Chronic treatment with small doses of cabergoline prevents dopa-induced dyskinesias in parkinsonian monkeys.
Levodopa continues to be the most effective agent for the symptomatic treatment of Parkinson's disease (PD). But over time, initial benefits decline in efficacy because of a rise in adverse effects such as dyskinesias. The pathophysiology of levodopa-induced dyskinesias (LID) is not completely understood, but it appears to result from deficient regulation by dopamine of corticostriatal glutamatergic inputs leading to a cascade of neurochemical changes in the striatum and the output pathways. In the present study, we examined if the addition of small doses of cabergoline (a long-acting D(2) receptor agonist) to levodopa could prevent LID. The major hypothesis is that sustained activation of postsynaptic D(2) receptors on medium spiny neurons even by small doses of cabergoline could prevent or reduce LID. The minor hypothesis, and the more controversial of the two, is that the long-acting stimulation by small doses of cabergoline could diminish the release of glutamate by the corticostriatal pathway and prevent LID. Eight MPTP-treated monkeys with a long-standing and stable parkinsonian syndrome and having never received dopaminergic agents were used. Two groups of four were treated for 1 month with levodopa/benserazide administered orally (100 mg/25 mg). The second group received in addition a threshold dose of cabergoline (dose ranging from 0.015 to 0.035 mg/kg, SC). During the treatment, we observed LID in the levodopa group but not in the group receiving levodopa+cabergoline. Furthermore, the combination produced a comparable antiparkinsonian effect in terms of quality but prolonged the duration (by 1 to 2 hours) and increased the locomotion (mean for 2 weeks congruent with 104%). Our data suggest that a small dose of a long-acting D(2) agonist combined with high doses of levodopa could be preventive of LID in patients with PD and could be an alternative to using antiglutamatergic agents for this purpose.
Bélanger
Nancy
N
Department of Medicine and Neuroscience Unit, Laval University and Research Center, Ste-Foy, Quebec, Canada.
Grégoire
Laurent
L
Hadj Tahar
Abdallah
A
Bédard
Paul J
PJ
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects*; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001522:Behavior, Animal / Q000187:drug effects; D000077465:Cabergoline; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004409:Dyskinesia, Drug-Induced / Q000209:etiology* / Q000517:prevention & control*; D004873:Ergolines / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D008124:Locomotion / Q000187:drug effects; D008252:Macaca fascicularis; D010300:Parkinson Disease / Q000188:drug therapy*; D011187:Posture
D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D004873:Ergolines; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000077465:Cabergoline