L-dopa-induced dyskinesia: beyond an excessive dopamine tone in the striatum

Abstract

L-dopa remains the mainstay treatment for Parkinson's disease (PD), although in later stages, treatment is complicated by L-dopa-induced dyskinesias (LID). Current evidence links LID to excessive striatal L-dopa-derived dopamine (DA) release, while the possibility of a direct involvement of L-dopa itself in LID has been largely ignored. Here we show that L-dopa can alter basal ganglia activity and produce LID without enhancing striatal DA release in parkinsonian non-human primates. These data may have therapeutic implications for the management of advanced PD since they suggest that LID could result from diverse mechanisms of action of L-dopa.

Figure 1

(A) L-dopa plasma levels after intravenous administration of 2.5 mg/kg together with benserazide (n = 4). Peak L-dopa plasma concentrations correspond to morning L-dopa dosages in Parkinson's disease patients with advanced disease and motor fluctuations. Data are shown as mean concentration (in nM) ± s.e.m. *P < 0.05 vs. baseline. (B) Time course of dialysate concentrations of DA and L-dopa in the striatum and GABA in the thalamus after L-dopa + BZD administration (time 0). Data correspond to the mean concentration ± s.e.m. of the dialysate content expressed in nM and result from the combination of data from two modalities of L-dopa + BZD administration (2.5 mg/kg i.v., n = 4 or 20 mg/kg p.o., n = 4). The inset reports the overall increase in extracellular L-dopa levels of each administration modality over the observation period of three hours. *P < 0.05 vs. baseline. (C) Time course of the striatal application of benserazide (BZD, 100 μM), L-dopa + BZD (100 μM each) or DA (10 μM) on DA and DOPAC extracellular levels. Drugs were applied using reverse microdialysis. The period of infusion, initially scheduled to last 40 minutes, was stopped after the first signs of dyskinesia, in order to avoid persistent and long term dyskinesia (dyskinesia duration corresponds to black bars). DA was subsequently applied after a recovery period using the same criteria. The inset provides a magnification of extracellular DA concentrations. Dialysate contents are expressed as mean concentration (in nM) ± s.e.m (n = 2). ^§P = 0.09 and 0.06 vs t = 20 min. ^#P = 0.09 and 0.06 vs t = 100 min. *P < 0.05 vs. t = 100 min. aCSF = artificial cerebrospinal fluid.