’s hedonia theory58—assume that
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
597
Review
Dopamine dysregulation syndrome in PD
Panel 1. Current working diagnostic criteria for dopamine
dysregulation syndrome28
Parkinson’s disease with documented levodopa responsiveness
Need for increased doses of DRT in excess of those normally required to
relieve Parkinsonian symptoms and signs
Pattern of pathological use: expressed need for increased DRT in the
presence of excessive and significant dyskinesias despite being “on”,
drug hoarding or drug-seeking behaviour, unwillingness to reduce DRT,
absence of painful dystonias
Impairment of social or occupational functioning: fights, violent
behaviour, loss of friends, absence from work, loss of job, legal
difficulties, arguments, or family difficulties
Development of hypomanic, manic, or cyclothymic affective syndrome in
relation to DRT
Development of a withdrawal state characterised by dysphoria,
depression, irritability, and anxiety with reduction of DRT
Duration of disturbance is of at least 6 months
drugs act as rewards because they induce some kind of
pleasure, and that this is what compulsive drug users seek.
Ethological theories of reward are commonly applied to
comparative studies of drug seeking: any stimulus that
elicits locomotor approach behaviour will serve as a reward
or “positive reinforcer”.59 Wise58 equated the approach
responses induced by rewards—as seen in conditioned
place preference—with the experience of pleasure: “It is the
approach response and the motivational arousal caused by
rewards which I believe to be most clearly associated with
pleasure”.
In patients with PD, acute dosage with levodopa can
lead to small increases in “happiness” and “positive mood”,
which may increase with escalating doses and over time.38,60
Many compulsive DRT users report peak-dose feelings of
euphoria and joy. There is little evidence, however, that
individuals who develop “dopamine dysregulation”
experience greater DRT-induced euphoria than individuals
who do not develop it; or that they possess personality
traits—eg, high sensation or novelty seeking—associated
with increased feelings of stimulant-induced euphoria.61–63
Large doses of DRT can lead to unpleasant feelings (table).
In fact, there are general problems for pleasure theories
of addiction.49,64,65 People will work for small doses of drugs
(eg, cocaine) that lack discernible pleasurable effects66,67 (ie,
the motivation to take drugs can be dissociated from druginduced pleasure).49,64,65 Attempts to rescue the pleasure
theory of addiction suggest that the pleasurable effects of
drugs may only be open to verbal report if they exceed a
given threshold.68,69 Most psychologists accept that a lack of
verbally reported pleasure does not mean a lack of pleasure
experience. Although pleasure is often defined as a conscious
feeling, it can exist without conscious awareness—which is
the product of a constructive process—rather than being a
direct “readout” of the underlying affective state.70
There are further problems for the hedonia model. If all
compulsively used drugs activate accumbens dopamine
systems, and if the use of these drugs is motivated by
pleasure, then destruction of dopamine neurons should
abolish pleasure.58 Berridge and colleagues64 have studied the
role of dopamine in the mediation of pleasure—by use of the
598
taste-reactivity paradigm—based on stereotyped reactions
emitted by rats to tastes, which are thought to be
homologous to human reactions to highly palatable food.71
Contrary to the hedonia hypothesis, near total dopamine
depletion induced by neurotoxins does not diminish facial
expressions of pleasure to sweet tastes, even though it
abolishes motivation to eat.64 So, even if the “pleasure”
experienced by addicts is unconscious, it is not the same as
the sensory pleasure experienced when eating, for example,
sweet foods.64 In human beings, dopaminergic blockade
diminishes self-reported drug “wanting” but not drug
“liking”.64
It may still be possible to argue for a pleasure theory of
addiction, if it is accepted that there may be different kinds
of pleasure, and that not all pleasures are sensory
pleasures.70,72,73 Frijda70 distinguishes sensory, aesthetic,
achievement/mastery, activity, relief, and social pleasures;
Rozin73 distinguishes sensory, aesthetic, and mastery
pleasures. Although dopamine does not mediate sensory
pleasure, it could mediate other forms of pleasure that
could be causally related to drug euphoria and to
compulsive drug use.74,75 Panksepp and colleagues69 have
proposed a similar approach. They argue that ultrasonic
vocalisations are expressions of particular emotional states
in rats. Rats emit vocalisations of about 50 kHz in several
reward-related situations (eg, during playful interactions,
before sexual intercourse, and while anticipating food).69
50 kHz ultrasonic vocalisations are also emitted in places
associated with previous psychostimulant administration
and can be elicited by injection of dopamine agonists into
the accumbens.69 Panksepp suggests that these responses are
homologous to states of euphoria, excitement, or joyful
anticipation in human beings.
An important issue that any variant of pleasure theory
must address is the induction of unpleasant effects after the
intake of large amounts of DRT.
Hedonic homoeostatic dysregulation (HHD)
Several models of addiction suggest that addicts are
motivated to take drugs not only for pleasure, but also—
and perhaps eventually primarily—by the desire to avoid
unpleasant withdrawal symptoms. Opponent process
theory76 proposes that pleasant doses of a drug activate a
dose-dependent “a” process in brain reward circuits, which
in turn triggers activation of an unpleasant opposite “b”
process, and which serves to restore homoeostasis.49,76 The
subjective state of the individual is created from summation
of the “a” and “b” processes. The “a” process causes
euphoria. The “b” process initially manifests as a decay of
euphoria after initial peak.76 With repeated drug use, the “b”
process becomes strengthened and manifests as tolerance to
euphoria. Unpleasant withdrawal is caused when the drug
effects wear off, since the “b” process is assumed to last
longer than the “a” state. It is only the “b” process that is
assumed to grow in magnitude and duration with repeated
drug use: even a small dose will reinstate it and trigger
withdrawal.76 Abstinence from the drug decays the “b”
process, and once it returns to normal, the individual is no
longer addicted.49,76
THE LANCET Neurology Vol 2 October 2003
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
Review
Dopamine dysregulation syndrome in PD
The hedonic homoeostatic dysregulation model of
Koob and Le Moal77,78 is a variant of opponent process
theory based on allostatic, rather than homoeostatic,
adaptation. Allostasis is the maintenance of stability
outside the normal homoeostatic range in response to
chronic demands. In HHD, before addiction, the
anticipation and experience of drug-induced pleasure
motivates the individual. However, HHD defines addiction
as the presence of an unpleasant emotional state of
dysphoria, irritability, and anxiety during abstinence.78
With repeated drug intake, the “b” process does not return
to normal homoeostatic baseline, resulting in an allostatic
state. This unpleasant state (allodynia or anhedonia [loss of
pleasure]) reflects a decrease in baseline pleasure levels—
associated with reduced dopamine function43—and an
increase in drug intake is needed to compensate for the
shift in baseline reward. There is evidence that some
patients with PD show reduced reward-related brain
activity,79 which, according to HHD, would confer
increased vulnerability to DRT addiction.77,78 A history of
depression with associated anhedonia may be a
predisposing factor in some cases (table).
Robinson and Berridge49,65 criticise the use of the term
“hedonic” in HHD. They argue that low dopamine
concentrations are not associated with anhedonia. The
notion of multiple types of pleasure,70,73 however, could be
used to counter this criticism.
In their initial account of compulsive DRT use in PD,
Giovannoni and colleagues28 labelled compulsive DRT use
in PD a form of HHD. Prominent unpleasant symptoms
can be a feature of the withdrawal state and these form part
of current working diagnostic criteria.28 Patients also report
feeling “relief” when given DRT. Kelleher and colleagues131
emphasise that the avoidance of being unmedicated was the
primary reason given for increased DRT intake. There are,
however, cases of long-term compulsive DRT use that show
no subjectively unpleasant withdrawal signs (table). A
further problem for withdrawal based explanations of
compulsive DRT use is that drug craving is often elicited by
DRT administration itself—in association with euphoria—
at the moment when withdrawal symptoms should be at
their weakest.28 Moreover, at least one report suggests that
pharmacological relief of unpleasant withdrawal symptoms
does not reduce compulsive DRT use.22
Withdrawal may have a role in compulsive drug use for
reasons other than simply the desire to avoid unpleasant
feelings. An alternative to avoidance theory views
withdrawal states as equivalent to natural motivational
states such as hunger.64,80 Incentive motivational accounts of
addiction assume that the withdrawal-state induced by
depriving an addict of drugs increases the incentive value of
the drug to such an extent that drug seeking becomes the
dominant behaviour.80
According to incentive motivational accounts, patients
with PD undergoing withdrawal are experiencing DRT
“hunger”, rather than just a desire to overcome an
unpleasant feeling. Indeed, some of the reports of
compulsive DRT users describe severe feelings of urgency
on withdrawal, “driving” them to take DRT.16
THE LANCET Neurology Vol 2 October 2003
Panel 2. Behavioural phenomena associated with
overuse of dopamine replacement therapy
Punding
Punding was first described as a distinctive stereotyped behaviour in
amphetamine addicts.32,33 It is homologous to the repetitive behavioural
stereotypy seen after psychostimulant administration in other
vertebrates.34,35 In human beings, it is characterised by intense
preoccupation with complex, repetitive manipulations of technical
equipment, handling, examining and sorting through common objects,
grooming, hoarding, and engagement in extended monologues that are
devoid of content.36,37 Punding is underreported in PD, but can be found
in medical publications described as “obsessive compulsive behaviour”
or “hypomania”. Motor restlessness and hyperactivity may occur, with
great distances being covered during “walkabouts” that occur without
purpose and with complete oblivion to time.
Euphoria and hypomania
Feelings of euphoria, perceived omnipotence and invulnerability, and
inappropriate joy can occur, with racing thoughts and grandiose ideation
(table).29 These feelings are similar to mania, but occur without
indiscriminate enthusiasm for interpersonal interactions.
Altered appetite
Compulsive eating is commonly seen during “on” phases. Some patients
develop uncontrollable food cravings.
Hypersexuality
Hypersexuality is common38–41 (table). An increase in erection frequency
and libido is common. Hypersexuality may lead to compulsive
masturbation, repeated demands for sexual intercourse, paraphilias
including exhibitionism, sadomasochism, fetishism, and rare attempts at
forced copulation. When paraphilias occur, there is frequently a
premorbid history of similar, possibly “repressed” proclivities.
Pathological gambling and shopping
Pathological gambling is seen in some patients42 (table), as is compulsive
buying (eg, of extravagant gifts for family members, which can be
financially ruinous).
Heightened aggression
Heightened aggression is common, and includes irritability, low tolerance
of frustration, angry outbursts, use of insulting language or gestures,
jealousy, aggressive threats, and occasional violence. Patients report
exaggerated feelings of power and dominance.
Craving and withdrawal
Craving for DRT is occasionally reported, and patients report being
“driven” to take DRT. Patients adopt strategies (eg, the simulation of
akinetic states), to gain access to additional medication. Craving can
occur in the absence of withdrawal symptoms (table). Withdrawal of DRT
can lead to feelings of sadness, inertia, fear, and anxiety; as well as
somatic symptoms including sweating and nausea. Patients report
feeling "relief" when DRT is given. These withdrawal symptoms closely
resemble the unpleasant affective states seen during withdrawal from
psychostimulants.43
Psychosis
Unchecked dopaminergic drug use leads to intoxication with a dosedependent reversible organic psychosis. Delirium, paranoia, delusional
thoughts, and hallucinations are commonly associated with severe
dyskinesias and hypomania. The psychosis responds well to
dopaminergic blockade and is very similar to amphetamine and cocaine
psychosis.35
Habit theory
Habit theory is a recent approach to addiction that
downplays the part of emotions, and places greater
emphasis on learning mechanisms.81 A habit is an
automatic action in a given situation, without direct
reference to the goal of that action. The premise of habit
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
599
Review
Dopamine dysregulation syndrome in PD
models is that, despite beginning as a goal-directed action,
in which individuals seek drugs based on the knowledge
and desire of the pleasure they produce, there is an
eventual progression to a form of automatic behaviour in
which voluntary control over drug use is lost.81,82 In
addition, stimuli consistently present in the environment
gain motivational power through their predictive
association with drugs, and thereby elicit and support
drug-seeking and cause relapse via associative-learning
mechanisms.81,83
This approach has gained attention partly owing to the
finding that dopamine neurons signal errors in reward
prediction that are critical for associative learning.84
Repeated exposure to psychostimulants facilitates such
learning and triggers neuroadaptations in dopamine
systems and intracellular signalling-pathways similar to
those seen during learning.85 Striatal dopamine is also
clearly involved in the development and reinforcement of
automatic stimulus-response habits.81,83,86
Habit theory provides a good explanation for the
stereotypical behavior seen in punding (panel 2)—a
common feature of compulsive DRT use in PD. These
stereotyped behaviours include prepotent, habitual routines
(eg, grooming), which are homologous to the complex
stereotyped responses seen in rats during hyperdopaminergic states.87,88 Strong stimulus-response habits
form the basis of such routine activities. Stereotypy
represents the culmination of a continuous process of
psychomotor stimulation and behavioural competition.89,90
Smaller doses of psychostimulant drugs potentiate the
approach responses to rewards, which are mediated by
accumbens dopamine.90,91 With increased doses, prepotent
stimulus-response habits—mediated by the dorsal striatal
structures—are potentiated and gain control over
behaviour.90,92 Stereotypies develop from prepotent habits,89
which are idiosyncratic, depending on individual lifehistories (eg, office workers stereotypically shuffle papers, a
seamstress will stereotypically collect and arrange buttons).
Individuals become unable to control automatic stimulusresponse selection mechanisms (ie, stereotypies are
purposeless, and there is a dissociation between knowledge
and behaviour).89,90 Patients realise that these behaviours are
irrational, but are unable to stop them.
Habit theory explains other features of compulsive DRT
use in PD less well. This theory may mistake automatic,
habitual action for motivational compulsion: no matter
how habitual drug-taking becomes, automatic stimulusresponse processes cannot in themselves confer compulsive
qualities to drug seeking and intake.49 In defense of habit
theory, it has been argued93 that the effects of vast doses of
DRT are far in excess of any normal physiological range,
and thus habits may have supranormal qualities. Habit
models cannot easily explain the apparently flexible goaldirected actions that patients with PD use to obtain DRT
(eg, faking akinetic states).
The habit model does not explain why most patients
with PD are not addicted to DRT. DRT use should become
habitual in all patients, but the incidence of compulsive
DRT use in PD is very low. Habit theorists must posit extra
600
pathology in susceptible individuals. For example, frontal
cortical pathology could cause additional loss of regulation
of habitual behaviours.94 Rats with lesions to the frontal
cortex show persistent responses to cocaine that are no
longer under the control of contingent presentation of
cocaine-associated cues.95 The ability to modulate habits
and conditioned responses can be impaired in some
patients with PD, and such deficits are exacerbated by
levodopa.96,97 Furthermore, the stereotyped collecting
behaviour seen in compulsive DRT users resembles that seen
in patients with frontal-lobe damage who have “forced
collectionism”.98 However, even with this additional
pathology, the criticism that habitual response and
motivational compulsion are not equivalent seems valid.
Incentive sensitisation theory (IST)
According to Robinson and Berridge’s incentive
sensitisation theory,49,65 compulsive drug use results from
progressive and persistent neuroadaptations induced in
dopamine projections to the accumbens-related
circuitry.49,65 These neuroadaptations can include: longlasting change in dopaminergic and GABAergic
neurotransmission, changes in intracellular signalling
pathways activated by these neurotransmitters, and even
persistent changes in the physical structure of neurons
themselves.49,65,85
The critical neuroadaptations for compulsive drug use
make these neural systems hypersensitive, or sensitised,
(where sensitisation is a progressive increase in drug effect
with repeated administration) to the incentive motivational
or rewarding effects of drugs.49,65 The systems sensitised,
according to this theory, mediate a subcomponent of reward
termed incentive salience.49,64,65 Incentive salience is neither a
hunger, nor a withdrawal state. Rather, it is one component
of normal appetite which, if attributed to stimuli, causes
them to become attractive and “wanted”, which triggers
approach and pursuit.49,65 This “wanting” is quite separate
from “liking’”(sensory pleasure).64
The process of neural sensitisation in the accumbenscircuitry eventually leads to excessive incentive salience
attribution to the drugs and drug-related stimuli that activate
this circuitry, making them highly attractive and
pathologically “wanted’” or craved.49,64,65 According to
incentive sensitisation theory, the system that causes
incentive salience attribution can produce drug seeking not
only in the absence of subjective pleasure (mediated by the
“liking” system), but also in the absence of conscious
awareness of “wanting” itself (ie, it can act as an unconscious
motivational process).49,65 Incentive salience is not the same as
incentive learning, although IST suggests a role for associative
learning in the expression of sensitisation.49,65 For example,
increased incentive salience following chronic amphetamine
treatment in rats can increase the salience of appetitive
stimuli in the environment which the animal has had no
opportunity to consume and thus learn the reward value of.99
Incentive sensitisation theory can be contrasted with theories
that emphasise incentive learning mechanisms.80,100
Psychomotor sensitisation is used as a marker of neural
sensitisation, because it is assumed that the neural substrate
THE LANCET Neurology Vol 2 October 2003
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
Review
Dopamine dysregulation syndrome in PD
that mediates the psychomotor-activating effects of drugs is
either the same as, or at least overlaps with, the neural
substrate for reward effects.11,49,65 Levodopa-induced
dyskinesia is generally thought to be a sensitisation
phenomenon.101,102 The development of dyskinesia in animal
models of PD requires the same drug schedule as that
necessary to induce psychomotor sensitisation by
Stimulant-induced
locomotor
psychostimulants.101
sensitisation is only seen when drugs are given
intermittently, and the most robust sensitisation occurs
when injections are widely spaced over time.65 Sensitisation
is strongest when high or rapidly escalating doses are given.65
Sensitised locomotor responses in rats are sensitive to
stress,49,65 as are dyskinesias in PD.103 “On” dyskinesias—
including dystonic, choreic, or stereotyped movements—are
commonly seen in individuals who compulsively use DRT
(table). The stereotypical actions seen in punding may also
result from psychomotor sensitisation processes.101
The neuroadaptations that cause dyskinesias and
punding are similar to those seen after psychomotor
sensitisation by, for example, amphetamine.65,85,101 They
occur, however, in the dorsolateral striatum, rather than the
accumbens-related circuitry.101 Although there is evidence of
a role for “motor” structures such as the dorsolateral
striatum in reward processing,86,104,105 and that both motor
and incentive phenomena share key characteristics, there are
clear dissociations between them. Locomotor sensitisation
that follows chronic amphetamine administration in rats
does not necessarily predict incentive sensitisation.99
Furthermore, even though compulsive DRT use in PD is
associated with dyskinesias, few dyskinetic patients are
compulsive DRT users.
Changes at the neuronal level induced by chronic
levodopa may be region specific and involve primarily the
dorsolateral striatum.106 However, data for unilaterally
6-hydroxydopamine-lesioned rats—the rodent analogue of
PD107—shows that repeated administration of levodopa
triggers dopamine D3 receptor overexpression in the
accumbens,108 which is a neuroadaptation involved in
compulsive drug use.85,108
Many of the symptoms seen in compulsive DRT users
are consistent with DRT having increased incentive salience.
Craving for DRT—in the absence of either heightened
pleasure or unpleasant withdrawal symptoms—can be seen.
Patients will go to extreme lengths to obtain medication,
despite the risk of harmful consequences,28 and will also
report being “driven” to take more DRT.16 Hoarding—itself
an accumbens dopamine dependent process109—of drugs has
been described, consistent with the drug’s increased
“attractiveness”.28
According to incentive sensitisation theory, the ability of
sensitisation to enhance responsiveness to rewards is not
confined to drug rewards: it also applies to other appetitive
behaviours.49,65 For example, an animal’s willingness to work
for various rewards can be increased by repeated exposure to
psychostimulants.49,65 In one study,99 chronic amphetamine
treatment in rats increased both amphetamine-induced
place preference and appetitive behaviour for food and
sexual rewards. Animals that developed the strongest
THE LANCET Neurology Vol 2 October 2003
amphetamine-induced place preference, however, were not
necessarily the same animals that developed magnified food
and sex-seeking behaviours. Such individual differences may
be due to pre-existing temperament factors.99
A global sensitisation of appetitive behaviours readily
accounts for symptoms of hypersexuality and compulsive
eating in PD. Furthermore, both money110,111 and consumer
goods112 activate the accumbens circuitry, which means that
symptoms of compulsive shopping and gambling could also
be explained by IST. These findings are relevant to the
debate as to whether or not behavioural and chemical
addictions share the same substrates.113,114 Similarly, certain
forms of aggression can be considered as appetitive
behaviours and are mediated by accumbens dopamine
release.115
Excessive “wanting” of DRT can override more stable life
goals and priorities, leading to impaired decision making.49,65
The ability of salient incentives to momentarily override the
influence of current goals on behaviour can lead to the
exploitation of novel opportunities and, therefore, can be
beneficial.116,117 When this behaviour becomes excessive,
potentially ruinous drug pursuit and the control of
behaviour by salient stimuli rather than long-term goals can
result.94 There are also data to suggest that chronic long-term
administration of large doses of psychostimulants can lead
to impairment in regions of the prefrontal cortex that are
important for regulation of behaviour by long-term goals.94
A synergistic increase of incentive sensitisation and impaired
goal-directed behaviour could lead to the dopamine
dysregulation syndrome in PD.49,94
In contrast to pleasure theories, incentive sensitisation
theory supposes that accumbens dopamine also has a role in
threat-related motivation,118 and it has been suggested that
heightened salience of threatening stimuli can explain
symptoms of anxiety, panic, and psychosis seen after very
high drug intake.118
Individual variability is an important feature of
sensitisation in both its development and its expression.49,65
Pharmacological,
genetic,
sex-related,
age-related,
temperamental, activity-level dependent, social, and
experiential factors are all important.49,65,119–121 Experiential
factors include cross-sensitisation between stress and
psychostimulants, and cross-sensitisation between different
drugs.49,65 Individual differences like these may eventually
help to explain the profile of patients with PD who are
vulnerable to compulsive DRT use: young-onset male cases,
with a past history of heavy alcohol or illegal-drug use, and
poor social circumstances.28 We are currently exploring the
role of factors such as temperament in the vulnerability to
compulsive DRT use.
Another feature of sensitisation is that it is not an
inevitable consequence of repeated drug exposure.49,65 Rather,
the ability of drugs to induce sensitisation—and the
expression of such sensitisation—is modulated by learning
and contextual factors.49,65 The ability of drugs to induce
sensitisation is greater in new than in familiar environments;
whereas the expression of incentive sensitisation appears
greatest in contexts distinctly related to drug-taking in the
past, and is also influenced by the diurnal state of the
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
601
Review
Dopamine dysregulation syndrome in PD
Search strategy and selection criteria
Data for this review were identified by searches of MEDLINE,
PsychInfo, PubMed, and Web of Science databases, together
with references from relevant articles. We used the search terms
“abuse”, “addiction”, “agonist”, “apomorphine”, “approach”,
“bromocriptine”, “cabergoline”, “dependence”, “dopamine”,
“dyskinesias”, “euphoria”, “habit”, “hedonic”, “hoarding”,
“levodopa”, “mood”, “nucleus accumbens”, “Parkinson’s”,
“pergolide”, “place preference”, “pleasure”, “pramipexole”,
“psychiatric”, “psychomotor”, “punding”, “reinforcement”,
“reward”, “ropinirole”, “self administration”, “sensitisation”,
“sexuality”, “side-effects”, “stereotypies”, “tolerance”, “ventral
striatum”, and “withdrawal”. Articles were also identified through
searches of the files of the authors. Only papers published in
English, German, and Spanish were reviewed.
animal.49,65,120 Notably, the effects of levodopa on locomotor
processes in rats are modulated by learning and contextual
factors.122
Although many features of compulsive DRT use in PD
seem quite compatible with incentive sensitisation theory,
the key prediction of IST is that neural sensitisation occurs in
the accumbens-related circuitry. We are currently testing this
hypothesis with PET neuroreceptor mapping and activation
techniques, together with experimental measures of reward
and incentive processing relevant to the predictions of IST.123
Implications for management
Ideally, the risk of developing compulsive DRT use should
be minimised, because once patients have developed the
disorder, long term management becomes difficult.
Differences between patients, and pharmacological and
environmental factors should be taken into account when
using DRT to treat patients with PD. The potential influence
of factors that might lead to an increased susceptibility to
both locomotor and incentive sensitisation can be
minimised by accounting for sex-related, pharmacological,
temperamental, environmental and social factors related to
heightened sensitisation. Long-acting dopaminergic drugs
that provide more continuous stimulation of dopamine
receptors may involve less risk than rapid, intermittent, or
pulsatile stimulation.102 The lowest doses of DRT that control
motor symptoms should be used, especially in those patients
thought to be susceptible.
If a pattern of compulsive levodopa use is established,
intermittent subcutaneous apomorphine should be avoided.
Hypomanic and psychotic episodes are best managed with a
reduction in DRT. Many of the disabling behavioural effects
of compulsive DRT use (panel 2) are clearly dopamine
responsive, and reductions in DRT can lead to cessation or
improvement in hypersexuality,13,14,18,24 pathological gambling
and shopping,24,29,124 and punding.36,37,125,126
Low doses of atypical antipsychotics (eg, quetiapine or
clozapine) can be effective in the control of episodes of
psychosis that may result from compulsive DRT use.
Intriguingly, low doses of clozapine block the induction of
psychomotor sensitisation.127 Acute psychosis commonly
settles rapidly, and is replaced by profound depression. In
some patients, this is associated with suicidal tendencies, and
602
needs close supervision. Antidepressant drugs can be helpful
in treating symptoms of depression, but do not abolish
compulsive DRT seeking and intake.22 It should also be
noted that certain antidepressants might themselves
promote incentive sensitisation if they act to increase
accumbens-dopamine activity.65
Patients should receive their drugs under strict
supervision, although dose reduction can prove difficult.
Supplying a single day’s dose at a time has proved practical,
although patients often find other sources for their drugs,
and restriction of access to medication by the patient’s
family may put them at risk of aggression from the patient.
Restriction of medication by the patient’s physician is
preferable. Various forms of psychotherapy are effective in
treating addiction: if patients have insight into their
problem, and agree, enrolment into a drug addiction
rehabilitation programme is appropriate. Psychosocial
support may also reduce factors such as stress and social
isolation, which influence the expression of sensitisation and
contribute to relapse.16,65,121
Deep brain stimulation of the subthalamic nucleus can
lead to dramatic reductions in daily levodopa requirements
and is effective for motor symptom control.128 Deep brain
stimulation may therefore prove useful in some cases.
However, this treatment is less effective in ameliorating the
emotional disturbance associated with PD.129 Increased
postoperative anxiety correlates with reduction in levodopa
dose achieved after deep brain stimulation,27 and many
patients find it difficult to dispense with dopamine
replacement therapy altogether.130 Deep brain stimulation
worsened levodopa-seeking in two cases: one patient also
developed devious strategies to obtain increases in his
stimulation parameters, and another patient developed
compulsive gambling and hypersexuality after deep brain
stimulation.27
Prognosis is generally poor and relapse to compulsive
DRT use is common (table).
Summary and conclusions
Compulsive use of DRT by patients with PD, although rare,
is of both clinical and theoretical importance. The major
theories of psychostimulant addiction may help explain
some of the phenomena seen in the dopamine dysregulation
syndrome. All of the major theories can partly explain the
syndrome, but it is unlikely that any one theory can explain
all the features. The theories are not necessarily mutually
exclusive, and dopamine dysregulation syndrome may not
represent a unitary phenomenon with a single set of
causative factors. The main predictions of addiction theories
have yet to be tested and further work is required to specify
the key psychological and biological processes underlying
compulsive drug use in human beings. The study of
dopamine dysregulation syndrome in PD provides a
valuable clinical paradigm in which to apply and extend
models of drug use developed primarily in comparative
neuropsychology, and may provide valuable insights not
only into compulsive DRT use, but also into other
compulsive behaviours that greatly affect patients, their
families and society in general.
THE LANCET Neurology Vol 2 October 2003
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
Review
Dopamine dysregulation syndrome in PD
Authors’ contributions
Role of the funding source
ADL wrote the first draft of the manuscript, which was then added to and
edited by AHE, AJL and ADL. The figure was prepared by Brian Cox.
ADL is funded by the UK Medical Research Council. AHE and AJL are
funded by the Reta Lila Weston Institute of Neurological Studies. Our
work on the dopamine dysregulation syndrome is funded by a grant
from the UK Parkinson’s Disease Society. No funding source had any
influence over the preparation of the manuscript or any part in the
decision to submit the paper for publication.
Conflict of interest
We have no conflicts of interest.
References
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Forno LS. Neuropathology of Parkinson’s disease.
J Neuropathol Exp Neurol 1996; 55: 259–72.
Hornykiewicz O, Kish SJ. Biochemical
pathophysiology of Parkinson’s disease. Adv Neurol
1986; 45: 19–34.
Kish SJ, Shannak K, Hornykiewicz O. Uneven
pattern of dopamine loss in the striatum of patients
with idiopathic Parkinson’s disease:
pathophysiologic and clinical implications.
N Engl J Med 1988; 318: 876–80.
Damier P, Hirsch EC, Agid Y, Graybiel AM. The
substantia nigra of the human brain, II: patterns of
loss of dopamine-containing neurons in Parkinson’s
disease. Brain 1999; 122: 1437–48.
Lewis DA, Sesack SR. Dopamine systems in the
primate brain. In: Bloom FE, Björklund A, Hökfelt T,
eds. Handbook of chemical neuroanatomy, volume
13: the primate nervous system, part I. Amsterdam:
Elsevier, 1997: 263–375.
Hoehn MM. The natural history of Parkinson’s
disease in the pre-levodopa and post-levodopa eras.
Neurol Clin 1992; 10: 331–39.
Obeso JA, Olanow CW, Nutt JG, eds. Basal ganglia,
Parkinson’s disease and levodopa therapy.
Trends Neurosci 2000; 23 (suppl 10): 1S–126S.
Fahn S. The spectrum of levodopa-induced
dyskinesias. Ann Neurol 2000; 47 (suppl 1): 2S–11S.
Goodwin FK. Psychiatric side effects of levodopa in
man. JAMA 1971; 218: 1915–20.
Damasio AR, Lobo-Antunes J, Macedo C.
Psychiatric aspects of parkinsonism treated with
L-dopa. J Neurol Neurosurg Psychiatr 1971;
34: 502–07.
Wise RA, Bozarth MA. A psychomotor stimulant
theory of addiction. Psychol Rev 1987; 94: 469–92.
Angrist B, Gershon S. Clinical effects of
amphetamine and L-DOPA on sexuality and
aggression. Comp Psychiat 1976; 17: 715–22.
Quinn NP, Toone B, Lang AE, Marsden CD,
Parkes JD. Dopa dose-dependent sexual deviation.
Br J Psychiatry 1983; 142: 296–8.
Vogel HP, Schiffter R. Hypersexuality—a
complication of dopaminergic therapy in
Parkinson’s disease. Pharmacopsychiatria 1983;
16: 107–10.
Priebe S. Levodopa dependence: a case report.
Pharmacopsychiatria 1984; 17: 109–10.
Nausieda PA. Sinemet “abusers”.
Clin Neuropharmacol 1985; 8: 318–27.
Tack E, De Cuypere G, Jannes C, Remouchamps A.
Levodopa addiction: a case study.
Acta Psychiatr Scand 1988; 78: 356–60.
Uitti RJ, Tanner CM, Rajput AH, Goetz CG,
Klawans HL, Thiessen B. Hypersexuality with
antiparkinsonian therapy. Clin Neuropharmacol
1989; 12: 375–83.
Soyka M, Huppert D. L-dopa abuse in a patient with
former alcoholism. Br J Addict 1992; 87: 117–18.
Weinman E, Ruskin PE. Levodopa dependence and
hypersexuality in an older Parkinson’s disease
patient. Am J Geriat Psychiat 1995; 3: 81–83.
Spigset O, von Scheele C. Levodopa dependence and
abuse in Parkinson’s disease. Pharmacotherapy 1997;
17: 1027–30.
Courty E, Durif F, Zenut M, Courty P, Lavarenne J.
Psychiatric and sexual disorders induced by
apomorphine in Parkinson’s disease.
Clin Neuropharmacol 1997; 20: 140–47.
Merims D, Galili-Mosberg R, Melamed E. Is there
addiction to levodopa in patients with Parkinson’s
disease? Mov Disord 2000; 15: 1014–16.
Gschwandtner U, Aston J, Renaud S, Fuhr P.
Pathologic gambling in patients with Parkinson’s
disease. Clin Neuropharmacol 2001; 24: 170–72.
Serrano-Duenas M. Chronic dopamimetic drug
addiction and pathologic gambling in patients with
Parkinson’s disease: presentation of four cases.
German J Psychiatry 2002; 5: 62–66.
Muller U, Reuter M, Hermann W, Gertz HJ.
Levodopa dependence in Parkinson’s disease: case
report and review. Nervenartz 2002; 73: 887–91.
Houeto JL, Mesnage V, Mallet L, et al. Behavioral
disorders, Parkinson’s disease and subthalamic
THE LANCET Neurology Vol 2 October 2003
stimulation. J Neurol Neurosurg Psychiatry 2002;
72: 701–07.
28 Giovannoni G, O’Sullivan JD, Turner K,
Manson AJ, Lees AJ. Hedonistic homeostatic
dysregulation in patients with Parkinson’s disease
on dopamine replacement therapies.
J Neurol Neurosurg Psychiatry 2000; 68: 423–28.
29 Kurlan R, Dimitsopulos T. Selegiline and manic
behavior in Parkinson’s disease. Arch Neurol 1992;
49: 1231.
30 Menza MA, Golbe LI. Hypomania in a patient
receiving deprenyl (selegiline) after adrenal-striatal
implantation for Parkinson’s disease.
Clin Neuropharmacol 1988; 11: 549–51.
31 Riley DE. Reversible transvestic fetishism in a man
with Parkinson’s disease treated with selegiline.
Clin Neuropharmacol 2002; 25: 234–37.
32 Rylander G. Psychoses and the punding and
choreiform syndromes in addiction to central
stimulant drugs. Psychiatr Neurol Neurochir 1972;
75: 203–12.
33 Schiorring E. Psychopathology induced by “speed
drugs”. Pharmacol Biochem Behav 1981;
14 (suppl 1): 109S–22S.
34 Randrup A, Munkvad I. Stereotyped activities
produced by amphetamine in several animal species
and man. Psychopharmacol 1967; 11: 300–10.
35 Lyon M, Nielson EB. Psychosis and drug-induced
stereotypies. In: Keehn JD, ed. Psychopathology in
animals. New York: Academic Press, 1979: 103–42.
36 Friedman JH. Punding on levodopa. Biol Psychiatry
1994; 36: 350–51.
37 Fernandez HH, Friedman JH. Punding on L-dopa.
Mov Disord 1999; 14: 836–38.
38 Brown E, Brown GM, Kofman O, Quarrington B.
Sexual function and affect in Parkinsonian men
treated with L-Dopa. Am J Psychiatry 1978; 155:
1552–55.
39 Harvey NS. Serial cognitive profiles in levodopainduced hypersexuality. Brit J Psychiatry 1988; 153:
833–36.
40 O’Sullivan JD, Hughes AJ. Apomorphine-induced
penile erections in Parkinson’s disease. Mov Disord
1998; 13: 536–39.
41 Jiménez- Jiménez FJ, Tallón-Barranco A,
Cabrera-Valdivia F, Gasalla T, Ortí-Pareja M,
Zurdo M. Fluctuating penile erection related with
levodopa therapy. Neurol 1999; 52: 210.
42 Molina JA, Sainz-Artiga MJ, Fraile A, et al.
Pathologic gambling in Parkinson’s disease: a
behavioral manifestation of pharmacologic
treatment? Mov Disord 2000; 15: 869–72.
43 Barr AM, Markou A, Phillips AG. A “crash” course
on psychostimulant withdrawal as a model of
depression. Trends Pharmacol Sci 2002; 23: 475–82.
44 American Psychiatric Association. Diagnostic and
statistical manual of mental disorders, 4th edn.
Washington: American Psychiatric Association,
1994.
45 Nutt JG, Carter JH, Woodward WR. Effect of brief
levodopa holidays on the short-duration response to
levodopa: evidence for tolerance to the
antiparkinsonian effects. Neurol 1994; 44: 1617–22.
46 Gancher ST, Woodward WR, Nutt JG.
Apomorphine tolerance in Parkinson’s disease: lack
of a dose effect. Clin Neuropharmacol 1996; 19:
59–64.
47 Menza MA, Sage J, Marshall E, Cody R, Duvoisin R.
Mood changes and ‘on-off’ phenomena in
Parkinson’s disease. Mov Disord 1990; 5: 148–51.
48 World Health Organization. International Statistical
Classification of Diseases and Related Health
Problems, 10th revision. Geneva: World Health
Organization, 1990.
49 Robinson TE, Berridge KC. Addiction.
Annu Rev Psychol 2003; 54: 25–53.
50 Bardo MT, Bevins RA. Conditioned place
preference: what does it add to our preclinical
understanding of drug reward? Psychopharmacol
2000; 153: 31–43.
51 Katajamäki J, Honkanen A, Piepponen TP,
Lindén I-B, Zharkovsky A, Ahtee L. Conditioned
place preference induced by a combination of
L-Dopa and a COMT inhibitor, entacapone, in rats.
Pharm Biochem Behav 1998; 60: 23–26.
52 van der Kooy D, Swerdlow NR, Koob GF.
Paradoxical reinforcing properties of apomorphine:
effects of nucleus accumbens and area postrema
lesions. Brain Res 1983; 259: 111–18.
53 Papp M. Different effects of short- and long-term
treatment with imipramine on the apomorphineand food-induced place preference conditioning in
rats. Pharmacol Biochem Behav 1988; 30: 889–93.
54 Hoffman DC, Dickson PR, Beninger RJ. The
dopamine D2 receptor agonists, quinpirole and
bromocriptine produce conditioned place
preferences. Prog Neuropsychopharmal Biol Psychiatr
1988; 12: 315–22.
55 Zito KA, Vickers G, Roberts DC. Disruption of
cocaine and heroin self-administration following
kainic acid lesions of the nucleus accumbens.
Pharmacol Biochem Behav 1985; 23: 1029–36.
56 Black KJ, Hershey T, Koller JM, et al. A possible
substrate for dopamine-related changes in mood and
behavior: prefrontal and limbic effects of a D3preferring dopamine agonist. Proc Natl Acad Sci USA
2002; 99: 17113–18.
57 Aristotle: the ethics.Thompson JAK, translator.
London: Penguin, 1976.
58 Wise RA. The anhedonia hypothesis: mark III.
Behav Brain Sci 1985; 8: 178–86.
59 Vaccarino FJ, Schiff BB, Glickman SE. A biological
view of reinforcement. In: Klein SB, Mowrer RR,
eds. Contemporary learning theories. Hillsdale:
Lawrence Erlbaum Associates,1989: 111–42.
60 Maricle RA, Valentine RJ, Carter J, Nutt JG. Mood
response to levodopa infusion in early Parkinson’s
disease. Neurol 1998; 50: 1890–92.
61 Hutchison KE, Wood MD, Swift R. Personality
factors moderate subjective and psychophysiological
responses to d-amphetamine in humans.
Exp Clin Psychopharmacol 1999; 7: 493–501.
62 Corr PJ, Kumari V. Individual differences in mood
reactions to d-amphetamine: a test of three
personality factors. J Psychopharm 2000; 14: 371–77.
63 Leyton M, Boileau I, Benkelfat C, Diksic M,
Baker G, Dagher A. Amphetamine-induced
increases in extracellular dopamine, drug wanting,
and novelty seeking: a PET/[11C]raclopride study in
healthy men. Neuropsychopharm 2002; 27: 1027–35.
64 Berridge KC, Robinson TE. What is the role of
dopamine in reward: hedonic impact, reward
learning, or incentive salience? Brain Res Revs 1998;
28: 309–69.
65 Robinson TE, Berridge KC. The psychology and
neurobiology of addiction: an incentivesensitization view. Addiction 2000; 95 (suppl 2):
91S–117S.
66 Lamb RJ, Preston KL, Schindler CW, et al. The
reinforcing and subjective effects of morphine in postaddicts: a dose response study. J Pharmacol Exp Ther
1991; 259: 1165–73.
67 Comer SD, Collins ED. Self-administration of
intravenous buprenorphine and the
buprenorphine/naloxone combination by recently
detoxified heroin abusers. J Pharmacol Exp Ther
2002; 303: 695–703.
68 Shizgal P. On the neural computation of utility:
implications from studies of brain stimulation
reward. In: Kahneman D, Diener E, Schwarz N, eds.
Well-being: the foundations of hedonic
psychology. New York: Russell Sage Foundation,
1999: 500–24.
69 Panksepp J, Knutson B, Burgdorf J. The role of
brain emotional systems in addictions: a neuroevolutionary perspective and new ‘self-report’
animal model. Addiction 2002; 97: 459–69.
70 Frijda NH. The nature of pleasure. In: Bargh JA,
Apsley DK, eds. Unravelling the complexities of
social life: a festschrift in honor of Robert B Zajonc.
Washington, DC: American Psychological
Association, 2001: 71–94.
71 Steiner J, Glaser D, Hawilo MH, Berridge KC.
Comparative expression of hedonic impact:
Affective reactions to taste by human infants and
other primates. Neurosci Biobehav Revs 2001; 25:
53–74.
72 Berlyne DE, Madsen KB, eds. Pleasure, reward,
preference. New York: Academic Press, 1973: 243–74.
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
603
Review
73 Rozin P. Pre-adaptation and the puzzles and
properties of pleasure. In: Kahneman D, Diener E,
Schwarz N, eds. Well-being: the foundations of
hedonic psychology. New York: Russell Sage
Foundation, 1999: 109–33.
74 Volkow ND, Fowler JS, Wang G-J. Role of
dopamine in drug reinforcement and addiction in
humans: results from imaging studies.
Behav Pharmacol 2002; 13: 355–66.
75 Drevets WC, Gautier C, Price JC, et al.
Amphetamine-induced dopamine release in human
ventral striatum correlates with euphoria.
Biol Psychiatry 2001; 49: 81–96.
76 Solomon RL, Corbit JD. An opponent-process
theory of acquired motivation, II: cigarette
addiction. J Abnorm Psychol 1973; 81: 158–71.
77 Koob GF, Le Moal M. Drug abuse: hedonic
homeostatic dysregulation. Science 1997; 278:
52–58.
78 Koob GF, Le Moal M. Drug addiction,
dysregulation of reward, and allostasis.
Neuropsychopharmacol 2001; 24: 97–129.
79 Künig G, Leenders KL, Martin-Sölch C, Missimer J,
Magyar S, Schultz W. Reduced reward processing in
the brains of Parkinsonian patients. NeuroReport
2000; 11: 3681–87.
80 Hutcheson DM, Everitt BJ, Robbins TW,
Dickinson A. The role of withdrawal in heroin
addiction: enhances reward or promotes avoidance?
Nature Neurosci 2001; 4: 943–47.
81 Everitt BJ, Dickinson A, Robbins TW. The
neuropsychological basis of addictive behaviour.
Brain Res Revs 2001; 36: 129–38.
82 Hogarth LC, Mogg K, Bradley BP, Duka T,
Dickinson A. Attentional orienting towards
smoking-related stimuli. Behav Pharmacol 2003;
14: 153–60.
83 Everitt BJ, Wolf ME. Psychomotor stimulant
addiction: a neural systems perspective. J Neurosci
2002; 22: 3312–20.
84 Waelti P, Dickinson A, Schultz W. Dopamine
responses comply with basic assumptions of formal
learning theory. Nature 2001; 412: 43–48.
85 Berke JD, Hyman SE. Addiction, dopamine, and the
molecular mechanisms of memory. Neuron 2000;
25: 515–32.
86 Ito R, Dalley JW, Robbins TW, Everitt BJ.
Dopamine release in the dorsal striatum during
cocaine-seeking behavior under the control of a
drug-associated cue. J Neurosci 2002; 22: 6247–53.
87 Young RK, Thiessen DD. Washing, drying, and
anointing in adult humans (homo sapiens):
commonalities with grooming sequences in rodents.
J Comp Psychol 1991; 105: 340–44.
88 Berridge KC, Aldridge JW. Super-stereotypy I:
enhancement of a complex movement sequence by
systemic dopamine D1 agonists. Synapse 2000;
37: 194–204.
89 Toates F. The interaction of cognitive and stimulusresponse processes in the control of behaviour.
Neurosci Biobehav Revs 1998; 22: 59–83.
90 Robbins TW, Mittleman G, O’Brien J, Winn P. The
neuropsychological significance of stereotypy
induced by stimulant drugs. In: Cooper SJ,
Dourish CT, eds. Neurobiology of stereotyped
behaviour. Oxford: Clarendon Press, 1990: 25–63.
91 Ikemoto S, Panksepp J. The role of nucleus
accumbens dopamine in motivated behavior: a
unifying interpretation with special reference to
reward seeking. Brain Res Rev 1999; 31: 6–41.
92 Whishaw IQ, Fiorino D, Mittleman G, Castañeda E.
Do forebrain structures compete for behavioral
expression? Evidence from amphetamine-induced
604
Dopamine dysregulation syndrome in PD
behavior, microdialysis, and caudate-accumbens
lesions in medial frontal cortex damaged rats.
Brain Res 1992; 576: 1–11.
93 Wise RA. Brain reward circuitry: insights from
unseen incentives. Neuron 2002; 36: 229–40.
94 Jentsch JD, Taylor JR. Impulsivity resulting from
frontostriatal dysfunction in drug abuse:
implications for the control of behavior by reward
related stimuli. Psychopharmacol 1999; 146: 373–90.
95 Weissenborn R, Robbins TW, Everitt BJ. Effects of
medial prefrontal or anterior cingulate cortex
lesions on responding for cocaine under fixed-ratio
and second-order schedules of reinforcement in
rats. Psychopharmacol 1997; 134: 242–57.
96 Cools R, Barker RA, Sahakian BJ, Robbins TW.
Enhanced or impaired cognitive function in
Parkinson’s disease as a function of dopaminergic
medication and task demands. Cereb Cortex 2001;
11: 1136–43
97 Cools R, Barker RA, Sahakian BJ, Robbins TW.
L-Dopa medication remediates cognitive inflexibility,
but increases impulsivity in patients with Parkinson’s
disease. Neuropsychologia 2003; 41: 1431–41.
98 Volle E, Beato R, Levy R, Dubois B. Forced
collectionism after orbitofrontal damage. Neurology
2002; 58: 488–90.
99 Nocjar C, Panksepp J. Chronic intermittent
amphetamine pretreatment enhances future
appetitive behavior for drug- and natural-reward:
interaction with environmental variables.
Behav Brain Res 2002; 128: 189–203.
100 Di Chiara G. Drug addiction as dopaminedependent associative learning disorder.
Euro J Pharmacol 1999; 375: 13–30.
101 Graybiel AM, Canales JJ, Capper-Loup C.
Levodopa-induced dyskinesias and dopaminedependent stereotypies: a new hypothesis.
Trends Neurosci 2000; 23 (suppl 10): 71S–7S.
102 Olanow CW, Schapira HV, Rascol O. Continuous
dopamine-receptor stimulation in early Parkinson’s
disease. Trends Neurosi 2000; 23 (suppl 10):
117S–26S.
103 Durif F, Vidailhet M, Debilly B, Agid Y. Worsening
of levodopa-induced dyskinesias by motor and
mental tasks. Mov Disord 1999; 14: 242–45.
104 Volkow ND, Wang GJ, Fowler JS, et al. “Nonhedonic”
food motivation in humans involves dopamine in the
dorsal striatum and methylphenidate amplifies this
effect. Synapse 2002; 44: 175–80.
105 Salamone JD, Correa M, Mingotte S, Weber SM.
Nucleus accumbens dopamine and the regulation of
effort in food-seeking behavior: implications for
studies of natural motivation, psychiatry, and drug
abuse. J Pharmacol Exp Ther 2003; 305: 1–8.
106 Mura A, Mintz M, Feldon J. Behavioral and
anatomical effects of long-term Ldihydroxyphenylalanine (L-DOPA) administration
in rats with unilateral lesions of the nigrostriatal
system. Exp Neurol 2002; 177: 252–64.
107 Cenci MA, Whishaw IQ, Schallert T. Animal models
of neurological deficits: how relevant is the rat?
Nat Rev Neurosci 2002; 3: 574–79.
108 Gullin O, Diaz J, Carroll P, Griffon N, Schwartz J-C,
Sokoloff P. BDNF controls dopamine D3 receptor
expression and triggers behavioural sensitization.
Nature 2001; 411: 86–89.
109 Kelley AE, Stinus L. Disappearance of hoarding
behavior after 6-hydroxydopamine lesions of the
mesolimbic dopamine neurons and its reinstatement
with L-dopa. Behav Neurosci 1985;
99: 531–45.
110 Koepp MJ, Gunn RN, Lawrence AD, et al. Evidence
for striatal dopamine release during a videogame.
Nature 1998; 393: 266–68.
111 Knutson B, Adams CS, Fong GW, Hommer D.
Anticipation of monetary reward selectively recruits
nucleus accumbens. J Neurosci 2001;
21: RC159, 1–5.
112 Erk S, Spitzer M, Wunderlich AP, Galley L,
Walter H. Cultural objects modulate reward
circuitry. NeuroReport 2002; 13: 2499–503.
113 Elster J, Skog OJ, eds. Getting hooked: rationality
and addiction. Cambridge: Cambridge University
Press, 1999.
114 Holden C. “Behavioral” addictions: do they exist?
Science 2001; 294: 980–82.
115 Lawrence AD, Calder AJ, McGowan SM,
Grasby PM. Selective disruption of the recognition
of facial expressions of anger. NeuroReport 2002;
13: 881–84.
116 Fiorillo CD, Tobler PN, Schultz W. Discrete coding
of reward probability and uncertainty by dopamine
neurons. Science 2003; 299: 1898–902.
117 Kakade S, Dayan P. Dopamine: generalization and
bonuses. Neural Netw 2002; 15: 549–59.
118 Kelley AE, Berridge KC. The neuroscience of natural
rewards: relevance to addictive drugs. J Neurosci
2002; 22: 3306–11.
119 Laviola G, Adriani W, Terranova ML, Gerra G.
Psychobiological risk factors for vulnerability to
psychostimulants in human adolescents and animal
models. Neurosci Biobehav Revs 1999; 23: 993–1010.
120 Abarca C, Albrecht U, Spanagel R. Cocaine
sensitization and reward are under the influence of
circadian genes and rhythm. Proc Natl Acad Sci USA
2002; 99: 9026–30.
121 Marinelli M, Piazza PV. Interaction between
glucocorticoid hormones, stress and
psychostimulant drugs. Eur J Neurosci 2002;
16: 387–94.
122 Carey RJ. Pavlovian conditioning of L-Dopa
induced movement. Psychopharmacol 1992;
107: 203–10.
123 Wyvell CL, Berridge KC. Incentive sensitization by
previous amphetamine exposure: increased cuetriggered “wanting” for sucrose reward. J Neurosci
2001; 21: 7831–40.
124 Driver-Dunckley E, Samanta J, Stacy M.
Pathological gambling associated with dopamine
agonist therapy in Parkinson’s disease. Neurology
2003; 61: 422–23.
125 Evans AH, Katzenschlager R, O’Sullivan J,
Vaughan PR, Lees AJ. Dopamine agonist
induced punding. Mov Disord 2002;
17 (suppl 5): 328S.
126 Meseguer Gancedo E, Garcia Ruiz PJ. Punding in
Parkinson’s disease. Neurologia 2002; 17: 228.
127 Meng ZH, Feldpaush DL, Merchant KM. Clozapine
and haloperidol block the induction of behavioral
sensitization to amphetamine and associated
genomic responses in rats. Mol Brain Res 1998;
61: 39–50.
128 Pollack P, Fraix V, Krack P, et al. Treatment results:
Parkinson’s disease. Mov Disord 2002;
17 (suppl 3): 75S–83S.
129 Funkiewiez A, Ardouin C, Krack P, et al. Acute
psychotropic effects of bilateral subthalamic nucleus
stimulation and levodopa in Parkinson’s disease.
Mov Disord 2003; 18: 524–30.
130 Iansek R, Rosenfeld JV, Huxham FE. Deep brain
stimulation of the subthalamic nucleus in
Parkinson’s disease. MJA 2002; 177: 142–46.
131 Kelleher M, Evans AH, Bearn J Lees AJ, Turner K.
Misuse of dopamine replacement therapies in
patients with Parkinson’s disease. Addiction (in
press).
THE LANCET Neurology Vol 2 October 2003
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.