Experimental reappraisal of continuous dopaminergic stimulation against L‐dopa‐induced dyskinesia

Abstract

The concept of ‘‘continuous dopaminergic stimulation’’ (498 occurrences on PubMed, of which 46 feature these words in their title) emerged in the 1980s primarily for managing the complex fluctuations in motor performances 1‐3 that are the major problem in the long-term management of Parkinson’s disease. Although motor fluctuations were the first targeted issues of the concept (and its pharmacological consequences), levodopa-induced dyskinesia was rapidly encompassed as a possible manifestation controllable by continuous dopaminergic stimulation. 4 The short plasma half-life of levodopa and the ensuing pulsatile stimulation of striatal dopamine receptors were thought to underlie the propensity of the drug to induce dyskinesia. Late-stage parkinsonian patients indeed benefit from continuous dopaminergic stimulation with notable improvement of established dyskinesia, 5 but large trials in de novo parkinsonian patients with either continuous delivery of levodopa in early Parkinson’s disease using Sinemet CR (CR-FIRST) 6 or the combination of levodopa with the C-O-methyltransferase inhibitor entacapone (STRIDE-PD) 7 failed to reduce the risk of dyskinesia induction. Because the experimental evidence on continuous dopaminergic stimulation has been skeletal, Papathanou et al report in this issue of Movement Disorders on the effect of duodenal compared with intraperitoneal levodopa administration on the induction and expression of abnormal involuntary movements in 6-hydroxydopamine (6-OHDA)‐lesioned rats. Their experimental data confirm that more continuous delivery of levodopa by intraduodenal infusion can exert a beneficial effect on the expression of established dyskinesia. Probably more interesting is their second claim: that continuous dopaminergic stimulation may not reduce the risk of dyskinesia induction, at least in this rodent model. This second claim contradicts both the concept of providing continuous dopaminergic stimulation for preventing dyskinesia incidence and the conclusions made by previous experimental studies obtained in the very same 6-OHDA-lesioned rat model 8 and in the MPTP-treated marmoset model of dyskinesia. 9 Those studies indeed showed that levodopa combined with entacapone delayed the onset of abnormal involuntary movements or dyskinesia, respectively and reduced their severity. 8,9 The question thus arises as to why the previous and current studies reached different conclusions, if they actually did. Two studies were performed in the medial forebrain bundle 6-OHDA-lesioned rat model 8,10 that produced extensive nigrostriatal lesions (more than 90%). They differed in their screening method, with one challenging the unlesioned hemisphere with amphetamine 10 and the other priming the