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Levodopa-induced dyskinesias and synaptic plasticity
1
Diellor Orliq Basha
Review Article
1 Second Year Undergraduate Student, Neuroscience Specialist Program, University of Toronto. Corresponding author email: [email protected].
Abstract
The treatment of Parkinson’s disease (PD) relies heavily on levodopa therapy. Although highly effective in ameliorating the debilitating symptoms of PD, levodopa treatment is largely associated with the development of abnormal involuntary movements. Several
studies have suggested that these motor complications, termed levodopa-induced dyskinesias (LIDs), are associated not only with the
medication regimen but also with the degree of nigrostriatal lesioning. The interplay between the pathology of PD and the medication
regimen produces an aberrant form of motor learning that may be responsible for the generation of dyskinesias. The formation of motor
memories at the cellular level occurs when the strength of the corticostriatal synapse is modified, a phenomenon termed synaptic plasticity. In intact animal systems, this effect is reversed physiologically by low frequency stimulation of cortical afferents to the striatum.
However, recent investigations indicate that dyskinetic animal models lack the ability to reverse the modification at the corticostriatal
synapse. The saturation of the synapses with unessential information and the failure of these motor memories to rescind are thought to
cause the sustained abnormal motor activity that is inherent to dyskinesias. This report offers a synopsis of the extensive research on the
origin and phenomenology of LIDs and discusses their relationship to synaptic plasticity. Furthermore, a novel approach to explaining
the LID phenomenon is proposed that focuses on the ratio of dopamine to dopaminergic neurons and the ratio’s relevance to synaptic
plasticity. The application of these findings to the management of both Parkinson’s disease and LIDs is also discussed.
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Introduction
32
The function of the striatum as a motor control
center is heavily dependent on the nigral contribution of dopamine [1]. Hence, the degradation of
dopaminergic neurons in the nigrostriatal pathway is heavily implicated in the motor impairments associated with Parkinson’s disease (PD)
[1]. These symptoms begin appearing gradually
but with increasing severity as the level of dopamine denervation exceeds a threshold of 50-60%
in the substantia nigra and as striatal dopamine
content drops to a level between 20% and 30% [2,
3]. Rigidity, postural instability and an overall diminishing of speed and agility of volitional movements are the resultant features of this pathology
[4]. Although PD is a largely hypokinetic disorder,
unmedicated parkinsonian patients also exhibit
involuntary movements such as rest tremors and
dystonic posturing [4]. The aetiology of the disease remains unknown and a cure for it does not
currently exist; however, a number of strategies
aimed at symptom relief are in operation [5].
Replenishing the dopamine deficiency
through the administration of levodopa remains
the most efficacious therapy for PD [6]. Levodopa,
a dopamine precursor, is taken up and processed
by nigrostriatal dopaminergic neurons and then
converted to dopamine by aromatic L-amino acid
decarboxylase (AADC) [7]. The converted levodopa is subsequently packaged into synaptic vesicles
Journal of Undergraduate Life Sciences
Figure 1. A simplified schematic representation of basal ganglia circuits involved in the pathology of PD and LIDs. Sensorimotor and cognitive information from the cortex is transmitted to the striatum through a massive
glutamatergic innervation (see black arrow from cortex to striatum). The
Substantia Nigra pars compacta (SNc) is the site of dopamine-containing
neurons, which influence the striatum with dopaminergic innervations. The
Globus pallidus internus (GPi) and Substantia Nigra (SNr) receives innervation
from the striatum; however, the innervation is largely GABAergic. SNr, together with GPi then project to the thalamus and on to the cortex and lower
motor neurons thus exerting a substantial degree of control on mobility. The
pathological hallmark of PD is the degeneration of the dopaminergic nigrostriatal pathway. The resulting dopamine deficiency seriously limits striatal
function and accounts for the motor impairments inherent to PD. Levodopa
therapy restores the dopamine in the striatum and substantia nigra; however,
depending on the extent of the nigrostriatal lesion, the clinical benefit may be
overshadowed by the adverse effects of the therapy.
Levodopa-induced dyskinesias and synaptic plasticity
Levodopa Dosage Required for the
Induction of Acute Dyskinesin
The Role of Parkinson’s Disease in Levodopa-induced
Dyskinesias
Nigrostriatal lesion
Onset of Levodopa therapy
Time
Figure 2. A schematic representation of the effect of PD and the effect of chronic levodopa treatment on the threshold required for
the induction of LID. The dose required to induce acute dyskinesia
becomes lower under the combined effect of prolonged levodopa
exposure and loss of dopaminergic neurons.
although not necessary, plays a role in the generation of
LIDs [13, 21-23]. Moreover, monkeys that undergo severe
lesioning of nigrostriatal pathways via treatment with the
neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) become dyskinetic after considerably shorter
periods of levodopa exposure [19, 24]. In addition to experimental investigations, numerous observational studies have shown that the severity and the duration of PD,
the duration of levodopa therapy and high initial dose of
levodopa are major risk factors associated with LIDs [20,
25, 26]. All together, the evidence suggests that prolonged
and extensive dopaminergic stimulation combined with
the shortage of dopaminergic neurons produces a maximal propensity for dyskinesias (Fig. 2).
The relationship between the nigrostriatal lesion and
the bioavailability of dopamine may also account for the
fluctuations in the quality of motor response to levodopa.
LIDs generally manifest themselves in two distinct temporal patterns: peak-dose and diphasic dyskinesias. Peakdose dyskinesias are the most common form and occur
when dopaminergic stimulation is at its maximum [27].
Conversely, diphasic dyskinesias are less common and occur when the levels of dopamine are in flux (rising or falling) [27, 28]. The patient typically experiences motor complications within 10 minutes after the intake of levodopa
and after the medication begins to “wear off”. In this
case, dyskinesias do not occur in the intermediate period
when plasma concentrations of levodopa are at a maximum [27]. In a recent study, Olanow et al. propose that the
occurrence of these fluctuations is due to the manner of
levodopa intake [29]. It is hypothesized that orally administered levodopa stimulates dopamine receptors in a pulsatile fashion [29]. Because dopamine receptors normally
receive tonic stimulation, the intermittent availability of
dopamine results in the sensitization of the dopamine receptor. In short, the phenomenology of LIDs and motor
Journal of Undergraduate Life Sciences
Vo l u m e 1 • N o . 1 • S p r i n g 2 0 0 7
Although levodopa therapy provides an enduring
relief of all parkinsonian symptoms, chronic use tends
to generate adverse effects such as dyskinesias and motor fluctuations in a vast majority of responding patients
[9]. The most prominent hyperkinetic features of dyskinesia are exhibited usually as a mixture of choreiform and
dystonic movements. In addition, involuntary writhing
movements along the axis of a limb, termed athetosis, are
idiosyncratic to levodopa-induced dyskinesias (LIDs) and
are typically disordered and uncoordinated [10]. About
30% of PD patients suffer from dyskinesia after 4-6 years
of levodopa therapy and almost 90% of them do so after 9
years of therapy [10]. It should be noted, however, that the
prevalence of LIDs may be underreported and more detailed investigations might reveal a more frequent occurrence in the population. It has been suggested that parkinsonian patients may be unaware of mild, unobtrusive signs
of dyskinesia and may consequently fail to report them to
their physicians [11]. Moreover, dyskinesias may not be
manifested if the administered dose of levodopa is below
the threshold required for their expression [11]. Challenges with large doses may exacerbate a latent tendency
for dyskinetic movements in levodopa-treated parkinsonian patients [12] and thus reveal a greater population frequency of LIDs. It is significant to mention, however, that
dyskinesias may even be induced in healthy subjects if the
levodopa dosage is sufficiently large. Repeated high doses of levodopa were shown to produce LIDs in primates
that had no anatomical or biochemical pathology in the
nervous system [13, 14]. Massive doses of the drug (up
to 80mg/kg daily for 3 months) rendered 75% of the intact
monkeys dyskinetic but small to normal doses (20-40 mg/
kg daily) failed to produce the idiosyncratic involuntary
movements. The duration of levodopa therapy accounts
for a further decrease in the dosage threshold required for
the generation of LIDs [15, 16]. These findings indicate circuitously that dyskinesias tend to occur when dopaminergic stimulation is extensive with respect to the availability
of dopaminergic neurons.
In fact, a review of the cumulative literature indicates that both the extent of nigrostriatal lesioning and
the availability of dopamine are involved in the generation of dyskinesias. A nigrostriatal lesion, for example,
significantly lowers the levodopa dosage threshold that is
required to induce acute dyskinesia [17, 18]. In primate
models of severe parkinsonism (dopaminergic neurons
in SNc are destroyed), dyskinesia is induced with substantially low doses of levodopa [19] indicating that PD,
Levodopa dose
by the vesicular monoamine transporter-2 and released
extracellularly upon stimulation [7, 8]. By supplying the
deficient basal ganglia with dopamine, treatment with levodopa restores the function of the striatum, resulting in a
dramatic improvement in mobility (Fig. 1).
33
Levodopa-induced dyskinesias and synaptic plasticity
fluctuations seems to depend on an interaction between
pathological processes and medication regimen, although
a detailed understanding of this interplay remains to be
elucidated.
Vo l u m e 1 • N o . 1 • S p r i n g 2 0 0 7
Neural Plasticity and Parkinson’s Disease: The Role of
Dopamine
34
The basal ganglia system displays an extraordinary
capacity for physiologic and molecular adaptability in
response to nigrostriatal alteration. The fact that parkinsonian symptoms only appear after an extensive degeneration of nigral neurons [2] is indicative of a powerful
compensatory mechanism within the nigrostriatal pathway. In fact, partial lesioning is widely known to generate numerous homeostatic responses in the nigrostriatal
system, an active process termed neural plasticity [30-32].
For example, vigorous axonal sprouting was observed in
rats that had their nigrostriatal system lesioned with 6-hydroxydopamine (6-OHDA) [31]. A similar investigation of
6-OHDA-lesioned rats (a common model for dopaminedeficiency) suggests a prominent increase in the biosynthesis and release of dopamine in response to the lesion
[32].
In addition to lesion-induced plasticity, the basal
ganglia exhibit a well documented capability for synaptic change in response to changes in neuronal activity.
In order to adjust their own excitability in response to
altered stimuli, neurons can either modify their existing
synaptic proteins or biosynthesize new proteins (Fig. 3)
[33, 34]. These processes lead to an enduring change in
the strength of the synaptic association of neurons, an
activity-dependent process called synaptic plasticity. Repetitive stimulation of a moderately active neuron can induce a potentiation of transmission across its respective
synapses [34, 35]. In intact systems, for example, repeated
stimulation of glutamatergic cortical afferents to the striatum can activate an intricate cascade of biochemical events
that ultimately leads to an increase in the strength of the
corticostriatal synapse (long-term potentiation (LTP))
[36]. Similarly, a weakening of synaptic transmission can
occur as a result of repetitive stimulation (long-term depression (LTD)) [37]. Electrophysiologically, LTP/LTD can
be established rapidly by a brief burst of high-frequency
stimulation (HFS) and can be quite persistent [36, 37].
Numerous studies have demonstrated LTP/LTD both in
vivo and in vitro [36-39]. At the corticostriatal synapse, the
LTP phenomenon is related to the synergistic activation of
glutamate and dopamine receptors (Fig. 3). The stimulation of n-methyl-D-aspartate (NMDA) receptors activates
a calcium-dependent cascade of biochemical events that
leads to the engagement of extracellular signal-regulated
kinases (ERK1/2) [40-42]. Subsequently, the ERK1/2 recruits transcription factors within the cell nucleus (cAMP
response element binding (CREB) protein and Elk-1) that
phosphorylate specific protein residues, resulting in an increase in the generation of transcription signals [40, 43].
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Figure 3. A simplified representation of the physiologic and molecular mechanisms implicated in corticostriatal synaptic plasticity.
Glutamatergic stimulation of NMDA receptors mobilizes an intricate calcium-dependent cascade of biochemical events (not shown
here) that ultimately activates a protein named extracellular signalregulated kinase (ERK1/2). Within the cell nucleus, ERK1/2 activates
transcription factors (CREB and Elk-1) that interact with enhancer
elements in order to induce transcription of the fosB gene. The fosB
gene is implicated in the elevated expression of NMDA receptors
although this mechanism remains poorly understood. Regardless,
the final outcome of this series of events is the biosynthesis of new
proteins that functionally modify the corticostriatal synapse. In
order for LTP to form, however, a concomitant stimulation of dopamine and glutamate receptors is required. Dopaminergic stimulation of the D1 dopamine receptor activates cAMP which, in turn,
recruits protein kinase A (PKA). PKA induces the phosphorylation
of NMDA receptor subunits and enhances the calcium currents at
the corticostriatal synapse. These events boost synaptic transmission and induce the production of NMDA receptors by facilitating
the aforementioned glutamatergic pathway (shown in green). The
availability of dopamine is hence crucial to the plastic processes at
the corticostriatal synapse, which may explain why untreated parkinsonian patients fail to exhibit LTP. On the other hand, chronic and
pulsatile application of levodopa may result in overactive and sensitized dopamine receptors. Persistent LTP associated with dyskinesia
may be an outcome of this levodopa-induced effect.
The ultimate result is the biosynthesis of new proteins
and a functional change in the synaptic association of
the corticostriatal pathway [34, 35]. The selective involvement of D1-subtype dopamine receptors, on the other
hand, induces a potentiation of NMDA receptors and is
required for plastic processes at the corticostriatal synapse
[44, 45]. The stimulation of the D1-subtype receptor employs cAMP and leads to the protein kinase A (PKA) de-
Levodopa-induced dyskinesias and synaptic plasticity
pendent phosphorylation of the NMDA receptor subunits
[44]. Increased NMDA receptor expression and enhanced
calcium currents also occur following D1 receptor stimulation [46, 47]. Moreover, the physical proximity of corticostriatal and nigrostriatal terminals allows for NMDA
and D1 receptors to influence each other thus permitting
a synergistic interaction between glutamatergic and dopaminergic inputs to the striatum [39, 45]. The establishment
of corticostriatal LTP, in fact, requires both NMDA and D1
receptors to be stimulated concurrently [44, 48]. The fact
that the phosphorylation of NMDA receptor subunits occurs upon the stimulation of the D1 receptor [46, 47] demonstrates that the induction of LTP in the basal ganglia is
highly dependent on the bioavailability of dopamine [44].
In fact, the lack of dopamine stimulation of the D1 receptors results in abrogated LTD expression [36]. In addition
to the lack of LTD, recent studies have demonstrated that
dopamine-depleted rats lack the capacity for expressing
LTP [37, 54]. This further corroborates the hypothesis that
the availability of dopamine is necessary for the plastic
processes at the corticostriatal synapse [49]. Nevertheless,
both LTP and LTD can be established by administering
levodopa at a therapeutic dosage similar to that used in
parkinsonian patients. Chronically administered levodopa, however, affects corticostriatal plasticity in a different
A
manner and gives rise to a number of other problems.
Synaptic Plasticity and Levodopa-induced Dyskinesias
In addition to their function as positive responses,
some forms of neural plasticity can become abnormal and
consequently maladaptive [40]. One such example is the
phenomenon of abnormal LTP formation in levodopainduced dyskinesias. A growing number of studies indicate that a glutamatergic excitation of NMDA receptors
might be also linked to the development of dyskinesias in
levodopa-treated animals. A decrease in motor response
complications was observed in both humans and MPTPtreated monkeys after the administration of NMDA antagonists [51, 52]. Following this possible association between
synaptic plasticity and levodopa-induced dyskinesias,
Picconi et al. induced LTP in levodopa-treated dyskinetic
rats [49]. In normal systems, the induced LTP/LTD can be
reversed by sustained low-frequency stimulation, a dynamic event known as synaptic depotentiation. Although
successful in expressing LTP, the dyskinetic rats failed to
express depotentiation suggesting that chronic levodopa
treatment affects the dopaminergic regulation of plasticity at the corticostriatal synapse (Fig 4). The formation of
the corticostriatal LTP is a principal substrate for the process of motor learning and in line with this idea, synaptic
B
C
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Figure 4. Chronic levodopa treatment restores LTP in parkinsonian rats but abrogates depotentiation in dyskinetic rats. A. In normal systems, high frequency stimulation of cortical afferents induces long-term potentiation (LTP) at the corticostriatal synapse. The synaptic association becomes enhanced as a result of physiological modifications that occur at synaptic terminals. The effect is long-lasting; however,
it can be reversed rapidly by stimulating the cortical afferents at a low frequency, a dynamic event termed synaptic depotentiation. These
mechanisms represent cellular substrates for motor memory formation and deletion respectively. B. LTP is readily induced in normal rats;
however, untreated parkinsonian rats fail to form LTP upon high frequency stimulation. C. Levodopa treatment restores LTP; however,
the rats that develop dyskinesias as a result of levodopa therapy, fail to depotentiate when low frequency stimulation is applied. Dyskinesia may therefore be a result of abrogated deletion of redundant information at the corticostriatal synapse. The persistent involuntary
movements that are inherent to LIDs could possibly be a consequence of consolidated motor memories that fail to rescind. The fact that
dopamine mediates the formation of LTP and the manner in which the level of dopamine stimulation affects the synaptic plasticity in the
lesioned rats is also noteworthy (see Table 1).
35
Levodopa-induced dyskinesias and synaptic plasticity
Table 1. The availability of dopamine with respect to the availability of dopaminergic neurons affects the neuronal capacity for
synaptic plasticity, resulting in motor complications. A ratio where
dopaminergic stimulation is large compared to the availability of
dopaminergic neurons results in sustained LTP. On the other hand,
low dopaminergic stimulation and the lack of dopaminergic neurons
abrogate the formation of LTP and produce parkinsonism. Normal
LTP formation seems to require a delicate balance between the degree of dopaminergic stimulation and the availability of dopamineprocessing neurons.
depotentiation is thought to be implicated in the mechanisms of “forgetting” [49]. The observed lack of depotentiation may cause dyskinesias through the retainment
of redundant information in the corticostriatal synapses
resulting, in turn, in the saturation of the basal ganglia’s
storage capacity [52]. Although the results of this experiment are remarkable, it would have been interesting to
see the behaviour of synaptic plasticity in dyskinetic rats
at different doses of levodopa. It has been widely established that there exists a therapeutic window for levodopa
treatment that cautiously balances the therapeutic benefits
of levodopa and its adverse effects [53]. Elucidating this
phenomenon with respect to synaptic plasticity would
yield an interesting perspective in the treatment and management of PD.
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Conclusions
36
Ever since its introduction in the 1960s, the maladaptive effect of chronic levodopa treatment has been noted;
however, an integrated understanding of this phenomenon
has remained elusive. At present, the cumulative review of
the literature suggests that i) in treated parkinsonian animals, the dyskinesiogenic effect of levodopa is associated
with sustained synaptic potentiation [49]; ii) in untreated
parkinsonian animals, synaptic potentiation cannot be induced [36, 54] and iii) in otherwise healthy animals, it is
possible to generate levodopa-induced dyskinesias (a possible correlate to synaptic potentiation) through the administration of unconventionally large doses of levodopa
[13, 14] (see Table 1). In view of these findings, it is tempting to speculate that the ratio of dopamine abundance to
the availability of dopaminergic neurons may play a key
role in the mechanisms of corticostriatal synaptic plasticity
and LIDs. From this perspective, the body of data suggests
that a normal content of dopamine in a dopamine-denervated environment results in a persistent form of synaptic
potentiation [49]. Conversely, low dopamine content in a
Journal of Undergraduate Life Sciences
dopamine-denervated system results in a complete lack
of potentiation [36, 45] and lastly, high dopamine content
in an intact system tends to generate dyskinesias (possibly due to sustained synaptic potentiation) [13, 14]. It is
apparent that a delicate balance in the amount of dopamine to nigrostriatal neurons is required for normal motor
learning to occur. An electrophysiological synaptic plasticity experiment where nigrostriatal systems with different
degrees of damage are exposed to a diverse range of levodopa dosages may lead to a more complete depiction of
the effects of levodopa. Furthermore, an integrated study
of this type that investigates the molecular mechanisms
at different levels of dopaminergic stimulation should
produce interesting results. This concept emphasizes the
need to investigate new routes that could possibly yield a
comprehensive description of the pathological and physiological mechanisms of both PD and LIDs.
Acknowledgements
The author’s interest in this area was motivated by the
enthusiastic guidance of William D. Hutchison, Ph.D.
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Diellor Basha is a second year Neuroscience student currently involved in a Physiology Research Opportunity Project (PSL299) under the supervision of Dr. William D. Hutchison. The research at this
laboratory focuses largely on the pharmacology of movement disorders, specifically that of Parkinson’s disease. His research interest
focuses on the aetiology of movement disorders, which he plans to
work on while pursuing graduate studies in neuroscience.
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