Continuous versus pulsatile administration of rotigotine in 6-OHDA-lesioned rats: contralateral rotations and abnormal involuntary movements

Abstract

Sustained drug delivery providing continuous dopaminergic stimulation is thought to prevent or delay the induction of motor complications (dyskinesia) in Parkinson's disease, whereas pulsatile administration is supposed to promote them. This study investigated the inducibility of sensitization and abnormal involuntary movements (AIMs), comparing continuous and pulsatile administration of rotigotine with pulsatile administration of 3,4-dihydroxy-L-phenylalanine (L-DOPA) for reference. Rats were unilaterally lesioned with 6 hydroxydopamine (6-OHDA). For pulsatile administration, L-DOPA-methylester (10 mg/kg L-DOPA i.p.) or rotigotine (1 mg/kg i.p.) were administered once or twice daily. For continuous administration, a slow release formulation of rotigotine was injected s.c. at a dose of 1 mg/kg every 48 h (experiment I) or every 24 h (experiment II). Pulsatile administration of rotigotine and L-DOPA caused contraversive rotations increasing progressively upon each successive treatment. AIMs started to occur after the second administration of L-DOPA but hardly after pulsatile rotigotine. Continuous rotigotine increased rotations, which reached a plateau after the second administration. No AIMs were observed under continuous administration. The continuous administration of rotigotine did not induce sensitization or AIMs, suggesting that continuous stimulation of dopaminergic receptors by rotigotine has no propensity to induce dyskinesia in this experimental model.

Drug-induced dyskinesia in Parkinson's disease. Should success in clinical management be a function of improvement of motor repertoire rather than amplitude of dyskinesia?

“…Several continuous drug delivery treatments are proposed as useful in reducing the incidence or treatment of dyskinesia [203,205-207], but there is insufficient evidence to characterize them as unequivocally effective [41]. For example, a study on an animal model of PD demonstrated that continuous delivery of rotigotine did not induce dyskinesia and functional sensitization, whereas using an oral formulation at different intervals did [208]. On the other hand, a pilot study on duodenal infusion of L-DOPA was shown to induce similar levels of dyskinesia as pulsatile delivery systems; however, once dyskinesia are present, switching to duodenal L-DOPA reduces the duration of dyskinesia [209].…”

Clinical pharmacology and efficacy of rotigotine (Neupro® patch) in the treatment of restless leg syndrome

“…A study in rats unilaterally lesioned with 6 hydroxydopamine investigated the inducibility of contraversive rotations by rotigotine compared to L-DOPA. The increased contraversive turning by both compounds indicated a post-synaptic activity [26]. This finding is further supported by another study showing that both continuous and pulsatile administration of rotigotine improved motor deficits and normalized motor function in MPTP-treated monkeys [27].…”

Rotigotine Transdermal Patch: A Review in Restless Legs Syndrome

“…In vivo, sustained rotigotine administration with a slowrelease formulation resulted in decreased extracellular dopamine levels (suggesting continuous receptor stimulation) [10], and reduced the risk of dyskinesia induction (which is observed with pulsatile administration of dopaminergic drugs) [11][12][13].…”