Pathophysiology of levodopa-induced dyskinesia: Potential for new therapies

Bézard, Erwan; Brotchie, Jonathan M.; Gross, Christian E.

doi:10.1038/35086062

Cited by 460 publications

(353 citation statements)

References 124 publications

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“…Specifically, dyskinesias, characterized by loss of motor control manifesting as tics, spasms, or myoclonus, are a common side effect of chronic levo (L)-dopa administration used in the treatment of Parkinson's disease. Dyskinesias are thought to result from behavioral sensitization to L-dopa-induced elevations in DA transmission (Bezard et al, 2001). Interestingly, MPTP-treated monkeys, an animal model of Parkinson's disease, exhibit a significant loss of D3R binding in the caudate nucleus , and L-dopa-induced dyskinesia in MPTP-treated monkeys is significantly attenuated by the D3R-selective partial agonist BP897, and antagonists nafadotride and ST 198 (Guillin et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Dose–response analysis of locomotor activity and stereotypy in dopamine D3 receptor mutant mice following acute amphetamine

McNamara

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Stanford

et al. 2006

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Accumulating evidence suggests that dopamine D3 receptor (D3R) stimulation is inhibitory to spontaneous and psychostimulant-induced locomotion through opposition of concurrent D1R and D2R-mediated signaling. To evaluate this model, we used homozygous D3R mutant mice and wildtype controls to investigate the role of the D3R in locomotor activity and stereotypy stimulated by acute amphetamine (AMPH) (0.2, 2.5, 5.0, 10.0 mg/kg). At the lowest dose tested (0.2 mg/kg), neither D3R mutant mice nor wild-type mice exhibited measurable change in locomotor activity or stereotypy relative to their respective saline-treated controls. D3R mutant mice exhibited a significantly greater increase in locomotor activity, but not stereotypy, relative to wild-type mice in response to treatment with AMPH 2.5 mg/kg. AMPH-induced locomotor activity and stereotypy were similar in both wild-type and D3R mutant mice at both the 5.0 and 10 mg/kg AMPH doses. These findings provide further support for an inhibitory role for the D3R in AMPH-induced locomotor activity, and demonstrate a more limited role for the D3R in modulating AMPH-induced stereotypy.

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Section: Discussionmentioning

confidence: 99%

Dose–response analysis of locomotor activity and stereotypy in dopamine D3 receptor mutant mice following acute amphetamine

McNamara

Logue

Stanford

et al. 2006

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“…Current models of basal ganglia dysfunction predict that dopamine-agonist induced dyskinesia results from D1 receptor-mediated over-activation of striatal neurons projecting to the basal ganglia output nuclei (direct pathway) plus D2 receptor-mediated inhibition of striato-pallidal neurons (indirect pathway) (reviewed by Obeso et al, 2000;and Bezard et al, 2001). These changes would release thalamo-cortical and brain stem circuits from tonic inhibition exerted by the basal ganglia output nuclei (Filion et al, 1991;Mitchell et al, 1992).…”

Section: Severity Of Fd Is Related To Striatal and Motor Cortex Bold mentioning

confidence: 99%

Mapping the Effects of Three Dopamine Agonists with Different Dyskinetogenic Potential and Receptor Selectivity Using Pharmacological Functional Magnetic Resonance Imaging

Delfino

Kalisch

Czisch

et al. 2007

Neuropsychopharmacol

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The mechanisms underlying dopamine agonist-induced dyskinesia in Parkinson's disease remain poorly understood. Similar to patients, rats with severe nigrostriatal degeneration induced by 6-hydroxydopamine are more likely to show dyskinesia during chronic treatment with unselective dopamine receptor agonists than with D2 agonists, suggesting that D1 receptor stimulation alone or in conjunction with D2 receptor stimulation increases the chances of experiencing dyskinesia. As a first step towards disclosing drug-induced brain activation in dyskinesia, we examined the effects of dopamine agonists on behavior and blood oxygenation level-dependent (BOLD) signal in the striatum and motor cortex of rats with unilateral nigrostriatal lesions. Rats were rendered dyskinetic before pharmacologic functional magnetic resonance imaging by means of a repeated treatment regime with dopamine agonists. The unselective agonist apomorphine and the selective D1/D5 agonist SKF-81297 induced strong forelimb dyskinesia (FD) and axial dystonia and increased BOLD signal in the denervated striatum. Besides, SKF-81297 produced a significant but smaller BOLD increase in the intact striatum and a symmetric bilateral increase in the motor cortex. The D2 family agonist quinpirole, which induced mild dyskinesia on chronic treatment, did not produce BOLD changes in the striatum or motor cortex. Further evidence to support an association between BOLD changes and dyskinesia comes from a direct correlation between scores of FD and magnitude of drug-induced BOLD increases in the denervated striatum and motor cortex. Our results suggest that striatal and cortical activation induced by stimulation of D1/D5 receptors has a primary role in the induction of peak dose dyskinesia in parkinsonism.

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“…The most common form of dyskinesia consists in a combination of dystonic and choreiform movements occurring at the time when L-DOPA is providing the maximal relief of parkinsonian symptoms ("on" dyskinesias; (Marconi et al, 1994). Several lines of evidence concur to suggest that L-DOPA-induced dyskinesia results from a pulsatile stimulation of brain dopamine (DA) receptors, triggering a complex cascade of molecular and synaptic alterations within the basal ganglia (Chase, 1998;Bezard et al, 2001;Picconi et al, 2003). Knowledge of the plastic changes that prime the basal ganglia for a dyskinetic motor response to L-DOPA would be greatly advanced by the availability of a dyskinesia model in mice, which lend themselves to genetic manipulation of specific molecular and synaptic components.…”

Section: Introductionmentioning

confidence: 99%