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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 1. Introduction........................................................... 157 2. Animal models of DID ..................................................... 157 3. Pathophysiology of DID .................................................... 158 4. Electrophysiological correlates of DID ............................................. 159 5. Molecular basis of dyskinesias ................................................. 159 5.1. DA receptors (DAR) .................................................. 159 5.2. g-Aminobutyric acid (GABA) receptors......................................... 160 5.3. Glutamate and N-methyl-d-asparatate (NMDA) receptors ............................... 160 5.4. Role of neuropeptides .................................................. 161 5.5. Fos-related antigens (FRA) ............................................... 161 5.6. Adenosine A2A receptors ................................................ 161 6. Pharmacokinetics of levodopa and DID ............................................ 161 7. Relevance of pathophysiology for treatment strategies of DID................................. 162 8. Surgical treatment of DID ................................................... 163 9. Future strategies ........................................................ 164 References .............................................................. 164 0165-0173/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2005.05.005 * Corresponding author. Fax: +1 216 445 1466. E-mail address: [email protected] (M. Deogaonkar). Brain Research Reviews 50 (2005) 156 – 168 www.elsevier.com/locate/brainresrev

Pathophysiological basis of drug-induced dyskinesias in Parkinson's disease

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Page 1: Pathophysiological basis of drug-induced dyskinesias in Parkinson's disease

www.elsevier.com/locate/brainresrev

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

. . . . . . 157

. . . . . . 157

. . . . . . 158

. . . . . . 159

. . . . . . 159

. . . . . . 159

. . . . . . 160

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. . . . . . 161

. . . . . . 161

. . . . . . 161

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. . . . . . 162

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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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . 164

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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).

Page 2: Pathophysiological basis of drug-induced dyskinesias in Parkinson's disease

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

Page 3: Pathophysiological basis of drug-induced dyskinesias in Parkinson's disease

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

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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

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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

Page 6: Pathophysiological basis of drug-induced dyskinesias in Parkinson's disease

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-

Page 7: Pathophysiological basis of drug-induced dyskinesias in Parkinson's disease

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

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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

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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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