Download Pathophysiology of motor fluctuations in Parkinson`s disease

Movement Disorders
Vol. 20, Suppl. 11, 2005, pp. S17–S22
© 2005 Movement Disorder Society
Pathophysiology of Motor Fluctuations in Parkinson’s Disease
Katherine Widnell, MD, PhD*
Regional Parkinson Center, Aurora Sinai Medical Center, Milwaukee, Wisconsin, USA
Abstract: Loss of dopamine neurons in Parkinson’s disease
(PD) initiates a complex stream of effects that results in the
development of tremor, bradykinesia, and rigidity. While levodopa remains the most effective drug for the symptomatic
treatment of PD, its chronic administration is associated with
the development of motor fluctuations and dyskinesias. The
risk of developing motor fluctuations has been linked to disease
severity, dosage of levodopa, and the age of the patient. A
recent body of preclinical data has demonstrated that alterations
in dopaminergic tone as well as in treatment patterns results in
cellular adaptations, including alterations in gene expression.
This body of preclinical data suggests that nonphysiological,
pulsatile stimulation of dopamine receptors induces the development of motor fluctuations and dyskinesias and raises the
possibility that nonpulsatile stimulation of dopamine receptors
(continuous dopaminergic stimulation) might induce fewer
fluctuations. We discuss the theory of continuous dopaminergic
stimulation and its implications for the management of motor
fluctuations in patients with advanced and early PD. © 2005
Movement Disorder Society
Key words: motor complications; Parkinson’s disease; motor fluctuations; dopaminergic stimulation
Loss of dopamine neurons in Parkinson’s disease initiates a complex series of changes in neuronal function
that results in clinical signs of tremor, bradykinesia, and
rigidity. Although levodopa remains the most-effective
drug for the symptomatic treatment of Parkinson’s disease (PD), its chronic use is complicated by the development of motor fluctuations and dyskinesias. A full
review of the mechanisms underlying the development
of motor complications is beyond the scope of this article, which will instead focus on some observed changes
in dopamine pathway signal transduction proteins.
Alterations in neuronal activity associated with prolonged use of L-dopa occur gradually over time and may
underlie the emergence of dyskinesias and/or motor fluctuations. The risk of developing motor fluctuations has
been linked to disease severity, dosage of L-dopa, and the
age of the patient.1 A growing number of preclinical and
clinical studies suggest that pulsatile stimulation of striatal dopamine receptors may increase the frequency, and
possibly even the development, of motor fluctuations.
However, the hypothesis that treatments that offer more
continuous dopaminergic stimulation may decrease the
development of motor fluctuations and dyskinesias has
not yet been tested directly in patients with PD.
BASAL GANGLIA ANATOMY
The basal ganglia consists of input and output stations
(see Fig. 1). The input stations include the striatum and
the subthalamic nucleus (STN), which receive excitatory
glutamatergic input from various regions of the cortex,
modulatory dopaminergic input from the substantia nigra
pars compacta (SNc), and serotonergic input from the
dorsal raphe nucleus.2– 6 The output stations include the
globus pallidus pars interna (GPi) and substantia nigra
pars reticulate (SNr). The cortical region of origin defines the function of the basal ganglia circuit as either
“motor,” “oculomotor,” “associative,” or “limbic”.
Voluntary movement involves activation of a motor
circuit that originates in the pre- and postcentral sensorimotor regions. As shown in Figure 1, neurons project
directly from the cortex to the putamen or indirectly by
means of the centromedian nucleus (CM) of the thalamus. The majority of neurons in the striatum are medium
␥-aminobutyric acid (GABA) -ergic projection cells.
Cortical glutamatergic projections terminate at the spine
heads of distal dendrites of the striatal medium spiny
neurons and excite these neurons by means of N-methylD-aspartate (NMDA), ␣-amino-3-hydroxy-5-methyl-4-
*Correspondence to: Dr. Katherine Widnell, Regional Parkinson Center, Wisconsin Institute for Neurologic and Sleep Disorders, 945 North
12th Street, Milwaukee, WI 53233. E-mail: [email protected]
Published online in Wiley InterScience (www.interscience.wiley.
com). DOI: 10.1002/mds.20459
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K. WIDNELL
dopamine receptor (D1 receptors) and contain the neuropeptides dynorphin and substance P. In contrast, striatal neurons that form the indirect pathway express high
levels of the type 2 dopamine receptor (D2 receptors)
and contain the neuropeptide enkephalin.9
FIG. 1. Basal ganglia anatomy: The striatum and subthalamic nucleus
(STN) receive excitatory glutamatergic (gray) input from various regions of the cortex, modulatory dopaminergic input from the substantia
nigra pars compacta (SNc), and serotonergic input from the dorsal
raphe nucleus (serotonergic input not shown). The output stations
include the globus pallidus pars interna (GPi) and substantia nigra pars
reticulate (SNr). The striatum projects directly to the GPe and SNr by
means of inhibitory ␥-aminobutyric acid (GABA, black) pathways and
indirectly to the GPi by means of (1) GABA-ergic projections to the
globus pallidus pars externa (GPe) and then (2) GABA-ergic projections from the GPe to the STN. Subthalamic projections use glutamate
as a neurotransmitter and result in excitation of neurons in the GPi/SNr.
CM, centromedian nucleus; VA/VL, pallidal-receiving area of the
thalamus; PPN, pedunculopontin nucleus.
isoxazolepropionic acid (AMPA), and kainate glutamate
receptors. In contrast, dopamine plays a modulatory role
in the basal ganglia. Nigral dopaminergic projections
terminate on dendritic shafts of the striatal medium spiny
neuron.6
Two distinct pathways connect the striatum to the
basal ganglia output stations. The striatum projects directly to the globus pallidus pars externa (GPe) and SNr
by means of inhibitory GABA pathways and indirectly to
the GPi by means of (1) GABA-ergic projections to the
GPe and then (2) GABA-ergic projections from the GPe
to the subthalamic nucleus (STN).7,8 Subthalamic projections use glutamate as a neurotransmitter, and result in
excitation of neurons in the GPi/SNr.
GPi/SNr projections to the thalamus are GABA-ergic
and therefore inhibit the excitatory (glutamatergic) pathway from the thalamus to the cortex. Striatal neurons that
form the direct pathway express high levels of the type 1
Movement Disorders, Vol. 20, Suppl. 11, 2005
BASAL GANGLIA PHYSIOLOGY
As shown in Figure 2, there are two distinct populations of dopamine receptors, which differentially regulate second messenger pathways in the striatum. D1
receptor activation leads to stimulation of adenyl cyclase,
the enzyme responsible for the synthesis of cyclic adenosine monophosphate (cAMP). D2 receptor activation
inhibits adenyl cyclase, which results in decreased synthesis of cAMP. Levels of cAMP regulate the activity of
cAMP-dependent protein kinase (PKA), which plays an
important role in cell phosphorylation events such as ion
channel modulation and regulation of gene expression.
Dopamine differentially regulates the direct and indirect pathways. The direct and indirect pathways work
together to balance the motor control wielded by the
basal ganglia. While the direct pathway facilitates movement by means of decreases in tonic inhibition of basal
ganglia output and disinhibition of thalamocortical and
brainstem pathways, the indirect pathway suppresses
movement by increasing the inhibitory basal ganglia
output to the thalamus. One of the roles of the direct and
indirect pathways is to scale movement by first inhibiting
GPi/SNr neurons by means of the direct pathway and
then disinhibiting the same GPi/SNr neurons to terminate
the movement.10 –12
Decreased dopaminergic input to the striatum from the
SNc in Parkinson’s disease results in a complex alteration in activity between input and output stations of the
basal ganglia. Decreased levels of dopamine result in
increased activity along the indirect pathway and decreased activity along the direct pathway, which together
result in increased excitation of GPi and SNr neurons,
then to increased inhibition of thalamic neurons, and
finally to decreased excitation of the cortex. Patterns of
neuronal discharge within the basal ganglia are disturbed
in PD. In particular, there is a tendency for neuronal
elements to synchronize at around 20 Hz in the absence
of dopaminergic treatment, whereas this activity can be
replaced by spontaneous synchronization at much higher
frequencies (⬎70 Hz) after dopaminergic treatment.13–15
Again, this simplistic approach to explain the clinical
features of PD does not take into account observed
changes in spontaneous discharge patterns observed in
the parkinsonian state.16 –18
The mechanisms by which chronic L-dopa results in
further perturbations of firing patterns of basal ganglia
PATHOPHYSIOLOGY OF MOTOR FLUCTUATIONS
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FIG. 2. Two classes of dopamine (DA) receptors exist (D1R and D2R) and differentially activate signal transduction pathways. The D1 receptor
increases the activity of adenyl cyclase (AC), which increases levels of cyclic adenosine monophosphate (cAMP), resulting in phosphorylation and
activation of protein kinase A (PKA). Activated protein kinase phosphorylates and activates cAMP-response element binding protein (CREB), which
leads to changes in gene expression. The D2 receptor decreases the activity of AC, which decreases levels of cAMP resulting in less phosphorylation
and decreased activity of PKA. Arrows represent either a positive (full line) or negative (dashed line) effect on the activity of the protein represented
in the figure. IEG, immediate early gene.
neurons is not well understood. It is also not known
whether L-dopa–induced motor fluctuations result from
chronic effects of dopamine denervation, chronic effects
of L-dopa administration or both. Attempts have been
made in animal models to correlate the behavioral
changes of motor complications to the neurobiological
and physiological adaptations observed at a single cell
level. These adaptations include changes in neurotransmitters and receptor expression, resulting in functional
alterations in signal transduction proteins that will be
detailed below.
CELLULAR ADAPTATIONS IN
PARKINSON’S DISEASE
Long-lasting, activity-dependent changes in neuron
function are thought to require alterations in gene expression. As shown in Figure 2, neurotransmitter receptor activation initiates intracellular signaling events that
culminate in (1) activation of a preexisting transcription
factor or (2) de novo synthesis of a transcription factor.
Transcription factors are proteins that bind to specific
DNA sequences in the regulatory regions of genes. The
binding of transcription factors to these regulatory sequences increases or decreases the rate at which those
genes are transcribed. Studies of the regulation of gene
expression in the striatum have focused on transcription
factors activated by both mechanisms. Basal levels of
cAMP response element binding protein (CREB) are
present in the striatum and can be activated by various
stimuli. CREB belongs to a family of leucine zipper
transcription factors that share certain structural motifs
and are activated after phosphorylation by PKA and
other protein kinases. Phosphorylated CREB regulates
expression of downstream target genes (such as fos) by
binding to DNA sequences (CRE sites) in their promoter
regions. In contrast, levels of c-Fos, c-Jun, and products
of other related immediate early genes (IEGs) are low
and must be expressed and translated in striatal cells.19
The newly synthesized fos messenger RNA (mRNA) is
translated into cFos protein, which associates with a
member of the Jun family, forming a complex that binds
to specific DNA sequences known as activator protein-1
(AP-1) sites in the promoter regions of target genes and
regulates their expression.19
Alterations in levels of IEGs, neuropeptides, and neurotransmitter receptors have been observed in animal
models of PD. It has become clear that dopamine depletion results in significant changes in cellular signaling
pathways. More recently, studies have suggested that
different patterns of treatment with dopaminergic agents
(L-dopa or dopamine agonists) results not only in differential behavior but also significant differences in patterns
of gene expression. It is not clear whether the observed
changes in gene expression result in a behavioral phenotype of motor fluctuations, but correlations have been
made between abnormal patterns of gene expression and
the development of motor complications.
Movement Disorders, Vol. 20, Suppl. 11, 2005
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K. WIDNELL
IMMEDIATE EARLY GENES
The induction of IEGs, such as c-fos, zif268, and other
transcription factors, is followed temporally by the expression of “late response genes”, which include many
neuropeptides. Alterations in patterns of IEG expression
may explain the development of functional responses of
striatal neurons to dopamine.2 For example, in animal
models, when cocaine (an indirectly acting dopamine
agonist) was administered to normal rats, a homogenous
induction of fos and related IEGs was observed in both
striosome and matrix compartments of the caudate and
putamen.2 This effect of dopamine agonist treatment was
even more profound in the setting of dopamine depletion.
In dopamine-depleted mice, D1 agonist treatment resulted in an abundance of IEG induction, suggesting that
dopamine depletion results in alterations of signal transduction mechanisms that regulate gene expression. Near
complete depletion of dopamine in the striatum must
occur for such a profound IEG response to be seen. In
normal rats, treatment with combinations of dopamine
D1 and D2 receptor agonists produces alterations in
normal behavior, including stereotyped behaviors such
as gnawing and biting.20 These changes are not seen after
treatment with either D1 or D2 agonists given alone.
Similarly, systemic administration of D1-selective agonists produces a strong and widely distributed pattern of
c-Fos expression in the striatum that was not seen after
D2-selective agonist treatment.20 Just as the induction of
behavioral changes was altered by coadministration of
D1 and D2 agonists, patterns of c-Fos expression in the
striatum changed when both D1 and D2 agonists were
given together, suggesting some sort of synergistic effect. However, such interactions between dopamine receptors appear to be significantly altered after dopamine
denervation, when stereotyped behaviors occur with activation of either class of receptor alone.20 In addition,
patterns of gene induction by D1 or D2 agonists in
dopamine-lesioned animals were significantly altered,
suggesting circuit-level modifications in the output pathways of the basal ganglia.
Further evidence that alterations in striatal expression
of IEGs may underlie clinical changes seen in Parkinson’s disease has been provided by studies that demonstrate that more than 40 IEGs are induced after D1agonist treatment in animal models of Parkinson’s
disease.2 These IEG changes are not observed in a dopamine-intact striatum. It has been postulated that the
development of dyskinesias results from aberrant activation of IEGs and resulting changes in expression of
downstream targets of the IEGS by D1-receptor activation in direct striatal pathway neurons.2 Further evidence
Movement Disorders, Vol. 20, Suppl. 11, 2005
that aberrant D1-receptor effects in the dopamine-depleted striatum has been provided by studies of the
Fos-related IEG ␦ FosB (a truncated form of FosB)
expression. In monkeys rendered parkinsonian by
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
treatment, there was a modest increase in striatal levels
of delta-FosB–like proteins, primarily in striatopallidal
neurons that express the D2 receptor.21 The development
of dyskinesia produced by twice daily (b.i.d.) injections
of the D1-agonist SKF-82958 was associated with large
increases in delta-FosB proteins. In contrast, injections
(every 48 hours) of the D2-agonist cabergoline did not
result in dyskinesias and reduced levels of delta-FosB
proteins in MPTP-lesioned animals to normal.21 Whereas
it is unlikely that changes in IEGs per se result in the
development of dyskinesias, it is tempting to suggest that
IEG-induced changes in signaling proteins, neuropeptides, or neurotransmitters result in alterations in cell
signaling, firing, and responsivity to dopamine.
NEUROPEPTIDES
After dopamine depletion in animal models of PD,
increases in striatal levels of preproenkephalin (PPE)
mRNA, along with decreases in levels of preprotachykinin (PPT) mRNA have been observed.22,23 Levels of PPE
mRNA in the striatum have been correlated with the
presence of more severe dyskinesias.22,24 Increased levels of PPE may reflect abnormal activity in the indirect
striatopallidal pathways, resulting in an imbalance in the
direct and indirect pathways that could explain the emergence of dyskinesias.24
When MPTP-lesioned animals were treated with pulse
treatment (injections of agonist twice a day) or continuous treatment (pump infusion) of the D2-dopamine receptor agonist U915356A, different behavioral responses
were observed: animals treated in a pulsatile mode developed dyskinesia, whereas after continuous infusion,
behavioral tolerance was observed but no dyskinesias
developed. In the putamen and lateral caudate nucleus,
elevated PPE mRNA expression generally was not
corrected by chronic L-dopa treatment. In general,
pulsatile administration of U91356A partially corrected the lesion-induced elevation of PPE mRNA
levels in the putamen and lateral caudate, whereas the
correction was most pronounced and widespread when
MPTP monkeys received continuous administration of
this drug.22
Additional studies have supported the concept that
more continuous stimulation of D2 receptors results in a
reversal of MPTP-induced alterations in levels of PPE
mRNA expression. Elevated PPE and decreased PPT
PATHOPHYSIOLOGY OF MOTOR FLUCTUATIONS
mRNA levels observed in monkeys after MPTP-lesioning were corrected after treatment with cabergoline (0.25
mg/kg every other day), a dose that had antiparkinsonian
effects but did not produce sustained dyskinesia. Not
only did pulsatile administration of the D1 agonist SKF82958 (3 times/day) not reverse the increase of PPE
mRNA levels, it actually significantly increased levels of
PPE mRNA and resulted in a shorter duration of motor
benefit (wearing-off) and dyskinesias in the animals.
Continuous treatment with SKF-82958 produced no
clear antiparkinsonian benefit in the animals, nor did it
alter the MPTP-induced increases in PPE or decreases in
PPT mRNA levels.23 The mechanism underlying
changes in PPE mRNA levels is unknown; it has been
postulated that increases in PPE mRNA due to dopamine
depletion may result from unchecked glutamatergic excitation after denervation.
NEUROTRANSMITTER RECEPTORS
In general, in monkey models of untreated Parkinson’s
disease, levels of D2 receptors have been shown to be
either normal or upregulated in the striatum, whereas
levels of D1 receptors are not clearly altered. In contrast,
studies have suggested that, after treatment with L-dopa
or other D2 agonists, D2 receptors are downregulated to
normal levels, whereas D1 receptors are decreased but
not affected greatly in monkey models as well as patients
with Parkinson’s disease.25
The location of alterations in dopamine receptor expression may also be important. In situ histochemistry
revealed that D1 receptor mRNA levels in rostral striatum decreased, whereas D2 receptor mRNA levels in
caudal striatum increased in MPTP monkeys compared
to control animals.26 As previously noted, pulse treatment of the D2 dopamine receptor agonist U915356A
resulted in dyskinesias in MPTP-lesioned monkeys, an
effect not seen after continuous infusion of
U915356A.22,25 Of interest, continuous administration of
U91356A reversed the MPTP-induced increase of D2
receptor mRNA, whereas the pulsatile administration did
not significantly correct these mRNA changes.22,25 Both
continuous or pulse treatment with U91356A partially
corrected the D1 receptor messenger RNA lesion-induced decrease in the striatum. Other studies have shown
that continuous occupancy of the D2 dopamine receptor
is required to maintain normal levels of D2 receptor
mRNA but that the decreases in D1 receptor mRNA are
not corrected by continuous treatment with D1 receptor
agonists and instead require single and repeated treatment.2
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CONTINUOUS DOPAMINERGIC
STIMULATION
The theory of continuous dopaminergic stimulation
suggests that the development of motor fluctuations is
related to pulsatile stimulation of dopamine receptors
and that treatments that offer more continuous dopaminergic stimulation may decrease the risk that motor fluctuations and dyskinesias will develop.
Clinical evidence has suggested that chronic (continuous) infusion of L-dopa or dopamine agonists (lisuride
or apomorphine) dramatically ameliorates motor fluctuations.27–31 An increasing body of preclinical data supports these findings. Administration of pulsatile doses of
L-dopa b.i.d. in MPTP-treated common marmosets resulted in marked dyskinesias.32 Further evidence supports the view that the combination of L-dopa with agents
that provide more continuous dopaminergic stimulation
can decrease the development of dyskinesias. This finding has been accomplished by treating MPTP-treated
common marmosets with frequent L-dopa doses (4 times/
day) in addition to entacapone or ropinirole, without
losing improvements in disability score or improvements
in on time.32 Similarly, MPTP-treated monkeys with a
long-standing and stable parkinsonian syndrome (that
had never received dopaminergic agents) were treated
for a month with L-dopa administered orally or with
L-dopa in addition to threshold doses of cabergoline.
L-Dopa–induced dyskinesias were observed in the L-dopa
group but not in the group receiving L-dopa and cabergoline.33
CONCLUSIONS
In summary, changes in the pattern of gene expression
and behavior occur after dopamine depletion and chronic
dopaminergic treatment. Although symptoms of PD decrease with chronic use of L-dopa, the development of
dyskinesias represents a serious side effect of this treatment strategy. The development of dyskinesia cannot be
attributed solely to the D1 or D2 receptors, and cooperation between the two receptors appears to be necessary
for this manifestation.34 However, the mechanism of
dopaminergic administration may play a crucial role in
the development of motor fluctuations. A significant
body of preclinical data suggests that avoiding pulsatile
dopaminergic stimulation may prevent the onset of dyskinesias and motor fluctuations. Continuous dopaminergic stimulation may be achieved with combinations of
L-dopa with dopamine agonists or with agents that prolong the half-life of L-dopa.
Movement Disorders, Vol. 20, Suppl. 11, 2005
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K. WIDNELL
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