Continuous Dopaminergic Stimulation in Parkinson’s Disease Figure 2: Schematic Representation of the 11C-raclopride Displacement Paradigm Scan 1: Baseline DA DA DA DA DA DA DA DA DA DA DA DA
DA L
DA
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DA
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Scan 2: Levodopa administration
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D2 receptors DA Endogenous dopamine 11C-raclopride
DA
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D2 receptors DA Levodopa-induced dopamineL
Changes in 11C-raclopride binding between baseline and post-treatment states (in this case administration of oral levodopa/carbidopa) represent a change in synaptic dopamine levels, reflecting the release of dopamine induced by levodopa administration. DA = dopamine.
To summarize, exposure to oral levodopa appears to have only mild
effects on the total availability of DA D1 and D2 receptors in PD patients. Having said that, current PET studies with antagonist tracers are unable to separate signal from high and low agonist affinity receptor conformations and it is possible that the relative sub-populations are altered. Additionally, they do not exclude that downstream neurotransmitter changes can be induced depending on the kinetics of DA-receptor stimulation.
Effect of Dopamine-replacement Treatment on
Striatal Dopamine Release 11C-raclopride PET can also be used to assess fluctuations in synaptic concentrations of DA following pharmacological or behavioral challenges (see Figure 2). Rises in synaptic DA levels translate into decreases in DA
D2-receptor availability, which can be detected as reductions in 11C-raclopride binding.11
T39 It has been estimated that a 10% reduction
This paradigm has recently been employed to assess the changes in synaptic DA levels after administration of a single dose of exogenous levodopa in PD patients (see Figure 3). Results from these studies have shown that striatal reductions in 11C-raclopride binding after a levodopa challenge become greater as motor disability increases and the disease progresses.22–25
in 11C-raclopride binding reflects a five-fold increase in synaptic DA levels.21
Changes in 11C-raclopride binding after
oral administration of standard levodopa/carbidopa (250/25) were assessed in a group of PD patients with and without peak-dose dyskinesias.24
Each patient received three 11C-raclopride PET scans. The first one was performed at baseline with the patient ‘off’ medication and the others at one hour and four hours after levodopa. PD patients with dyskinesias had larger increases in synaptic DA levels than patients with stable response to levodopa one hour after administration, whereas there were no between-group differences at four hours. This finding suggests that peak-dose dyskinesias are associated with enhanced
US NEUROLOGY
The increased synaptic DA levels that result from levodopa administration in dyskinetic and in more advanced PD patients probably reflect the reduced DA storage capacity of the severely affected putamen. However, another explanation could be the reduction of DA transporters (DAT) available to clear the transmitter. In line with this theory, Sossi and colleagues26
found a significant negative correlation
between changes in synaptic DA concentration and binding of the DAT marker 11C-methylphenidate. Greater reductions in 11C-raclopride, indicative of lower changes in synaptic DA concentration and
39 Baseline T39 Levodopa challenge Images taken at baseline and after oral administration of standard levodopa/carbidopa (250/25). pulses of DA release induced by levodopa administration. In line with this
interpretation, our group has recently reported that large putaminal 11C-raclopride binding changes induced by Sinemet® 275 were directly associated with higher dyskinesias scores during the scan session.25
Figure 3: 11C-raclopride Positron-emission Tomography Images from a Parkinson’s Disease Patient
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