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Brain Research Reviews
Review
Pathophysiological basis of drug-induced
dyskinesias in Parkinson’s disease
Milind Deogaonkar*, Thyagarajan Subramanian
Departments of Neuroscience and Neurology, NB 20, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
Accepted 13 May 2005
Available online 18 July 2005
Abstract
Drug-induced dyskinesias (DID) represent a troublesome, dose-limiting, and common complication of long-term pharmacotherapy in
Parkinson’s disease (PD) patients. The pathophysiological basis and clinical nature of DID is of major interest for clinicians and
neuroscientists. In this review article, we evaluate the theories of pathophysiology and molecular basis of DID, validity of various animal
models used in DID related research, and electrophysiological characteristics of various basal ganglia nuclei during DID. We also discuss the
relevance of various treatment strategies to the pathophysiological mechanisms.
D 2005 Elsevier B.V. All rights reserved.
Theme: Disorders of the nervous system
Topic: Degenerative disease: Parkinson’s
Keywords: Levodopa; Dyskinesia; Parkinson’s disease; Basal ganglia; MPTP
Contents
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1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Animal models of DID . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Pathophysiology of DID . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Electrophysiological correlates of DID . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Molecular basis of dyskinesias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1. DA receptors (DAR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2. g-Aminobutyric acid (GABA) receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3. Glutamate and N-methyl-d-asparatate (NMDA) receptors . . . . . . . . . . . . . . . . . . . . . . . . .
5.4. Role of neuropeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5. Fos-related antigens (FRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6. Adenosine A2A receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. Pharmacokinetics of levodopa and DID . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. Relevance of pathophysiology for treatment strategies of DID. . . . . . . . . . . . . . . . . . . . . . . . . . .
8. Surgical treatment of DID . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9. Future strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . 164References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
0165-0173/$ - s
doi:10.1016/j.br
* Correspondi
E-mail addr
50 (2005) 156 – 168
ee front matter D 2005 Elsevier B.V. All rights reserved.
ainresrev.2005.05.005
ng author. Fax: +1 216 445 1466.
ess: [email protected] (M. Deogaonkar).
M. Deogaonkar, T. Subramanian / Brain Research Reviews 50 (2005) 156–168 157
1. Introduction
Parkinson’s disease (PD) is a common neurodegener-
ative disorder that affects the basal ganglia and is
characterized by the triad of symptoms; bradykinesia
(slowness of movement), rigidity (stiffness), and tremor.
Oral antiparkinsonian medications control these symptoms
adequately for a prolonged period of time. Levodopa and
synthetic dopamine agonists are the mainstay of pharma-
cological therapy for PD. However, chronic intermittent
therapy with levodopa and dopamine agonists are both
associated with the development of involuntary move-
ments called drug-induced dyskinesias (DID). DID are
defined as abnormal, excessive, and involuntary move-
ments associated with longer duration of dopaminergic
therapy in PD patients. Several groups have studied the
prevalence of DID. Duvoisin in 1974 reported that, after 6
months of dopaminergic therapy, 53% of patients devel-
oped DID, which increased to 81% after 12 months of
continued dopaminergic therapy in PD patients [46]. A
more recent study by the Parkinson Study Group reported
a figure of 20 to 30% after a mean dopaminergic
(levodopa) therapy for 20.5 months [115]. As the duration
of dopaminergic treatment increases to a mean of 6 years,
over two-thirds of patients will develop DID [34,35,
90,120]. Nearly all young-onset PD patients were reported
to develop DID within 5 years of initiating dopaminergic
treatment [81]. These dyskinesias are not only a major
source of disability and anxiety to the patients but they
also act as a dose-limiting factor thereby preventing
satisfactory control of parkinsonism. Cotzias and col-
leagues were first to identify DID in 1969 and noted that
they occur late in the course of treatment and subside after
lowering the dose of dopaminergic medications [40]. In
the same year, Yahr and colleagues noted DID in 37 of
their 60 PD patients on levodopa therapy [147]. Despite
being identified as the most common dose-limiting
problem of levodopa therapy, there are a lot of con-
troversies about cause, prevention, and treatment of DID.
There are diverse opinions about etiopathology, molecular
mechanisms and relevance of various animal models of
DID. The purpose of this review is to evaluate animal
models used in DID research and discuss various
pathophysiological theories for DID.
Table 1
Different animal models used in Parkinson’s research classified according to spec
Animal models of PD Stable disease
Early PD Advanced P
Rat models 6-OHDA striatal lesioning 1. 6-OHDA
2. Dual (MF
Primate models Unilateral intra-carotid MPTP 1. Systemic
2. Bilateral
2. Animal models of DID
The development of animal models of Parkinson’s
disease is of great importance in order to test medical, cell
transplantation, surgical, or neuroprotective strategies for
Parkinson’s disease. Such models should mimic the main
pathological characteristics of the disease, such as a
selective and progressive lesion of dopaminergic neurons
in substantia nigra compacta. However, not all animal
models available today, mimic the progressive nature of the
disease (Table 1). The model that has been used the most is
the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
monkey model of bilateral parkinsonism. MPTP-induced
parkinsonism has been demonstrated in M. mulatta,
Macaca fascicularis, Saimiri sciurea, and the marmoset.
This model has been extensively used to evaluate several
medications that have preventative and ameliorative effects
on dyskinesias [17,61] and a very well validated rating scale
exists for evaluating these DID [22,71]. MPTP monkey
model could be either unilateral or bilateral depending on
the route of administration of the toxin. Systemic MPTP
administration produces bilateral nigro-striatal loss creating
a model of advanced parkinsonism while the intra-carotid
administration of MPTP creates hemiparkinsonian monkeys
who resemble early parkinsonism. DID can be induced in
these models with levodopa administration. In monkey
models, the extent of nigro-striatal damage needed to
produce DID differs according to various researchers. Some
groups have clearly demonstrated that even normal M.
fascicularis monkeys develop DID with chronic levodopa
administration [119,148] and squirrel monkeys develop
DID with minimal nigro-striatal degeneration [45]. The
reason for these differences is different primate species
probably have different thresholds of behavioral sensitiza-
tion to levodopa. Recently, a progressive over-lesioned
primate model of PD in the Rhesus monkey has been
described [105] in which the intra-carotid injections of
MPTP initiates the parkinsonian syndrome primarily in one
hemisphere and the subsequent intravenous doses further
produces an asymmetric bilateral lesion with fewer side
effects and such animals exhibit DID. The nonhuman
primate MPTP model of Parkinson’s disease has been
highly predictive of clinical effectiveness of anti-dyskinetic
properties of various pharmacological agents.
ies, stage of disease, and progression
Progressive disease
D
MFB lesioning Rotenone osmotic pump infusion model
B and striatal) lesioning
MPTP Overlesioned model
intra-carotid MPTP Stage 1: Unilateral intra-carotid MPTP
Stage 2: Systemic MPTP in small doses
Fig. 1. Changes in the basal ganglia resulting in parkinsonian syndrome.
GPi and SNr become overactive causing thalamic and cortical inhibition
leading to akinesia. Red arrows in the picture suggest inhibitory control and
green arrows indicate excitatory effect.
M. Deogaonkar, T. Subramanian / Brain Research Reviews 50 (2005) 156–168158
The rat model for DID was described by Cenci et al.
[30,31,145] in the 6-hydroxydopamine (6-OHDA)-lesioned
animals and has been used to investigate the effects of fetal
ventral mesencephalon (FVM) transplantation [134]. DID
exhibited by 6-OHDA-lesioned rats after giving dopami-
nergic medications consist of frequent grooming, stereotypic
oro-facial chewing and grimacing and vigorous shaking of
the affected forepaw when the animal is ‘‘cornered’’ in the
test cage. While these movements may represent the
equivalent movements to dyskinesias in the PD patient,
the phenomenology appears to be substantially different in
the human that are characterized by chorea, athetosis, and
dystonia [77,141]. The dyskinetic movements exhibited by
the MPTP-treated monkey are substantially similar to that
exhibited by PD patients and are characterized by choreo-
form movements of the limbs and occasional dystonic
posturing [13,112,113,131]. Furthermore, the levodopa-
dosing pattern in these rats does not represent the clinical
scenario. In spite of these objections, it is a very useful and
valuable model of DID. A recent 6-OHDA-lesioned mouse
model of DID has also been described [76]. The site of
nigro-striatal lesioning in this model and the range of
abnormal involuntary movements are similar to that of rat
model. The preclinical research carried out using the rodent
or primate models mainly aims at understanding patho-
physiology of DID, the molecular mechanisms involved,
and to test pharmacological therapies for DID.
Fig. 2. Pathophysiological theories of DID: It is suggested that an excessive
decrease in GPi activity due to levodopa therapy (bold black arrow)
disinhibits the motor thalamus and the cortex, giving rise to abnormal
increase in cortical drive and consequent excessive motor movements.
Others suggest abnormal parallel pattern of discharges received by GPe–
STN–GPi circuits (A) resulting into similar abnormal pattern translating in
the thalamo-cortical projections (B) resulting in the dyskinesias. It is also
suggested that increased enkephalinergic activity in striatum possibly due to
increased activity in the cortico-striatal projections (C) may be responsible
for DID [26,101].
3. Pathophysiology of DID
The functional models of basal ganglia have predicted
that, during DID, there is abnormally low activity in all the
output nuclei and some animal studies suggest that such
reduction in neuronal activity does occur in at least the globus
pallidus internus (GPi) [113]. In the parkinsonian state with
denervation of the nigro-striatal dopaminergic pathway, the
gamma-aminobutyric acid (GABA)-ergic striatal inputs
make external segment of globus pallidus (GPe) hypoactive.
This causes disinhibition of sub-thalamic nucleus (STN) due
to reduced GABAergic inputs from GPe to STN. STN
overactivity results in excessive excitatory inputs through the
glutamatergic projection to internal segment of globus
pallidus (GPi) and substantia nigra pars reticularis (SNr)
causing GPi and SNr overactivity. At the same time, there is
reduced activation of the D1 receptor bearing striatal neurons
acting through the direct pathway on GPi, thereby reducing
the inhibition of GPi and SNr and adding to the hyperactivity
at these output nuclei induced by STN [101,102]. Hyper-
activity of GPi and SNr leads to excessive inhibition of motor
cortex and thalamus causing akinesia and other parkinsonian
features (Fig. 1). Levodopa therapy is hypothesized to
normalize the GPi activity by altering the changes in both
direct and indirect striatal output pathways. Thus, the
antiparkinsonian effects of levodopa and other dopamine
replacement therapies may be mediated via the reduction in
overactivity that exists in GPi. The current functional models
of DID suggest that excessive decrease in GPi activity in turn
disinhibits the motor thalamus and the cortex, giving rise to
abnormal increase in cortical drive and consequent excessive
motor movements [113,143,144] (Fig. 2). Excessive reduc-
tion in the output from the main output nuclei like GPi and
SNr should be able to explain the overactivity of thalamo-
cortical projections leading to DID. In keeping with this
hypothesis, lesioning of STN has shown to produce
dyskinesia in parkinsonian primates [11,53]. But there are
problems with this hypothesis as a selective lesion of GPi
dramatically improves the dyskinesias [4,5,74] and lesioning
of GPe aggravates rather than abolishes the dyskinesias.
These and other similar inconsistencies in this model of DID
have led others to postulate alternative models. Obeso and
M. Deogaonkar, T. Subramanian / Brain Research Reviews 50 (2005) 156–168 159
colleagues [101] proposed a functional model where they
suggest abnormal pattern of discharges received by GPe–
STN–GPi circuits resulting into similar abnormal pattern
translating in the thalamo-cortical projections resulting in the
dyskinesias. The model also suggests relative hyperactivity at
GPe, STN, and increased enkephalinergic activity in striatum
possibly due to increased activity in the cortico-striatal
projections (Fig. 2). Various studies that evaluate the effect of
levodopa and other dopamine agonists on basal ganglia
nuclei in humans and animal models have suggested that GPi
firing rate reduces [113], GPe firing rate increases [75], STN
activity reduces [43,75], and SN activity also reduces
[43,93]. These changes in basal ganglia circuitry may be
reflected in the electrophysiological correlates of DID.
Fig. 3. Theories of molecular basis of DID: In this functional model of basal
ganglia with DID, various receptors are shown in yellow (DAR—DA
receptors, NMDAR—NMDA receptors, adenosine A2A receptors, and
GABA receptors), and neuropeptides that affect the striato-nigral outflow
are shown in gray (dynorphin, enkephalin, PPE, substance P).
4. Electrophysiological correlates of DID
Most of the present electrophysiological studies of DID
are linked to an excessive decrease in activity at the GPi. In a
study by Filion et al. [48], mixed (D1 and D2) dopamine
agonist apomorphine was injected in MPTP monkeys. They
showed all GPi neurons decreased their firing rate following
apomorphine. The reverse was true of the predominant
neuronal population in the GPe. A similar study by Boraud et
al. [19] supports the correlation between dyskinesia and an
excessive decrease in the firing frequency of GPi neurons. A
similar excessive decrease was reported by Papa and
colleagues [113] in MPTP-treated monkeys treated with
levodopa. This study showed that during dyskinesias, the
firing rates declined profoundly in almost all cells of GPi,
with decrease as low as 97% in individual cells. Lozano and
colleagues [75] in parkinsonian patients treated with
apomorphine found that dopaminergic agents act by decreas-
ing GPi and STN activity, and increasing GPe activity, and
that DID results from a large reduction in GPi firing. A
change in the firing pattern of neurons from bursting to
random pattern has also been implicated in the genesis of
dyskinesia [100]. We studied the effect of levodopa on the
firing rate and firing patterns of STN and SNr neurons in
MPTP-treated parkinsonian monkeys. We found that levo-
dopa induced a significant reduction of the mean firing rates
of STN neurons (P = 0.0011) and of SNr neurons (P =
0.0002), but did not induce a significant change in firing
patterns [43]. These unmitigated pattern abnormalities may
contribute to development of DID and other motor fluctua-
tions. There is also some interest in the pallidal Fborder cell_as the peri-pallidal dopaminergic innervations remain
unaffected in the parkinsonian state [12]. The firing rate in
these cells is restored with levodopa therapy without
restoration of firing pattern. In a recent study that recorded
local field potentials (LFP) from STN using an externalized
deep brain stimulator (DBS) electrode, a desynchronizing
effect of levodopa was noticed on two separate rhythms of
STN [122]. The oscillatory activity increased at low
frequency (2–7 Hz range), while the beta oscillations
significantly decreased in low-beta range. Similar effects
were observed with apomorphine [122]. Since STN is a
rhythm-generating center in this neuronal circuitry, imbal-
ance of multiple rhythm systems could lead to DID. The only
proven electrophysiological signature of DID at present is
the excessive decrease in GPi activity [48,113]. This
decrease in GPi activity is further pronounced in patients
with diaphasic dyskinesia almost mimicking a Fchemical
pallidotomy_ and peak dose dyskinesias are replaced by DIDoccurring before and after the peak dose is reached [75].
Further studies on the electrophysiology of DID must take
into account the present results, especially those regarding
firing patterns, and explore the finer aspects of discharge
characteristics like the multiple rhythms, oscillations, and
synchronization in various regions of basal ganglia circuitry.
These neuronal circuitry changes are basically a reflection of
multiple changes taking place at the molecular level.
5. Molecular basis of dyskinesias
The clinical course of DID, their appearance and severity,
varies extensively. The difficulty in treating DID is com-
pounded by a variety of hypotheses delineating the molecular
and biochemical alterations responsible for them. The most
accepted hypothesis is nigro-striatal denervation, coupled
with non-physiological dopaminergic stimulation, leads to
persistent changes in basal ganglia eliciting dyskinesia.
However, further studies have shown that things are not so
simple. There are a variety of neurochemical and molecular
factors responsible for DID (Fig. 3). We will try to review the
main arguments associated with each of the hypotheses.
5.1. DA receptors (DAR)
Dopamine receptors in basal ganglia have been exten-
sively studied in pathogenesis of PD as well as DID.
Denervation super-sensitivity of DAR has been blamed for
M. Deogaonkar, T. Subramanian / Brain Research Reviews 50 (2005) 156–168160
the appearance of DID. There are five subtypes of DAR
located in various structures of the basal ganglia. D1
receptors are mainly located in the striatum, D2 in the striatal
spiny neurons, D3 in nucleus accumbens, D4 on medium
spiny neurons, and D5 on the striato-pallidal neurons and
nigral neurons. D1 and D2 receptors both play a major role in
mediating the antiparkinsonian effects of dopamine agonists.
The induction of D2 receptors in PD is confirmed by
increased D2 DAR-binding sites in the striatum of parkinso-
nian patients [72] and MPTP-treated primates [1]. All
available dopamine agonists act in part through D2 receptors.
The messenger ribonucleic acid (mRNA) expression specific
for D2 receptor is high in untreated parkinsonian monkeys
but is reported to come back to normal after chronic levodopa
therapy [88]. Similarly, an increase in the striatal D2 receptor
protein induced by denervation normalizes after levodopa
therapy [25,72]. Drugs acting through D2 receptors have less
potential to induce DID. D1 subtype of DAR on the other
hand, do not show any specific up- or down-regulation in
either PD patients or primate models. However, there is some
evidence of interactions between D1 and D2 output system
reflected in the D1 and D2 mRNA concentrations. There are
also couplings between the D1 and D2 receptors at the sub-
cellular level that may account for the altered responses in the
striatal output neurons. DAR denervation super-sensitivity
leading to DID could also be a result of their coupling with
the G-proteins. Marcotte and colleagues [78] have shown
increased levels of the alpha-subunits of Gs and Golf in
parkinsonian rats. Another sub-group of DAR, D3 receptors
have also been implicated in the pathogenesis of DID. A
study by Bordet and colleagues [20] has shown that
development of dyskinesia due to levodopa therapy is
accompanied by a progressive increase in the D3 receptor
mRNA and binding sites in the denervated caudate and
putamen from which this receptor subtype is normally
absent. They argue that the enhanced behavioral response
to levodopa is mediated by the newly synthesized D3
receptor, sustained enhancement of prodynorphin mRNA
level, and a progressively decreasing expression of the
preprotachykinin gene. They propose that imbalance
between dynorphin and substance P release from the same
striato-nigral motor efferent pathway, related to D3 receptor
induction, is responsible for DID. The role of D3 receptors is
being studied more extensively as newer D3 receptor specific
agonists are being developed as neuroprotective agents. The
exact role of D4 and D5 receptors is not known both in
pathogenesis and treatment of PD.
5.2. c-Aminobutyric acid (GABA) receptors
GABA neurotransmission is widely seen in the basal
ganglia. Though these GABA-secreting interneurons are not
primarily affected as a part of disease process in PD, there
are changes in GABA receptors seen as a consequence of
dopamine depletion. GABA up- or down-regulation is seen
in PD and other motor disorders like tardive dyskinesias
(TD). GABA receptors are also suspected to play a role in
the development of DID. Chronic intermittent dopaminergic
therapy causing pulsatile dopaminergic stimulation is shown
to cause up-regulation of GABA receptors. In a study in
MPTP monkeys, DID were associated with up-regulation in
GABA receptor sites in GPi, while those monkeys that
failed to show any dyskinesia did not show any elevation in
GABA receptor sites [24]. Calon and colleagues [23] have
shown increased GABA(A) receptors content in the GPi in
dyskinetic parkinsonian patients compared to nondyskinetic
patients in postmortem samples. In a recent study [149],
high doses of modafinil was shown to reduce the GABA
receptor binding sites in GPi and partially reverse parkinso-
nian symptoms.
5.3. Glutamate and N-methyl-D-asparatate (NMDA)
receptors
Glutamate is the main excitatory neurotransmitter in the
basal ganglia circuitry. All three glutamate receptor subtypes
(NMDA, AMPA-kainate, and metabotropic) are found on
dopaminergic neurons. Glutamatergic neurotransmission in
the STN-GPi pathway is thought to be overactive following
dopaminergic denervation. NMDA receptors are seen in
many basal ganglia structures like STN, SN, GP, but are
mainly located in the striatum. NMDA receptor binding was
shown to be increased by 53% in the putamen of PD
patients with motor fluctuation when compared to those
without [27]. Papa and colleagues [111] have shown in
MPTP monkeys, systemic administration of competitive
nonselective NMDA antagonist abolished oral dyskinesias
and diminished choreic dyskinesias by 68% and did not
reduce the antiparkinsonian response to levodopa. Their
findings suggest that NMDA receptor blockade may
ameliorate the dyskinetic complications of long-term levo-
dopa therapy, without diminishing the beneficial effects of
levodopa therapy on parkinsonian signs. A similar effect has
been shown with the use of NR1A/NR2B-selective NMDA
receptor antagonists [15,52]. In a double-blind, placebo-
controlled, cross-over study, NMDA antagonist was given
to six PD patients with motor fluctuations; average and
maximum dyskinesia scores improved by >50% without
compromising the antiparkinsonian response magnitude or
duration of levodopa in these patients [140]. These findings
support the view that drugs acting to inhibit glutamatergic
transmission at the NMDA receptors can ameliorate
levodopa-associated dyskinesias and strongly implicate
these receptors in the pathogenesis of DID. The role of
AMPA receptors in DID is more controversial. Though a
study has shown increased AMPA receptor binding (+23%)
in lateral putamen of PD patients [27], another study claims
that AMPA receptor binding is unaltered in parkinsonian
and dyskinetic primates [133]. AMPA receptor blockade has
shown to prevent DID in a primate study [67]. Metabo-
trophic glutamate receptors (groups I and II) are currently
being evaluated as a target for antiparkinsonian drug therapy
M. Deogaonkar, T. Subramanian / Brain Research Reviews 50 (2005) 156–168 161
[21,98], but they do not seem to have a role in pathogenesis
of DID.
5.4. Role of neuropeptides
Various neuropeptides like dynorphin, enkephalins, pre-
porenkephalins, and substance P play an important role in the
striatal output pathways. The role of these neuropeptides in
PD and in pathogenesis of DID remains controversial.
Though initial studies documented a down-regulation of
striatal neuropeptides in experimental animals with hyper-
locomotion [146] and PD patients [42,47], an increase in
these neuropeptide levels has been demonstrated in striatum
of dyskinetic rats [30,50] which could be secondary to an up-
regulation of striatal fosB expression [2,29]. Henry and
colleagues [54] also suggest that the synthesis of opioid
peptides enkephalin and dynorphin appears to be enhanced
in neurons projecting to the pallidum in parkinsonian
animals following repeated treatment with dopamine-replac-
ing agents that also cause dyskinesia. In contrast, dopamine
receptor agonists such as bromocriptine that are not known
to cause dyskinesia do not elevate peptide synthesis. Calon
and colleagues have also studied the role of preporenkepha-
lin expression in the pathogenesis of DID [26]. They studied
the expression of preproenkephalin messenger RNA in the
brain of PD patients treated with levodopa. A significant
increase of preproenkephalin messenger RNA levels was
observed in the putamen of dyskinetic patients in comparison
to controls and nondyskinetic patients. These findings
suggest that increased synthesis of preproenkephalin in the
medium spiny output neurons of the striato-pallidal pathway
plays a role in the development of dyskinesias following
long-term levodopa therapy in PD. On the other hand, a
study in squirrel monkeys questions the role of striatal
preproenkephalin in the pathogenesis of DID [123].
5.5. Fos-related antigens (FRA)
FRA are induced in brain regions in response to chronic
stimulation. Different isoforms of FRA are formed by
differing stimuli. These isoforms are specific to the target
genes and relate to the degree of expression of immediate
early genes (IEG). In parkinsonian rats, DFosB and its
isoforms are induced as shown by Vallone and colleagues
[139]. These induced FRAs form diamers called AP-1
complexes and can affect genes bearing AP-1 sites that
regulate neurotransmitters or modulate receptors like DAR,
NMDA receptors, and neuropeptides. These modulations
trigger changes in GABAergic and glutamatergic trans-
missions responsible for abnormal motor responses like
DID [25].
5.6. Adenosine A2A receptors
Brain adenosine A2A receptors have recently attracted
considerable attention because of their interaction with the
dopaminergic system and as potential targets for PD
pharmacotherapy. Adenosine A2A receptors are G-protein-
coupled receptors involved in motor control and located in
various structures in the basal ganglia. These receptors are
up-regulated in parkinsonian rats and patients with DID
[28,38,137]. Calon and colleagues [28] studied adenosine
A2A receptor mRNA and binding sites for adenosine A2A
receptor in the brain of PD patients with and without DID.
They found that, in patients with DID, A2A receptor mRNA
levels were significantly increased in the putamen compared
with controls. A2A receptor specific binding was also
significantly increased in the GPe of PD patients. These
findings suggest that increased synthesis of adenosine A2A
receptors in the striato-pallidal pathway neurons is associated
with the development of dyskinesias following long-term
levodopa therapy in PD. In a recent study, enhancement of the
striatal adenosine A2A was shown in 6-OHDA-lesioned
hemiparkinsonian rats showing behavioral sensitization to
levodopa [137]. Adenosine A2A antagonists have since been
tried as a therapy for levodopa-induced motor complications
in PD including DID [36,39,60,62,108].
6. Pharmacokinetics of levodopa and DID
A basic requirement for appearance of DID is presumed to
be nigro-striatal degeneration. Normal individuals or patients
with other neurological diseases on levodopa are reported not
to develop DID [32]. Repeated dosing of levodopa in PD
leads to concurrent D1 and D2 receptor stimulation and
induces DID. Repeated dosing of levodopa is essential for
emergence of dyskinesias in PD. This pulsatile stimulation
due to the repeated dosing causes sensitization. Number of
drug doses, size of the dose, and interval between the two
doses are important determinants of this levodopa sensitiza-
tion. The time duration necessary for this sensitization to
occur decides the time of appearance of DID. Many studies
have documented that DID emerged after weeks or months of
initiation of treatment with levodopa. A large, prospective
multicentric study has shown that DID are relatively
uncommon in the first year of treatment with levodopa
[18]. Therapeutic benefits from levodopa and appearance of
DID generally have a similar time course making it difficult
to adjust the dosing schedule. Since the early reports of DID,
it has been agreed that DID are most prominent in patients
who have good clinical responses to levodopa therapy [40].
Dyskinetic dose response to levodopa appears to be an all-or-
nothing response, with amaximum effect that is not increased
by a further increment in dose [94]. Larger doses of levodopa
induce dyskinesias which are present for longer period of
time, just as the antiparkinsonian response [95]. Nutt and
colleagues [96] have correlated appearance of DID to the
response to long-term levodopa therapy. Dyskinesia
appeared at comparatively similar points of time in patients
with stable responses and those with fluctuating responses to
levodopa. The plasma half-life clearance, volume of distri-
Table 2
Preventive and treatment strategies of DID based on the theories of
pathogenesis
Theories of pathogenesis of DID Mode of treatment
Pulsatile stimulation of
dopamine receptors
1. Delaying the need of levodopa
2. Using slow release formulations
of levodopa
3. Using longer acting dopamine
M. Deogaonkar, T. Subramanian / Brain Research Reviews 50 (2005) 156–168162
bution, and maximum plasma concentrations of levodopa did
not differ between both these groups. They further suggest
that a larger long-duration response, rather than a shortened
one, is more important to the development of fluctuations.
Improving the baseline or practically defined off-motor
function to reduce the magnitude of the short-duration
response may be a strategy to treat fluctuations [97].
agonists like bromocriptine
Progressive nigro-striatal
degeneration
Neuroprotective agents like selegiline
D2/D3 receptors 1. Ropinirole
2. Pramipexole
3. Terguride
NMDA receptors 1. Amantadine
2. Dextromethorphan
5HT receptors 1. Ritanserin
2. Mirtazapin
3. Risperidone
Other receptors 1. Alpha 2 antagonists
2. Opioid receptor antagonist
3. Levitiracetam
4. Adenosine A2A receptor antagonists
GPi inhibition Pallidotomy
Thalamic hyperactivity VoA, VoP thalamotomy
STN inhibition 1. Subthalamotomy
2. STN stimulation
7. Relevance of pathophysiology for treatment strategies
of DID
The discussion in the preceding sections points to pulsatile
stimulation being the most important causative factor for
DID. Pulsatile stimulation is essentially dependent on the
half-life of dopaminergic agents used. DID can be potentially
prevented by providing dopaminergic stimulation in a more
continuous fashion by using dopamine agonists that have a
longer half-life than regular formulations of levodopa.
Levodopa has a half-life of 60 to 90 min and has been shown
to induce DID in MPTP monkeys more frequently than
dopamine agonist with longer half-life like bromocriptine
(half-life 6 to 12 h) [7]. Improvement in the dyskinesias has
been recorded when dopaminergic drugs were administered
by continuous intravenous infusion [91]. A second important
factor that governs the occurrence of DID is the extent of
striato-nigral degeneration. In the later stages of disease due
to extensive nigral neuronal depletion, there are fewer striatal
dopaminergic terminals. This leads to insufficient storage of
dopamine to buffer fluctuations in plasma levodopa which
fails to prevent striatal dopamine receptors being exposed to
fluctuations in levodopa concentration. Plasma levodopa
concentration can influence the striatal dopamine concen-
tration and bring about the pulsatile stimulation of dopamine
receptors [33,99]. Thus, protection or augmentation of striatal
dopamine terminals can be a useful approach to prevent DID
(Table 2). The strategies used in preventing dyskinesias are
(1) delaying the need for levodopa, (2) reducing the
cumulative dose of levodopa, (3) avoiding the pulsatile
stimulation of dopamine receptors, and (4) Fneuroprotection_to slow down disease progression [125].
One such drug that is supposed to have neuroprotective
effect is Selegiline. Selegiline is shown to have neuro-
protective effect in variety of laboratory animals [106].
Studies have shown that it delays the need for levodopa,
allows sparing of levodopa dose, and reduces levodopa-
induced motor fluctuations. The neuroprotective effect of
selegiline is mediated through the anti-apoptotic mecha-
nisms. This effect of selegiline (deprenyl) was evaluated in a
large trial carried out by Parkinson Study Group called
DATATOP (Deprenyl And Tocopherol Antioxidative Ther-
apy Of Parkinsonism) [115]. This study failed to show any
reduction in the occurrence of dyskinesia or extension of life
as an effect of selegiline, though it delayed the need of
levodopa therapy [73,80,116,132]. Slow release formula-
tions of levodopa have also been used to reduce the pulsatile
stimulation. The FCR FIRST Study Group_ carried out a trialin PD patients never exposed to levodopa therapy. In this
FCR FIRST_ study they were randomized to (Sinemet CR
50/200) sustained-release or immediate-release (Sinemet 25/
100) carbidopa/levodopa preparations in 35 centers world-
wide. This study failed to demonstrate usefulness of these
formulations in reducing the risk of DID [18]. Several other
drugs have been tried for early use in order to reduce the risk
of dyskinesias. These drugs include COMT inhibitors,
anticholinergics, and amantadine, which is an NMDA
receptor agonist. There is no conclusive data available yet
as to their usefulness in preventing dyskinesias. Dopamine
D2 agonists like bromocriptine are in fact the only group of
drugs that has shown some efficacy in reducing the risk of
dyskinesias in MPTP-treated monkeys [7] as well as PD
patients [127]. As the agonists are ineffective as mono-
therapy alone, strategies such as combining dopamine
agonist with levodopa early in the treatment or introducing
levodopa as an add-on to the agonists as late as possible in
the therapy have yielded some positive results [87]. Rinne
and colleagues [130] carried out a multicenter, randomized,
double-blind study designed to assess whether initial
therapy with cabergoline alone or in combination with
levodopa prevents or delays the occurrence of DID in
patients with early PD. They noticed that development of
motor complications was significantly less frequent in
patients treated with cabergoline than in levodopa recipients.
The relative risk of developing motor complications during
treatment with cabergoline was more than 50% lower than
with levodopa. In conclusion, their study shows that,
starting treatment with cabergoline significantly delays the
development of motor complications like DID. In another
M. Deogaonkar, T. Subramanian / Brain Research Reviews 50 (2005) 156–168 163
prospective, randomized, double-blind study, Rascol and
colleagues [128] compared the safety and efficacy of the
dopamine D2/D3-receptor agonist ropinirole with that of
levodopa in early PD. The primary outcome measure in this
study was the occurrence of dyskinesia. The analysis of the
time to dyskinesia showed a significant difference in favor
of ropinirole. At 5 years, the cumulative incidence of
dyskinesia, regardless of levodopa supplementation, was
20% in the ropinirole group and 45% in the levodopa group.
Rascol [125] hypothesized three major strategies to treat
Fpeak dose_ dyskinesias:
1. To prevent the priming of dyskinesias
a. Delay the need for levodopa.
b. Reduce the cumulative dose of levodopa.
c. Smoothing or avoiding pulsatile dosing of levodopa.
d. Neuroprotection to slow down disease process.
2. To reverse the priming of dyskinesias
a. To stop and resume levodopa treatment, a concept of
Fdrug holiday_.b. To reduce the dose of levodopa and add an adjunct
like COMT inhibitor.
c. Surgical strategies.
3. To avoid expression of dyskinesias in already primed
patients
a. Lower levodopa doses.
b. Partial D2 agonists: Baronti and colleagues [6] have
shown that Terguride, a partial D2 agonist, produced a
dose-dependent decrease in levodopa-induced dyski-
nesias (up to 53%).
c. D2/D3 dopamine agonists: In a recent study [58],
cabergoline, pramipexole, and ropinirole were similarly
effective in reducing the risk for dyskinesia relative to
levodopa. The reduction in risk for dyskinesia was
slightly more evident for pramipexole and ropinirole
than cabergoline. When high doses of ropinirole were
used as an adjunct to levodopa in patients with
advanced PD [41], there was a significant reduction
in DID. In the CALM-PD (Comparison of the agonist
pramipexole with levodopa on motor complications of
Parkinson’s disease) study, initial treatment of prami-
pexole was compared with initial treatment with
levodopa in early, symptomatic Parkinson’s disease
and was analyzed with regard to the development of
DID. The results showed a significant reduction in
dopaminergic motor complications (wearing off, DID,
‘‘on–off’’ effects) in pramipexole group [117].
d. Drugs acting on NMDA receptors: Amantadine
possesses NMDA antagonistic properties and has
been found to be effective in reducing DID in
MPTP-treated monkeys [14] as well as PD patients
[16,124–126]. Dextromethorphan, another NMDA
antagonist, has shown to improve average and
maximum dyskinesia scores by >50%, without com-
promising the antiparkinsonian response magnitude of
levodopa therapy.
e. Drugs acting on serotonergic system: 5-HT antago-
nists like ritanserin [83], mirtazapin [83], and risper-
idone [82] have been reported to improve DID in
various studies in PD patients.
f. Other drugs: Alpha-2 antagonist, idaxzoxan has been
shown to reduce DID without affecting the antipar-
kinsonian effect of levodopa [129]. Opioid receptor
antagonists like naloxone and naltrexone have also
been used to reduce the incidence of DID [49,54,66].
Recently, Levetiracetam, an antiepileptic drug that
counteracts neuronal hyper-synchronization, was
shown to cause significantly less dyskinesia, in animal
models of PD [55,56] and in PD patients [138].
Selective adenosine A2A receptor antagonists may
also represent a new class of drugs potentially useful
in treating DID.
8. Surgical treatment of DID
Dissociation between antiparkinsonian response and
dyskinetic response of levodopa can be achieved by various
surgical interventions in PD patients with dyskinesia.
Functional neurosurgical procedures in PD patients have
been reported to show a variable effect on DID. Anti-
dyskinetic effect of thalamotomy has been widely discussed
in the literature but is not uniformly accepted. Efficacy of
thalamic lesioning appears to vary according to the location
of lesion in ameliorating the DID. Narabayashi and
colleagues [92] compared the lesion involving ventral
intermediate nucleus (Vim) and ventralis oralis complex
(Vo) in PD patients. They concluded that DID alleviated
almost completely by stereotaxic surgery using a micro-
electrode technique for the Vo anterior and posterior nuclei
of the thalamus, but much less by Vim surgery. The
importance of lesioning the Vo complex containing pallidal
afferents to prevent or reverse dyskinesias has been
demonstrated by experimental studies [109,110]. A selective
combined Vim–Vo thalamotomy has been shown to be
quite successful for the treatment of dyskinesia by some
recent studies [103,104].
Pallidotomy has consistently demonstrated anti-dyski-
netic effect. Posteroventral medial pallidotomy improved
contralateral dyskinesias by 83% and ipsilateral dyskine-
sias by 45% in a study by Lang and colleagues [70]. A
recent randomized trial of pallidotomy versus medical
treatment for PD by Vitek and colleagues [142] showed
marked improvement in DID following pallidotomy.
Although the greatest improvement occurred on the side
contralateral to the lesion, significant ipsilateral improve-
ment was also observed in dyskinesias. Parkin and
colleagues [114] evaluated the outcome of unilateral and
bilateral posteroventral pallidotomy and concluded that
bilateral pallidotomy appears to be more effective, partic-
ularly in reducing dyskinesia. Baron and colleagues [5]
have shown contralateral dyskinesia scores improved by
M. Deogaonkar, T. Subramanian / Brain Research Reviews 50 (2005) 156–168164
82% at 1 year and by 64% at 4 years after unilateral
pallidotomy. Similar results have been reproduced by other
groups [51,69,74].
STN plays a major role in the pathophysiology of the
motor dysfunction of Parkinson’s disease (PD) and STN
inhibition improves parkinsonian dysfunction. Lesioning
of STN or Fsubthalamotomy_ has been used to ameliorate
DID [79]. In a clinical study aimed at evaluating the
effects of a unilateral lesion placed in the STN in
predominantly hemiparkinsonian patients, there was a
significant reduction in DID presumably due to reduction
of levodopa dose [118]. Similar results were noted in
another clinical trial of unilateral subthalamotomy [135].
Deep brain stimulation of the STN in PD patients is also
currently being evaluated as a therapy for DID. STN
stimulation has been shown to improve all types of DID,
with the most dramatic effect being on dystonia [9]. The
improvement in DID may be due to a decrease in
dopaminergic medications. In a double-blind study to assess
efficacy of GPi and STN stimulation [64], two advantages of
GPi and STN stimulation were identified. Firstly, the
stimulation supplemented a reduced action of levodopa
during the off-period and secondly, the stimulation replaced
part of the action of levodopa during the on-period. It thus
reduced DID through a reduced dose of medication. More
importantly, the stimulation improved the daily activities in
dopa-intolerant patients receiving multiple small doses of
levodopa because of unbearable side effects. In addition, GPi
stimulation has its own inhibitory effect on DID. Various
other studies have described considerable decline in DID
following STN stimulation [8–10,44,57,59,63–65,68,86,
89] (Table 2).
Recent observations from clinical trials of neural grafting
for PD have demonstrated that grafted dopamine neurons can
cause ‘‘off’’ period dyskinesias in some graft recipients
[37,107,121,134]. This deleterious side effect reveals a new
challenge for neural transplantation, that of elucidating
mechanisms underlying these post-graft dyskinesias. The
post-graft dyskinesias are thought to be due to unregulated
production of dopamine by the grafted tissue and are
sometimes referred to as Frunaway dyskinesias_. It is
postulated that heterotopic placement of dopaminergic
neurons in striatum fails to regulate the dopamine secretion
from the cells. The grafted cells are not under regulatory
influences as they are not placed orthotopically in the SN
[136]. To avoid these post-graft Frunaway dyskinesias_, twopotential strategies have emerged. Placement of intranigral
grafts along with intra-striatal (dual) grafts has shown to
reduce the incidence of post-graft dyskinesias [84,85]. Use
of non-neuronal dopaminergic cells like human retinal
pigment epithelial (hRPE) cells is another way to avoid the
unregulated dopamine release. A recent open label pilot
study by Bakay and colleagues [3] of hRPE cell trans-
plantation in patients with advanced PD showed improve-
ment in the dyskinesias and did not cause any Frunawaydyskinesias_.
9. Future strategies
Most of the research on DID today is focused on pulsatile
stimulation by dopamine, changes in post-synaptic D1 and
D2 receptors, and molecular alterations in median spiny
neurons and is based on existing rodent or primate models.
Future research needs to take into account hitherto unex-
plored areas like extent of nigro-striatal loss essential to
produce DID. Use of primate models that depict progressive
nigro-striatal degeneration is necessary. We know that with
increased nigral neuronal depletion, there is more likelihood
of developing dyskinesias. Studies aimed at finding out the
Fthreshold_ of nigro-striatal cell loss that is responsible for
the development of DID will help in better understanding of
the causative mechanisms of DID. It will also help in
developing Fneuroprotective strategies_ based on gene
therapy in slowing down the loss and arresting the disease
progression. Research aimed at identifying exact electro-
physiological Fsignature_ of DID can help in better under-
standing of electrophysiological events in basal ganglia
during dyskinesias. Similarly, identifying the striatal expres-
sion of genes that are up- or down-regulated in patients with
DID and identification of specific FRAs and IEG expression
may lead to developing therapeutic tools that can prevent or
reverse DID. Better understanding of neuroanatomical,
electrophysiological, molecular, and genetic correlates of
DID will help in exploring newer strategies for the
prevention and treatment of DID, which in turn will have
an enormous impact on our ability to effectively treat PD.
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