Does an inhibitory action of levodopa contribute to motor fluctuations?

The possibility that levodopa can both acutely improve as well as worsen motor function was investigated in eight fluctuating parkinsonian patients by administering 2-hour infusions of placebo and of levodopa at suprathreshold, threshold, and subthreshold rates when the subjects had been without medication overnight. Plasma levodopa and clinical status were monitored for an hour before, during, and for 3 hours after the infusions. Placebo infusions were associated with a mild deterioration in motor status during the period of monitoring. Subthreshold infusions were associated with greater motor deterioration than were placebo infusions in five of six subjects, but this deterioration did not occur in any specific temporal relation to the infusion. Threshold infusion rates in three subjects produced a transient improvement in motor function followed by deterioration to below the scores during the hour preceding the infusion and then returned to baseline. Suprathreshold rates in seven of the eight subjects were associated with motor improvement for ¹/₂ to 3¹/₂ hours followed by worsening to below baseline for 30 to 90 minutes and then spontaneous improvement to baseline function. These observations suggest that levodopa causes an acute deterioration in motor function following drug-induced improvement. Thus, the nadir of motor function in levodopa-treated patients may not be simply loss of dopaminergic stimulation and return to the untreated state, but may represent an inhibitory effect of levodopa.