Decreased expression of l-dopa-induced dyskinesia by switching to ropinirole in MPTP-treated common marmosets.

Current concepts suggest that pulsatile stimulation of dopamine receptors following L-dopa administration leads to priming for dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated primates, while continuous dopaminergic stimulation with long-acting dopamine agonists does not. We investigated whether L-dopa-induced dyskinesia is reduced by switching to a dopamine agonist. MPTP-treated marmosets received chronic treatment with L-dopa or ropinirole in doses producing equivalent motor activity and reversal of motor deficits. Administration of L-dopa led to the rapid onset of moderate to severe dyskinesia, whereas ropinirole produced only mild dyskinesia. Animals initially treated with L-dopa were switched to an equivalent dose of ropinirole and those treated with ropinirole were switched to an equivalent dose of L-dopa for 56 days. L-dopa-primed animals that were switched to ropinirole showed a trend towards a reduction of dyskinesia intensity, whereas animals initially treated with ropinirole and switched to L-dopa showed a trend toward increased dyskinesia intensity. A subsequent, acute L-dopa challenge reversed motor deficits and induced intense dyskinesia in both groups. This suggests that L-dopa leads to the priming and expression of dyskinesia, but that expression is not maintained when switching to a long-acting dopamine agonist. In contrast, dopamine agonists may prime for dyskinesia, but do not lead to its full expression.

Switching from levodopa to the long-acting dopamine D2/D3 agonist piribedil reduces the expression of dyskinesia while maintaining effective motor activity in MPTP-treated primates.

BACKGROUND: The control of motor complications following dopaminergic medication in late-stage Parkinson disease remains problematic. OBJECTIVE: We now investigate the potential of oral administration of the long-acting dopamine D2/D3 agonist piribedil to decrease the expression of dyskinesia induced by prior exposure to levodopa in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated primates. METHODS: MPTP-treated common marmosets were treated with equieffective doses of levodopa (10.0-12.5 mg/kg PO, twice daily) or piribedil (3.0-4.0 mg/kg PO, once daily) for 30 days and then switched to the alternative treatment for a further 35 days. RESULTS: Levodopa administration markedly improved motor function, but dyskinesia rapidly appeared and intensified as treatment progressed. Administration of piribedil produced a similar reversal of MPTP-induced motor deficits but with comparatively mild dyskinesia. On switching from levodopa to piribedil, the intensity of dyskinesia decreased without altering the improvement in motor deficits. However, on switching from piribedil to levodopa, the rapid increase in dyskinesia despite the improvement in motor function being maintained suggests that piribedil also primes for but does not markedly express dyskinesia. CONCLUSION: The study confirms the low dyskinesia expression resulting from piribedil treatment compared with an equieffective dose of levodopa. Importantly, the results show that switching from levodopa to piribedil rapidly results in a sustained decrease in dyskinesia intensity.

Multiple small doses of levodopa plus entacapone produce continuous dopaminergic stimulation and reduce dyskinesia induction in MPTP-treated drug-naive primates.

Long-acting dopamine agonist drugs induce a lower incidence of dyskinesia in MPTP-treated primates and patients with Parkinson's disease compared to pulsatile treatment with levodopa, supporting the concept of continuous dopaminergic stimulation as a means of dyskinesia avoidance. We examined the effects of L-dopa administered with or without the COMT inhibitor entacapone on dyskinesia induction in previously untreated MPTP-treated common marmosets. Administration of L-dopa (12.5 mg/kg p.o.) plus carbidopa twice daily produced fluctuating improvement in motor behavior coupled with dyskinesia. Coadministration with entacapone produced similar patterns of motor improvement and dyskinesia that were not different from that produced by L-dopa alone. Treatment with L-dopa (6.25 mg/kg p.o.) plus carbidopa four times daily reversed motor disability and induced dyskinesia in a manner that was not different from the twice-daily treatment regimens. However, coadministration with entacapone produced more continuous improvement in locomotor activity with less dyskinesia than animals treated with L-dopa four times daily alone. These data support the notion that pulsatile stimulation contributes to the development of dyskinesia and suggests that more frequent dosing of L-dopa plus entacapone may be a useful treatment strategy for patients in the early stages of Parkinson's disease.

Effect of 5-HT1B/D receptor agonist and antagonist administration on motor function in haloperidol and MPTP-treated common marmosets.

An interaction between brain serotonergic and dopaminergic systems involving 5-HT(1B) receptors may contribute to motor complications arising from the drug treatment of neurological and psychiatric disorders. This study assessed the effects of treatment with a non-selective 5-HT(1B/D) receptor agonist and a selective 5-HT(1B) receptor antagonist on akinesia induced in marmosets by long-term treatment with haloperidol and on motor disability and l-3, 4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets. In marmosets treated chronically with haloperidol, the 5-HT(1B) agonist SKF-99101-H reduced locomotor activity and induced motor disability, whereas the 5-HT(1B) antagonist SB-224289-A had no effect on motor behaviour. Haloperidol administration induced a suppression of locomotor activity which was not reversed by co-administration of either SKF-99101-H or SB-224289-A. In MPTP-treated common marmosets, neither SKF-99101-H nor SB-224289-A induced any significant change in motor function. However, SKF-99101-H inhibited L-DOPA-induced dyskinesia and the reversal of motor deficits whereas SB-224289-A was without effect. The results of this study indicate that the 5-HT(1B) receptor appears not to be an appropriate target for the treatment of Parkinson's disease (PD) or for the control of drug-induced motor complications developed as a tong-term consequence of neuroleptic or L-DOPA treatment.

Beginning-of-dose and rebound worsening in MPTP-treated common marmosets treated with levodopa.

A wide range of motor fluctuations develop in Parkinson's disease (PD) patients after prolonged levodopa (L-dopa) treatment, but few experimental models exist in which these can be investigated. We report on motor fluctuations occurring in MPTP-treated common marmosets (Callithrix jacchus) treated repeatedly with L-dopa. All animals showed an improvement in motor function in response to L-dopa, and rapidly developed peak-dose dyskinesia. During the period of L-dopa action, brief periods of immobility were occasionally observed. After acute L-dopa challenge, animals exhibited a worsening of motor function before improvement, and after the beneficial response to L-dopa declined, motor performance showed rebound worsening to below-baseline values. Before L-dopa challenge and during wearing-off and rebound worsening, leg dystonias were observed. Although these findings cannot necessarily be generalized to all MPTP-treated nonhuman primates, they demonstrate that MPTP-treated marmosets show a range of different motor fluctuations analogous to those seen in PD patients chronically treated with L-dopa. Therefore, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates can provide a model in which the pathophysiology of treatment complications can be investigated.