Levodopa‐induced dyskinesia in MPTP‐treated macaques is not dependent on the extent and pattern of nigrostrial lesioning

Abstract

The extent of nigrostriatal denervation is presumed to play a role in the genesis of levodopa-induced dyskinesia. Yet some parkinsonian patients who have been treated over a long period do not develop dyskinesia, raising the possibility that the pattern of denervation is as important as the extent of lesioning as a risk factor. Here we study the extent and pattern of nigrostriatal denervation in a homogeneous population of parkinsonian macaque monkeys chronically treated with levodopa. Based on the characteristics of the lesioning, non-dyskinetic animals could not be differentiated from those with dyskinesia. Indeed, the number of tyrosine-hydroxylase (TH)-immunopositive neurons in the substantia nigra pars compacta, striatal dopamine transporter (DAT) binding and TH immunostaining, as well as the overall TH striatal content measured by Western blotting were identical. Moreover, the patterns of lesioning assessed by a detailed analysis of the TH- and DAT-immunopositive striatal fibers were comparable in all functional quadrants and at all rostro-caudal levels considered. These data indicate that neither the extent nor the pattern of nigrostriatal lesioning are sufficient to explain the occurrence of levodopa-induced dyskinesia.

Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with l -dopa–induced dyskinesia

“…Starting at 8 wk postsurgery, animals were examined every 2 d for behavioral responses to their tailored dose of L-dopa, the D1 agonist SKF-38393 (1.5 mg/kg, s.c.), or the D2/D3 agonist quinpirole (1.5 mg/kg, s.c.) (46). Postmortem processing was carried out as described (47).…”

RGS9–2 Negatively Modulates l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Experimental Parkinson's Disease

“…The animals used for the Western blotting study have been presented in previous publications. Their motor behavior (Bezard et al, 2003), the extent of lesion (Guigoni et al, 2005a) and various postmortem indexes have been published using this brain bank (Aubert et al, 2005(Aubert et al, , 2007 (Table 1).…”

“…Dyskinesia developed by MPTPlesioned animals was similar to the LID observed in PD patients. The extent of lesion was checked for ensuring they had identical parameters to those of the animals used in the Western blot analysis (Guigoni et al, 2005a) (Table 1).…”

“…Chelatec, Nantes, France) was measured as previously described Guigoni et al, 2005a). Processing of mesencephalic sections for tyrosine hydroxylase (TH) immunohistochemistry, counterstaining with cresyl violet (Nissl staining) and cell counts (Visioscan version 4.12; Biocom, Les Ulis, France) were performed as described previously Guigoni et al, 2005a).…”

“…Processing of mesencephalic sections for tyrosine hydroxylase (TH) immunohistochemistry, counterstaining with cresyl violet (Nissl staining) and cell counts (Visioscan version 4.12; Biocom, Les Ulis, France) were performed as described previously Guigoni et al, 2005a). The boundaries of the SNc were chosen on three consecutive sections corresponding to a representative median plane of the SNc by examining the size and shape of the different TH-immunoreactive neuronal groups, cellular relationships to axonal projections and nearby fiber bundles.…”