Levodopa-treated Parkinson's disease is often complicated by the occurrence of 
motor fluctuations, which can be predictable ('wearing-off') or unpredictable 
('on-off'). In contrast, untreated dopa-responsive dystonia (DRD) is usually 
characterized by predictable diurnal fluctuation. The pathogenesis of motor 
fluctuations in treated Parkinson's disease and diurnal fluctuation in untreated 
DRD is poorly understood. We have developed a mathematical model indicating that 
all these fluctuations in motor function can be explained by presynaptic 
mechanisms. The model is predicated upon the release of dopamine being subject 
to probabilistic variations in the quantity of dopamine released by exocytosis 
of vesicles. Specifically, we propose that the concentration of intravesicular 
dopamine undergoes dynamic changes according to a log-normal distribution that 
is associated with different probabilities of release failure. Changes in two 
parameters, (i) the proportion of vesicles that undergo exocytosis per unit of 
time and (ii) the proportion of dopamine subject to re-uptake from the synapse, 
allowed us to model different curves of levodopa response, for the same degree 
of nigrostriatal damage in Parkinson's disease. The model predicts the following 
periods of levodopa clinical benefit: 4 h for stable responders, 3 h for 
wearing-off fluctuators, and 1.5 h for on-off fluctuators. The model also 
predicts that diurnal fluctuation in untreated DRD should occur some 8 h after 
getting up in the morning. All these results fit well with clinical 
observations. Additionally, we calculated the probability of obtaining a second 
ON period after a single dose of levodopa in Parkinson's disease (the 'yo-yoing' 
phenomenon). The model shows that the yo-yoing phenomenon depends on how fast 
the curve crosses the threshold that separates ON and OFF states, which explains 
why this phenomenon is virtually exclusive to patients with on-off fluctuations. 
The model supports the idea that presynaptic mechanisms play a key role in both 
short-duration and long-duration responses encountered in Parkinson's disease. 
Dyskinesias may also be explained by the same mechanisms.