Involvement of Sensorimotor, Limbic, and Associative Basal Ganglia Domains in L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia

Abstract

Dyskinesia represents a debilitating complication of L-3,4-dihydroxyphenylalanine (L-dopa) therapy for Parkinson's disease. Such motor manifestations are attributed to pathological activity in the motor parts of basal ganglia. However, because consistent funneling of information takes place between the sensorimotor, limbic, and associative basal ganglia domains, we hypothesized that nonmotor domains play a role in these manifestations. Here we report the changes in 2-deoxyglucose (2-DG) accumulation in the sensorimotor, limbic, and associative domains of basal ganglia and thalamic nuclei of four groups of nonhuman primates: normal, parkinsonian, parkinsonian chronically treated with L-dopa without exhibiting dyskinesia, and parkinsonian chronically treated with L-dopa and exhibiting overt dyskinesia. Although nondyskinetic animals display a rather normalized metabolic activity, dyskinetic animals are distinguished by significant changes in 2-DG accumulation in limbic-and associative-related structures and not simply in sensorimotorrelated ones, suggesting that dyskinesia is linked to a pathological processing of limbic and cognitive information. We propose that these metabolic changes reflect the underlying neural mechanisms of not simply motor dyskinesias but also affective, motivational, and cognitive disorders associated with long-term exposure to L-dopa.

Nur77 mRNA levels and L-Dopa-induced dyskinesias in MPTP monkeys treated with docosahexaenoic acid

“…Therefore, the correlation of Nur77 mRNA levels and LIDs in the anterior dorsal striatum suggests that Nur77 might modulate cognitive and learning aspects of motor processes. This is in accordance with the hypothesis that dyskinesias should not be regarded simply as a movement disorder, but also as a limbic and cognitive disorder (Guigoni et al, 2005). In rodents, we did observe a spatial correlation between Nur77 expression and L-DOPA-induced dyskinesia accompanied (whole striatum) or not (lateral part of the striatum) with locomotor sensitization in unilaterally lesioned 6-OHDA rats in a previous report (Sgambato-Faure et al, 2005).…”

Pharmacological Analysis Demonstrates Dramatic Alteration of D1Dopamine Receptor Neuronal Distribution in the Rat Analog of l-DOPA-Induced Dyskinesia

“…Animals displaying both an impaired stepping test (Olsson et al, 1995;Winkler et al, 2002;Pioli et al, 2008), measured on days 18 -20 (supplemental Fig. 1, available at www.jneurosci.org as supplemental material), and a loss of tyrosine hydroxylase-immunopositive fibers in the striatum Ͼ95% (Bezard et al, 2001b;Guigoni et al, 2005), assessed after completion of all experiments (supplemental Fig. 1, available at www.jneurosci.org as supplemental material), were retained for final analysis.…”

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

“…Experiments were conducted according to previously published procedures and methods (Bezard et al, 2003;Aubert et al, 2005;Guigoni et al, 2005b). Eighteen monkeys received once daily intravenous injections of 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) hydrochloride (0.2 mg/kg) until they displayed parkinsonian symptoms (mean number of injections, 15 Ϯ 1) , whereas four received vehicle only ( Fig.…”

“…Parkinsonian condition (and its reversal) was assessed on a parkinsonian monkey rating scale using videotape recordings of monkeys as previously described (Bezard et al, 2003;Guigoni et al, 2005b). A score of 0 corresponds to a normal animal and a score above 6 to a parkinsonian animal.…”