The short-duration response, long-duration response, and dyskinetic response to levodopa change during long-term levodopa therapy. How these responses evolve, and which changes contribute to the emergence of motor fluctuations, remain unclear. We studied 18 subjects with Parkinson's disease before they began levodopa therapy and after 6, 12, 24, and 48 months of long-term levodopa therapy. The responses to 2-hour levodopa infusions after overnight and after 3 days of levodopa withdrawal were studied from 6 months onward. The mean magnitude of the short-duration response and the long-duration response measured after overnight without antiparkinsonian medications did not change during the 4 years. However, after 3 days without levodopa, it was apparent that the short-duration-response magnitude was progressively increasing (p < 0.0001) and that the long-duration response was decaying more rapidly (p = 0.0004). The short-duration-response magnitude at 4 years was inversely related to the long-duration-response magnitude (p = 0.022), suggesting that the long-duration response was one determinant of the short-duration-response magnitude. Dyskinesia increased progressively in severity during the study (p = 0.013). The duration of the short-duration response and dyskinesia did not change during the 4 years. Subject reports of motor fluctuations tended to be associated with a large short-duration response (p = 0.054). We suggest that a larger long-duration response, rather than a shortened one, is more important to the development of fluctuations. Improving the baseline or practical-off motor function to reduce the magnitude of the short-duration response may be a strategy to treat fluctuations.

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The cause of motor fluctuations occurring during constant-rate levodopa infusions is unknown. We examined whether known pharmacokinetic factors could explain the fluctuations and looked for clues to pharmacodynamic causes. Eleven subjects with stage III-V Parkinson's disease (PD) and a fluctuating response to levodopa underwent constant-rate infusions for 36-110 h. Levodopa, 3-O-methyldopa (3-OMD), and plasma large neutral amino acids (LNAAs) were measured at 2- to 6-h intervals and PD was monitored hourly from 07:00 to 22:00 h with tapping speed. Ten subjects had motor fluctuations during the infusions. Zero to 68% of the variability of tapping speed could be explained by variation in plasma LNAA concentrations in individual subjects. Fluctuations occurred more commonly later in the day, which may be related to the tendency for LNAAs to increase during the day. Motor fluctuations were not associated with minor variations in levodopa or 3-OMD concentrations. Fluctuations during constant infusions were more marked in patients using larger daily doses of oral levodopa; severity of PD did not predict fluctuations during the infusions. There was no trend for fluctuations or dyskinesia to decrease or increase during several days of constant-rate levodopa infusion. A portion of motor fluctuations occurring during constant levodopa infusions can be explained by peripheral pharmacokinetic mechanisms. Fluctuations are more prominent in subjects who have taken larger daily doses of levodopa, implicating pharmacodynamic factors as well.

We determined whether methylphenidate, a dopamine transporter blocker, modifies motor, cognitive, or affective responses to L-Dopa in Parkinson's disease (PD). Five patients who reported benefit from L-Dopa/carbidopa and motor fluctuations were admitted and withdrawn from their usual antiparkinsonian medications. On 3 consecutive days in a randomized double-blinded fashion, they took 0.2 mg/kg oral methylphenidate or placebo followed 30 minutes later by a 1-hour intravenous L-Dopa (2 mg/kg per h) or placebo infusion. Vital signs, tapping, walking, dyskinesias, mood, anxiety, concentration, and arousal were monitored every 30 minutes. Cognitive testing was performed before and following the infusion. Methylphenidate combined with L-Dopa led to greater peak right-hand tapping speed than either alone. Dyskinesia severity increased most when methylphenidate and L-Dopa were co-administered. There were no differences between conditions on the Stroop test, digit ordering, simple reaction time, or covert orienting of attention validity effect. Methylphenidate alone led to improvement in choice reaction time. Change in self-assessed analogue ratings of mood, anxiety, arousal, or concentration did not differ between conditions. Methylphenidate increased the motor effects of L-Dopa with minimal effects on cognitive or affective functions, suggesting a physiologic role for the dopamine transporter in patients with PD with motor fluctuations.