Alterations in striatal neuropeptide mRNA produced by repeated administration of L-DOPA, ropinirole or bromocriptine correlate with dyskinesia induction in MPTP-treated common marmosets
Section snippets
Animals
Adult common marmosets (Callithrix jacchus, n=20) of both sexes, weighing 280–360 g, were used. Animals were housed in pairs under standard conditions in a temperature- (27±1°C) and humidity (relatively 50%)-controlled room with a 12-h light/dark cycle. The animals had free access to food pellets and tap water and also received Mazuri marmoset jelly and fresh fruit. All procedures were performed in accordance with the Home Office guidelines, Animals (Scientific Procedures) UK Act 1986.
Drug treatments
Marmosets
[3H]Mazindol binding
In normal animals, high levels of specific [3H]mazindol binding were observed in both the caudate nucleus and putamen. There was a marked decrease in [3H]mazindol binding in MPTP-treated animals compared to controls (98–99%; P<0.01) in these areas (Fig. 1). None of the drug treatments had any significant effect on [3H]mazindol binding compared to the MPTP-treated drug naive group and no differences were found between treatment groups.
PPE-A mRNA
The mRNA for PPE-A was strongly expressed in cell clusters
Discussion
This study set out to establish whether long acting D2-like DA agonists, such as bromocriptine and ropinirole, which induce lower levels of dyskinesia than L-DOPA differentially alter biochemical markers of the direct and indirect output pathways from the caudate nucleus and putamen. There was a marked loss in striatal dopaminergic uptake sites to the same extent in all MPTP-treated groups and none of the drug treatments had any effect on the degree of nigro-striatal innervation as judged by
Conclusion
These results show that L-DOPA treatment producing severe dyskinesia in MPTP-lesioned primates normalises the decrease in PPT mRNA (direct pathway) but fails to attenuate the elevated PPE-A mRNA (indirect pathway), while equi-effective doses of the D2/D3 agonists ropinirole and bromocriptine that produce mild dyskinesia reverse the increase in PPE-A mRNA but had no effect on PPT mRNA suggesting that the D2-mediated indirect pathway may play a prominent role in the pathogenesis of dyskinesias.
Acknowledgements
This work was supported by a grant from National Parkinson Foundation, Miami, FL, USA, the Parkinson’s Disease Society, UK, and SmithKline Beecham Pharmaceuticals, UK.
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