www.thelancet.com/neurology Vol 8 December 2009
Chronic dopaminergic stimulation in Parkinson’s disease:
from dyskinesias to impulse control disorders
Valerie Voon, Pierre-Olivier Fernagut, Jeff Wickens, Christelle Baunez, Manuel Rodriguez, Nancy Pavon, Jorge L Juncos, José A Obeso, Erwan Bezard
Dopamine is an essential neurotransmitter for many brain functions, and its dysfunction has been implicated in both
neurological and psychiatric disorders. Parkinson’s disease is an archetypal disorder of dopamine dysfunction
characterised by motor, cognitive, behavioural, and autonomic symptoms. While eff ective for motor symptoms,
dopamine replacement therapy is associated not only with motor side-eff ects, such as levodopa-induced dyskinesia,
but also behavioural side-eff ects such as impulse control disorders (eg, pathological gambling and shopping, binge
eating, and hypersexuality), punding (ie, abnormal repetitive non-goal oriented behaviours), and compulsive
medication use. We review clinical features, overlapping molecular mechanisms, and a specifi c cognitive mechanism
of habit learning that might underlie these behaviours. We integrate these mechanisms with the emerging view of the
basal ganglia as a distributive system involved in the selection and facilitation of movements, acts, and emotions.
Dopamine neuromodulation is intrinsic to processes of
movement and motor learning, cognition, reward
processing, food intake, nociception, and endocrine and
autonomic regulation. Dopaminergic dysfunction is
implicated in neurological and neuropsychiatric disorders
such as Parkinson’s disease (PD), schizophrenia, and drug
addiction. PD is associated with both dopamine-related
motor and behavioural side-eff ects and provides a useful
model to understand the similarities and diff erences
underlying the eff ects of dopamine on motor and
PD is characterised by the loss of dopaminergic
nigrostriatal A9 neurons (and, to a lesser extent, retrorubral
A8 and mesolimbic A10 neurons); with disease
progression, non-dopaminergic nuclei, such as the locus
coeruleus, the nucleus basalis of Meynert, and the dorsal
raphe, are aff ected, and Lewy body pathology becomes
widespread.1 The dopamine replacement therapies, which
include the dopamine precursor levodopa and dopamine
agonists, are very eff ective in treating motor symptoms,
but can cause substantial motor and behavioural adverse
events. These side-eff ects include motor fl uctuations and
levodopa-induced dyskinesia (LID),2 and non-motor
symptoms such as mood and anxiety fl uctuations,
psychosis, and impulse control disorders (ICDs). LIDs are
defi ned as involuntary, purposeless, irregular but
sometimes repetitive movements, which are mainly
choreic, and generally coincide with the peak
anti-parkinsonian eff ect of levodopa.3 LIDs aff ect at least
90% of patients with PD after 10 years of levodopa
treatment4 and are a major cause of disability. ICDs (ie,
pathological gambling, compulsive shopping, hyper-
sexuality, and binge eating), punding (ie, abnormal
repetitive non-goal oriented behaviours) or hobbyism, and
compulsive medication use are associated with
dopaminergic therapy and are increasingly recognised
in PD.5–15 Overall, the ICDs in the general population have
similarities to disorders of substance addiction, hence
ICDs have been viewed as behavioural addictions.16 The
pathology of PD and the mechanisms underlying LIDs, a
dopamine-associated motor side-eff ect, are better defi ned
than are the mechanisms underlying ICDs, for which
much less is understood. In this Review, we provide
insights into potential mechanisms underlying ICDs and
discuss potential similarities and diff erences between
LIDs and ICDs.
Dyskinesias and behavioural abnormalities:
The clinical features and major presentation types of LIDs
have been described and discussed extensively in the
literature (panel 1).17,18 LIDs commonly occur in patients
with motor fl uctuations and are related to levodopa intake.
The main risk factors associated with LIDs are disease
severity, disease duration, daily dose of levodopa, and age
at onset (ie, 50% of patients aged 45 years or less develop
LIDs within the fi rst 2 years of treatment).3,4 Monotherapy
with dopamine agonists such as ropinirole or rotigotine
can also induce dyskinesia in monkeys treated with MPTP
patients with PD, but these side-eff ects are less common
and less severe than those commonly seen with
levodopa.19,20 Treatment of LIDs can be diffi cult, particularly
in patients with severe “on-off ” fl uctuations as any minor
reduction in levodopa or dopamine agonist dose to reduce
dyskinesia leads to unbearable “off ” episodes. Continuous
delivery of subcutaneous apomorphine, intraduodenal
levodopa, and oral delivery of the non-specifi c glutamate
blocker amantadine, are the preferred pharmacological
options for managing severe LIDs. Surgical treatment (ie,
pallidotomy or bilateral deep brain stimulation [DBS] of
the globus pallidus pars interna or subthalamic nucleus
[STN]) is an effi cient therapy to treat LIDs.
Dopamine-induced behavioural disorders
PD is associated with several non-motor symptoms,
which include changes in cognition, mood, psychosis,
anxiety, fatigue, and autonomic systems. We focus on the
behavioural symptoms associated with dopaminergic
medications, particularly in ICD, punding, and
Lancet Neurol 2009; 8: 1140–49
Wellcome Trust Centre for
Neuroimaging, Institute of
Neurology, University College
London, London, UK
(V Voon MD); Université Victor
Segalen-Bordeaux 2, Centre
National de la Recherche
Scientifi que, Bordeaux
Institute of Neuroscience,
UMR 5227, Bordeaux, France
(P-O Fernagut PhD,
E Bezard PhD); Neurobiology
Research Unit, Okinawa
Institute of Science and
Technology, 12–22 Suzaki,
Uruma City, Okinawa, Japan
(J Wickens PhD); Laboratoire de
Neurobiologie de la Cognition,
CNRS UMR 6155, Aix-Marseille
Université, Marseille, France
(C Baunez PhD); Laboratory of
Department of Physiology,
Faculty of Medicine, University
of La Laguna, Tenerife, Spain
(M Rodriguez PhD); Centro
Neurológica (CIREN), Havana,
Cuba (N Pavon MD); Neurology
Department, Emory University,
Atlanta, GA, USA
(J L Juncos MD); Department of
Neurology, Clinica Universitaria
and Medical School and
Neuroscience, CIMA, University
of Navarra, Pamplona, Spain
(J A Obeso MD); Centro
(CIBERNED), and Instituto
Carlos III, Ministerio de
Sanidad, Spain (M Rodriguez,
J A Obeso)
Valerie Voon, Wellcome Trust
Centre for Neuroimaging,
Institute of Neurology,
University College London,
12 Queen Square, London
WC1N 3BG, UK
www.thelancet.com/neurology Vol 8 December 2009 1141
compulsive medication use. We consider the ICDs
separately given their proven association with dopamine
agonists in multiple case control studies,5–8 as compared
with compulsive medication use, which seems more
closely associated with levodopa,9–11 and punding, in
which the association between levodopa and dopamine
agonists is not as clear.12–14
Impulse control disorders
The ICDs reported in patients with PD include
pathological gambling, hypersexuality, compulsive
shopping, and binge eating. Their defi nitions have been
extensively reviewed elsewhere21 and are summarised in
panel 2. These ICDs are characterised by the maladaptive
nature of the preoccupations in the patient, the inability
to control the urges or impulses, and other pathological
behaviours (such as lying or stealing) that arise to act on
these urges. Although these behaviours have diff erent
levels of severity, pathology is defi ned by the consequences
of clear distress or interference with social, fi nancial, or
occupational functioning. The behaviours should not
occur exclusively within a manic episode.
Gambling behaviours can include excessive gambling
or preoccupation with various lotteries, betting, casinos,
bingo, and, most recently reported, internet gambling.24
One study reported that, of 297 patients screened, all ten
patients who were identifi ed to have problems related to
pathological gambling (3·4%) preferred slot machines
and scratch lottery cards, suggesting a behaviour related
to immediate gratifi cation, lower cognitive resources,
and repetitive motor acts.15 The consequences can be
drastic: one study reported a mean amount of US$10 000
lost among ten patients with PD owing to pathological
gambling along with a pronounced detrimental eff ect on
the patients’ relationships.15 Common
reported in hypersexuality include inappropriate or
excessive requests of sex from a spouse or a partner,
preoccupation with pornography, telephone sex lines,
masturbation, or compulsive promiscuity.5
In a study that compared patients with PD with general
medical patients, the frequency of gambling was 6·1% in
patients with PD compared with 0·25% in controls.6 In a
recent multicentre study of 3090 patients with PD in the
USA, 13·6% of patients had ICDs.25 There were 6·0% of
patients whose ICDs included compulsive buying, 5·2%
with problem or pathological gambling, 4·3% with a
binge eating disorder, and 3·5% with compulsive sexual
behaviour. ICDs were more common in patients treated
with dopamine agonists (17·1%) compared with those
who received other treatments (6·9%). There were no
diff erences in frequency of ICDs between those treated
with pramipexole (17·7%) or ropinirole (15·5%). This
frequency and association of ICDs with dopamine
agonists as a class are similar to those reported in
previous publications.6,8,15 This multicentre study reported
that the risk factors associated with ICDs were younger
age (60·3 years vs 64·4 years), treatment with dopamine
agonists, high levodopa dose, being unmarried, and a
family history of gambling problems. The study did not
fi nd an association with higher dopamine agonist dose
but did fi nd a link with higher levodopa dose, thus
suggesting an intrinsic role for levodopa. Other associated
factors reported include higher novelty seeking, a
personal or family history of alcohol use disorders,
impulsivity, younger onset PD, and depressed mood.8,9,13,26
These factors overlap with those associated with
substance use disorders and gambling disorders, thus
suggesting similar underlying mechanisms. The
prevalence of pathological gambling in PD reported in
North America is similar to that reported in other
countries, including Scotland (4·4%), Italy, (6·1%), and
Pathological gambling, compulsive shopping, and
hypersexuality behaviours also occur in patients with
restless legs syndrome who are treated with dopamine
replacement therapy, although the prevalence is less
well established.28 In the general population in North
America, the lifetime prevalence of pathological
gambling is 1·5% and that for problems related to
pathological gambling is 3–5%,29 and the estimated
point prevalence (ie, cross-sectional) is 5·8% for
compulsive buying and 2–6% for binge eating
disorder.30,31 Whether the rates of these behaviours in
PD are increased beyond that of the general population
is not clear6 but their signifi cance lies in their de novo
onset after the initiation of dopamine replacement
Panel 1: Common clinical presentations of
levodopa-induced dyskinesias in Parkinson´s disease
“Peak dose”, “benefi t of dose” or “on” dyskinesia
• Coincide with the antiparkinsonian benefi t (“on”
response) and are predominantly choreic in nature
• Neck, axial, and proximal upper limbs are predominantly
involved; these symptoms are worsened by dopaminergic
medications and disappear after stopping treatment
“Diphasic” or “beginning and end-of-dose” dyskinesia
• Appear at the beginning of the eff ect of levodopa before
full anti-parkinsonian benefi t is obtained and might
reappear when levodopa action starts to wear off
• Movements typically consist of repetitive, reciprocal
activation of antagonist muscles of the lower limbs in
a stereotypic manner
• While the legs are “kicking”, there is tremor or other
parkinsonian features in the upper limbs and (facial)
“Off ” period dystonia
• Prolonged muscular spasms and postures present when
levodopa is not eff ective (“off ” periods)
• More commonly present in one foot in the early morning
but might be segmental or generalised and occur during
any “off ” period
www.thelancet.com/neurology Vol 8 December 2009
therapy. PD itself might be “protective” (ie, associated
with less risky behaviour) with lower rates of novelty
seeking, smoking, and alcohol use compared with the
general population, before appearance of motor
symptoms.32 ICD behaviours might be less likely before
initiation of dopaminergic medications; however, the
premorbid rates of these behavioural disorders in
patients with PD before dopamine replacement therapy
are not known.
Punding or hobbyism
Punding was fi rst described in the 1970s and is associated
with psychostimulant abuse in the general population.33
Punding is defi ned as an intense fascination with
excessive, repeated, non-goal-oriented, unproductive
repetitive behaviours that can be simple (ie, manipulating
objects or instruments or sorting of common objects) or
complex hobbyism (ie, hoarding, gardening, cleaning,
singing, writing, or computer use).12 The behaviours might
be due to the disinhibition of previously learned behaviours
as the phenomenology seems associated with individual
factors.12 For example, an accountant was reported to be
more likely to shuffl e papers, whereas housewives were
more likely to clean or clean handbags.12 The behaviours
are disruptive, excessive, and can interfere with social and
occupational function. Interruption of the behaviours
leads to irritability and dysphoria.
The reported prevalence of punding in patients with
PD ranges between 1·4% and 14%, with prevalence
associated with diff erences in case ascertainment,
medication practices, and clinic population.12,14 Factors
associated with punding include younger disease onset,
impulsivity, and higher dopamine agonist dose.12,13
Compulsive medication use
Compulsive medication use is also known as dopamine
dysregulation syndrome and has also been described as
hedonistic homoeostatic dysregulation. This behaviour is
defi ned as excessive dopaminergic medication use
associated with motor side-eff ects of LIDs and behavioural
side-eff ects of ICDs, hypomania, and psychosis.10 The
reported prevalence of compulsive medication use ranges
between 3·4% and 4%10,11 and is associated with younger
age, younger age of disease onset, higher impulsivity,
higher sensation seeking, smoking, experimental drug
use, and depressed mood.9 The actual extent of abuse in
this younger subpopulation is probably underestimated as
patients typically minimise reporting their levodopa
intake. The associated factors suggest underlying
mechanistic similarities with substance use disorders.
Psychotic symptoms such as hallucinations, illusions,
and delusions are also commonly associated with
dopaminergic medications in patients with PD and occur
in up to 40% of patients. ICDs are associated with
dopamine agonists and data from a recent study also
suggested an association of psychotic symptoms with
dopamine agonists rather than with levodopa therapy.34
ICDs do not correlate with psychotic symptoms,
suggesting diff erences in underlying pathophysiology.35
Psychotic symptoms are associated with older age,
Panel 2: Dopaminergic medication-related compulsive behaviours
Pathological gambling (DSM IV defi nition22)
A Persistent and recurrent maladaptive gambling behaviour as indicated by fi ve or more
of the following:
1 Preoccupied about gambling
2 Increasing amount of money spent
3 Repeated unsuccessful attempt to control gambling
4 Restless or irritable when reducing time spent on gambling
5 Means of escape from problems or to relieve dysphoric mood
6 Chasing losses
7 Lies to others about gambling
8 Illegal acts to fi nance gambling
9 Jeopardised relationship, work, or education
10 Relies on others for money
B Does not occur exclusively during periods of hypomania or mania
Similar to pathological gambling but is indicated by only three to four of the ten criteria
Proposed operational diagnostic criteria5
A The sexual thoughts or behaviours are excessive or an atypical change from baseline
indicated by one or more of the following:
1 Maladaptive preoccupation with sexual thoughts
2 Inappropriately or excessively requesting sex from spouse or partner
3 Habitual promiscuity
4 Compulsive masturbation
5 Use of telephone sex lines or pornography
B The behaviour must have persisted for at least 1 month
C The behaviour causes at least one or more of the following:
1 Visible distress
2 Attempts to control thoughts or behaviour unsuccessful or result in marked
anxiety or distress
3 Behaviours are time-consuming
4 Interferes substantially with social or occupational functioning
D The behaviour does not occur exclusively during periods of hypomania or mania
E If all criteria except C are fulfi lled, the disorder is subsyndromal
A Maladaptive preoccupation with buying or shopping, whether impulses or behaviour,
1 Are experienced as irresistible, intrusive, and/or senseless
2 Result in frequent buying of more than can be aff orded, items that are not needed,
or for longer periods of time than intended.
B Causes visible distress, is time-consuming, substantially interferes with social or
occupational functioning, or results in fi nancial problems
C The behaviours do not occur exclusively during periods of hypomania or mania
(Continues on next page)
www.thelancet.com/neurology Vol 8 December 2009 1143
disease duration and severity, cognitive impairment,
dementia, and sleep disorders, indicating an association
with PD pathology (reviewed elsewhere36). Data from
pathological studies have also shown an association
between psychosis, atrophy, and Lewy body deposition in
the parahippocampus, amygdala, and frontal, temporal,
and parietal cortices.37 Pronounced cholinergic defi cits
have been reported and both a serotonergic-dopaminergic
or a monoaminergic-cholinergic imbalance have been
implicated in the pathophysiology of psychotic
symptoms.36 Psychosis in PD probably implicates an
interaction between dopaminergic
(including their serotonergic eff ects) and the pathology
of PD (particularly the balance of neurotransmitter
degeneration and the extent and distribution of Lewy
body deposition), as well as possible age-related atrophic
or microvascular changes aff ecting the visual processing
system. By contrast, the available evidence of ICDs in PD
to date implicates a greater interaction between
susceptibility of an individual, aff ecting systems that are
implicated in motivation and reward. The pathology of
PD, including the role of diff erent neurotransmitters,
likely has a facilitative role in developing ICDs but the
exact mechanisms remain to be established.
and an underlying
Dopaminergic mechanisms and abnormal
The main dopaminergic projections are part of the
retrorubral fi eld (A8), nigrostriatal (A9), meso-
corticolimbic (A10), diencephalospinal (A11), and hypo-
thalamo infundibular (A12, A13, A14) systems.37 Although
dopamine cell group projections are topographically
organised, the segregation is not absolute; the motor
dorsal striatum and limbic ventral striatum receive
innervation from all three mesencephalic dopamine cell
groups.38 Furthermore, the midbrain dopaminergic
neurons are reciprocally connected in a series of ascending
spiralling loops from the ventral to the dorsal striatum.39
Thus, the anatomical organisation of the dopamine
projections can aff ect motor and behavioural systems.
Extracellular dopamine homoeostasis is maintained by
opposing regulatory mechanisms of dopamine release
and uptake. Dopamine can be released from synaptic
vesicles via exocytosis or directly from the cytoplasm
across the cell membrane to the synaptic cleft.40,41 By
contrast, the uptake mechanisms replenish dopamine
vesicular storage via the dopamine transporter across the
neuronal membrane and the vesicular monoamine
transporter across the vesicular membrane; in PD, the
vesicular monoamine transporter route is altered.42 These
processes can be directly regulated43 and also indirectly
modulated by the volume fraction or the spatial
confi guration of the extracellular space.44 Diff ering
microstriatal zones can also favour dopamine release or
uptake within the dorsal striatum, an organisational
process known as a fountain-drain matrix.45
This capacity for both rapid focal regulation and
diff usion over long distances allows dopamine to act both
as a fast, focal (nm), and short-acting (<10 ms) transmitter
(ie, a neurotransmitter) and as a slow, diff use (μm to
mm), and long-acting (>10 ms to s) transmitter (ie, a
volume transmitter).46 Theoretically, levodopa should be
able to restore the neurotransmitter action of dopamine,
and both levodopa and dopamine agonists should restore
its action as a volume transmitter. However, in the context
of severe nigrostriatal denervation, the extrasynaptic
conversion of levodopa into dopamine and the persistent
actions of dopamine agonists, dopaminergic replacement
therapy probably cannot restore both types of physiological
functions. Thus, the non-physiological stimulation of
postsynaptic receptors probably has a fundamental role
in the motor and behavioural disorders induced by
chronic dopaminergic medication in PD.
Abnormal dopaminergic stimulation leading to ICDs
The molecular mechanisms of LIDs have been extensively
discussed elsewhere.2,47,48 Here, we outline these
mechanisms to provide further insights into potential
links between LIDs and ICDs. LIDs are associated with
the pulsatile stimulation of dopamine receptors leading
(Continues from previous page)
Binge eating (DSM IV research diagnostic criteria22)
A Recurrent binge eating characterised by eating large amounts in a discrete period
along with a loss of control
B Three of more of the following:
1 Rapid eating
2 Feeling uncomfortably full
3 Eating large amounts when not hungry
4 Eating alone because of embarrassment of amounts
5 Feeling disgusted or guilty after overeating
C Visible distress
D Occurs 2 days per week for 6 months
E Does not occur with compensatory behaviours or during anorexia or bulimia nervosa
• An intense fascination with complex, excessive, repetitive, non-goal-oriented
• The behaviours include less complex acts such as shuffl ing papers, reordering bricks, or
sorting handbags, or more complex acts such as hobbyism (gardening, painting),
writing, or excessive computer use
Compulsive medication use
A Clinical diagnosis of levodopa-responsive Parkinson’s disease
B Need for increasing dopamine replacement therapy in excess of that required for
motor signs and symptoms
C Pathological use despite severe behavioural disturbances and drug-induced
D Social or occupational impairment
E Development of a dopaminergic withdrawal state with dose reduction
www.thelancet.com/neurology Vol 8 December 2009
to downstream changes in gene and protein expression.
These changes, and their interaction with abnormalities
in non-dopaminergic transmitter systems, can lead to
altered neuronal signal fi ring patterns between the basal
ganglia and the cortex.2,47,48 These molecular changes, also
known as neuronal adaptation or sensitisation, are
thought to underlie the motor sensitisation in LIDs.
The neuronal adaptations underlying LIDs can occur on
either a presynaptic or a postsynaptic level. Presynaptic
alterations of dopamine transmission after chronic
levodopa treatment have been implicated in the
development of LID and compulsive medication use. For
example, in ¹¹C-raclopride PET studies, patients with PD
and LID have greater dopamine release in the caudate
and putamen with levodopa compared with patients with
PD but without ICDs or LIDs,49 and, similarly, patients
with PD with compulsive medication use have greater
dopamine release in the ventral striatum with levodopa
than those without ICDs or LIDs.50 In the latter study, the
fi ndings suggested a link between ventral striatal
dopamine activity and the desire or incentive for levodopa
and thus support the theory of incentive sensitisation for
models of addiction.51 However, this remains to be
confi rmed through use of other neurophysiological
measures. Finally, patients with PD with punding
behaviour are more likely to have comorbid LIDs,
suggesting similar underlying mechanisms.52 A link
between LIDs and the behaviours of compulsive
medication use and punding might be more obvious
given their common association with levodopa rather
than dopamine agonists. However, although ICDs are
associated with dopamine agonists, the ICD behaviours
in patients with PD are also related to high doses of
levodopa,25 suggesting a potential sensitising or
synergistic eff ect of levodopa. Thus, presynaptic
alterations of dopamine transmission after chronic
levodopa treatment seem to occur in both LIDs and
Postsynaptic adaptations in neurotransmitter and
receptor interactions, as well as in signalling cascades,
have been detected in animal models of LIDs. Several
lines of evidence indicate that LIDs are associated with
excessive expression53,54 and sensitisation53,55 of D1
receptors in striatonigral neurons in rodent and primate
models. Levodopa (via D1 receptor stimulation) is
associated with aberrant and excessive expression of the
D3 receptor in the denervated dorsal striatum,56,57 thus
providing a potential priming role on subsequent
exposure to dopamine agonists stimulating the D3
receptor. In turn, D3 receptor stimulation maintains
aberrant membrane D1 receptor localisation,56 thus
indicating a direct eff ect of dopamine agonists in
modulating D1 receptor activity. The role of the D2
receptor should not be dismissed, as behavioural
pharmacology studies have shown that D2 receptor
stimulation can have a role in behavioural sensitisation
to levodopa in rats and non-human primates.58 Thus,
stimulation of diff erent dopamine receptors via dopamine
agonists will have specifi c eff ects on neuroadaptation.
Other neurotransmitters have also been implicated in
sensitisation other than dopamine. For example,
adenosine 2A receptor expression is increased in
D2-expressing striatopallidal neurons in patients with
PD and with LID and in experimental animal models of
LID.59 The adenosine 2A receptor has a regulatory role in
the downstream signalling of D2 and glutamate receptors
and might result in an imbalance of intracellular
signalling. Increased expression of adenosine 2A receptor
expression can also
self-administration in rats.60 Glutamate dysfunction, such
as impaired synaptic plasticity61 and alterations in striatal
receptors,62 has also been
pathophysiology, and might underlie the observation that
amantadine can be effi cacious in treating LIDs.63
occur during cocaine
implicated in LID
Abnormalities in signalling cascades have been detected
in rodent and primate models of LID and occur
particularly in D1-expressing neurons. The cAMP
signalling cascade53 and the extracellular signal-regulated
kinase (ERK) signalling pathway are activated both in
animal models of LIDs
administration.64–67 Specifi cally, increased phosphorylation
of DARPP-32 (also known as PPP1R1B) at threonine 34
occurs both in LID and after cocaine treatment in D1
neurons.65,68 Both signalling pathways are implicated in
the pathophysiology underlying substance use disorders
and learning processes,69,70 suggesting potential links
between LIDs and ICDs.
Physiologically, LIDs are further characterised by
reduced fi ring frequency, changes in fi ring patterns, and
synchronisation of the STN and globus pallidus pars
externalis.71–74 STN DBS is eff ective for both LID and for
compulsive medication use and pathological gambling in
patients with PD.75,76 Whether this eff ect is due to a
decrease in medication dose, to changes in neural fi ring
pattern, or possibly to the shift from a pulsatile to steady
state stimulation with a concomitant decrease in
sensitisation is not known. Whether neuronal adaptation
occurs in the full range of ICD behaviours, and how the
adaptations could be similar to or diff erent from LIDs on
a molecular, anatomical (ie, ventral versus dorsal), or
fi ring pattern level, remain to be investigated.
and after cocaine
Role of dopamine and the striatum in automatisms or
The phenomenology of LID, and also of punding, involves
sequences of actions from the simplest pattern (a repetitive
stereotyped movement of the lower limb as in diphasic
dyskinesias) to the most complex movements (a repetitive
www.thelancet.com/neurology Vol 8 December 2009 1145
behaviour such as ceaseless manipulation of an object).
ICDs and compulsive medication use have similarities to
substance use disorders, which are characterised by a shift
from goal-oriented behaviours towards habitual or
stimulus-response behaviours. Although several cognitive
mechanisms could be implicated in the dopamine-
associated behavioural disorders and need to be
investigated,77 we restrict this discussion to mechanisms
that might overlap with LIDs. Whereas the study of
dopamine and the striatum has historically focused on
movement control, associated behavioural and cognitive
disorders also indicate that the striatum is involved in
fundamental information processing. Next, we discuss
the role of the striatum and dopamine in sequential
actions and in habit or stimulus-response learning.
Several independent lines of evidence implicate the
neostriatum in triggering sequences of actions.
Sequential movements are disrupted in patients with
PD, as evidenced by movement slowing when undertaken
as part of a sequence.78,79 In primates, putaminal single
unit recordings detect neuronal activation before action
onset done as part of a sequence, but not when the same
actions are outside of the sequence.80 In birds, basal
ganglia lesions impair the capacity to learn new songs,
with little eff ect on previously learned behaviour.81,82
While problems in switching behaviour are often reported
in patients with PD,83 suggesting the coexistence of
learning-dependent and learning-independent functions,
most studies indicate sequence learning impairment in
PD and other movement disorders.84 Thus, basal ganglia
involvement in sequential activity might be specifi cally
associated with an important role in action learning.
Habit learning or stimulus-response associative learning
Rodent, primate, and human studies have provided
evidence that the basal ganglia, and particularly the
dorsolateral striatum, have a key role in habit learning.
Habit learning is defi ned as learning from repeated
positive reinforcement of a particular behaviour, and is a
form of stimulus-response associative learning.85,86 An
important distinction has been made between habit
learning and goal-oriented learning, which depends on
diff erent striatal regions. Goal-oriented learning is
defi ned as a behaviour that is sensitive to the value of the
reward, also known as action-outcome learning. This
learning process can be measured by observing how the
changing reward value produces an immediate
behavioural eff ect. For example, the reward value of a
particular food can be reduced by satiation, resulting in
cessation of goal-oriented behaviour rewarded by that
particular food. By contrast, a habit is not immediately
sensitive to such a change (eg, satiation), and habits
persist after the outcome has become unrewarding.
However, the reduced reward value would gradually lead
to extinction. Repeated training normally leads to
progression from goal-oriented action to habit.87,88 This
aspect of habit learning is particularly relevant to ICDs,
in which behaviour that might once have led to reward
continues despite negative consequences.
The neural circuits underlying habit and action-outcome
learning are beginning to be elucidated. Early studies
that used large striatal lesions established the importance
of the striatum in learning.89–91 In rats, dorsal striatal
lesions impair acquisition of tasks requiring the
development of a habitual response92 and lesions of the
ventral striatum impair approach to rewarding stimuli.93,94
Smaller lesions, together with modern behavioural
techniques, have identifi ed regional specialisation of
learning functions within the striatum. Progression from
goal-oriented to habitual responding is disrupted by
dorsolateral striatal lesions.95,96 Rather than progressing
to habits, animals with lesions in the striatum remained
sensitive to reward devaluation throughout their training.
By contrast, progression to habitual responding occurs
normally with dorsomedial striatal lesions. Such evidence
suggests that the dorsolateral striatum, but not the
dorsomedial striatum, is implicated in the stimulus-
response associations thought to underlie habitual
responding. Furthermore, dopamine innervation of the
dorsolateral striatum is absolutely required for habit
formation in instrumental conditioning.97
Behavioural measures in human beings with neuro-
degenerative diseases of the basal ganglia also show that
these diseases are associated with defi cits in such learning
processes.98,99 Electro physiological recording studies in
primates and rats are consistent with a role of the striatum
and other basal ganglia structures such as the STN in
these processes, by indicating reward-related activity at
the cellular level100–104 and changes in single unit responses
during acquisition of habits.105 The cellular mechanism
underlying habit formation probably involves dopamine-
dependent plasticity of corticostriatal synapses106 brought
about by phasic release of dopamine.107
Habit formation is also frequently referred to in the
context of addiction, typically considered a dopamine-
mediated dysregulated behaviour. There is indeed a
development of habits in drug-seeking behaviour.
Although the dopamine system has a crucial role in this
behaviour via the ventral striatum, the dorsal striatum
plays a key role at the stage of habit formation.108 This
dopamine-mediated behaviour is also modulated by the
control of the STN, as experimental subthalamotomy can
reduce motivation for drugs of abuse such as cocaine,
while increasing motivation for food,109 and STN DBS
can reduce compulsive medication use and pathological
gambling in patients with PD.75,76 However, this STN DBS
eff ect might not necessarily be a direct eff ect, as patients
receive substantially less medication after surgery.
Interpretations regarding the mechanism of the eff ects
of STN DBS on ICDs are diffi cult because of concomitant
changes in medications, the fact that STN DBS can also
be associated with greater impulsivity under high confl ict
www.thelancet.com/neurology Vol 8 December 2009
conditions,110 and that the precise mechanism of action of
high frequency stimulation is not well defi ned.
Conclusions: are behavioural and motor
disorders in PD part of the same continuum?
The basal ganglia forms a complex network that is
involved in the selection and facilitation or the inhibition
of movements, acts, and emotions.111 This integrated view
leads to the natural speculation that the pathological
consequences of dopamine dysfunction might involve
unwanted movements, acts, and emotions. We suggest
that the involuntary movements of LIDs and behavioural
disorders of ICDs, punding, and compulsive medication
use are part of a continuum and are the motor, cognitive,
and emotional pathological expressions mediated by
intrinsically similar physiological mechanism acting
through diff erent basal ganglia channels or subregions.
For example, LID, while clearly a motor manifestation,
can involve limbic domains of the basal ganglia.112
Characteristically, LIDs are often described as being
triggered or enhanced in patients with PD by emotional
factors such as stress, talking in public, or when eating.
Thus, LID, rather than a simple medication-related motor
manifestation, might also involve a cognitive and limbic
Several unanswered questions remain. For example,
what diff erentiates the patients that develop ICDs from
those patients that do not develop ICDs even if they
receive the same medication? Although we are starting to
understand the clinical features associated with ICDs,
this question remains unanswered at the level of neuronal
function. Furthermore, why do diff erent patients develop
diff ering behaviours? Is this associated with individual
susceptibilities (ie, either diff erences in environmental,
cultural, or learned factors or genetic or biological factors)
or with the disease process? Pre-set or learned neural
representations of behavioural patterns might be
disinhibited in the context of dopaminergic medications.
ICDs seem more likely to be associated with various
premorbid or external factors that are less relevant to
LIDs. However, on neuroanatomical grounds, we suggest
that the diff erent behavioural expressions and the
individual susceptibilities might also indicate diff erences
in striatal denervation patterns of dopamine neuronal cell
loss,113,114 which might diff erentially aff ect movement,
behaviours, and personality traits. The preferred motor or
behavioural outcome might thus be predicted by the
PD-related denervation pattern of the fountain-matrix
organisation of the striatum or by diff erences in premorbid
striatal functioning. Thus, what may seem as an individual
susceptibility to ICDs (eg, the association with smoking
or a family history of gambling) could also refl ect
underlying diff erences in basal ganglia functioning.
Several questions also remain regarding the association
between LIDs and ICDs. The association with young age,
high levodopa dose, and the improvement seen with STN
DBS suggests potential similarities between the disorders.
Punding seems to be associated with LIDs, but an
association between LIDs and ICDs remains to be
established. Similarly, greater ventral striatal dopamine
release of levodopa in compulsive medication use has
been suggested to potentially refl ect the eff ects of neuro-
adaptation. However, whether neuroadaptation does
indeed occur for the range of ICD behaviours, and if this
is similar to or diff erent from LIDs on a neuroanatomical
(eg, ventral versus dorsal) or molecular basis remains to
As discussed above, why do only some patients exposed
to the same medication present with ICDs and why do
they have diff erent behavioural presentations? What is
the association with ICDs, LIDs, and substance use
disorders in the general population? What are the
clinical, cognitive, and neurophysiological correlates?
Which of these correlates are state-related (ie, medication
eff ect or related to the presence of the ICD),
sensitisation-related (chronic medication exposure), or
trait-related (premorbid diathesis). What is the role of
the neurodegeneration and compensation associated
with PD given that these symptoms also present in
patients treated with dopaminergic agents in disorders
such as restless legs syndrome? As exogenous
medications aff ect several brain regions beyond that of
the striatum, what is the role of other neural regions
such as the prefrontal or orbitofrontal cortex, amygdala,
or insula and of other neurotransmitters? What are the
clinical risk factors that might allow screening of patients
at high risk for the development of these disorders?
Currently, selection of movements, actions, and
behaviours is seen as a fundamental and primary function
of the basal ganglia. We have emphasised here that both
involuntary movements and abnormal behaviour in
patients with PD might represent part of a pathological
continuum secondary to abnormal dopaminergic stim-
ulation. We believe that understanding the common
factors in addition to the diff erences between LIDs and
ICDs on a molecular, cognitive, and neurophysiologic
level might provide insights into basic mechanisms
underlying not only these disorders but also motor and
behavioural functioning. These apparently disparate
motor and behavioural symptoms might be the resulting
features of dopamine interacting with individual pre-
morbid susceptibilities (which might be genetic or
biological factors or environmental or learned factors)
and individual or PD-related diff erences in striatal
Search strategy and selection criteria
References for this Review were identified through searches of
PubMed with the terms “dopamine”, “parkinson”, “dyskinesia”,
“compulsive”, “behaviour”, and “addiction” from 1966 until
March, 2009. Articles were also identified through searches of
the authors’ own files. Only papers in English were reviewed.
www.thelancet.com/neurology Vol 8 December 2009 1147
All authors contributed equally to this Review.
Conflicts of interest
EB is a shareholder of Motac Holdings and Chief Scientifi c Offi cer of
Motac Neuroscience. Motac is a contract research organisation that tests
therapeutic strategies for cognitive (eg, mild cognitive impairment and
Alzheimer’s disease) and movement (eg, Parkinson’s disease and
levodopa-induced dyskinesia) disorders. All other authors have no
confl icts of interest.
The content of this Review is derived from a meeting (The Role Of
The Basal Ganglia In Movement, Behavior And Emotions) held in
December, 2008, at the Centro Internacional de Restauración
Neurológica (CIREN) in Havana, Cuba. The meeting was supported
by the CIREN and the Neuroscience Department, CIMA, Unviersity
of Navarra, Pamplona, Spain, and sponsored by charitable donations.
Authors are grateful to Julian Alvarez (president of CIREN) for his
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