Effect of non-dopaminergic drug treatment on Levodopa induced dyskinesias in MPTP monkeys : common implication of striatal neuropeptides

Authors: Tamim, Mohamed KhalilSamadi, PershiaMorissette, MarcGrégoire, LaurentOuattara, BazoumanaLévesque, DanielRouillard, ClaudeDi Paolo, Thérèse
Abstract: Dopamine denervation in Parkinson's disease and repeated Levodopa (L-DOPA) administration that induces dyskinesias are associated with an enhancement of basal ganglia neuropeptide transmission. Various adjunct non-dopaminergic treatments to Levodopa were shown to reduce and/or prevent dyskinesias. The aim of this study was to seek if non-dopaminergic drug treatments to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned monkeys combined with L-DOPA to prevent dyskinesia were associated with changes of striatal neuropeptides. Chronic treatment with Ro 61-8048 a kynurenine hydroxylase inhibitor, docosahexaenoic acid (DHA) a polyunsaturated fatty acid (omega-3), naltrexone an opioidergic antagonist and CI-1041 an N-methyl-d-aspartate (NMDA) glutamate receptor antagonist with L-DOPA prevented dyskinesias to various extents except naltrexone whereas all MPTP monkeys treated with L-DOPA alone developed dyskinesias. Striatal preproenkephalin (PPE), preprodynorphin (PPD) and preprotachykinin A (PPT-A) mRNA levels were measured by in situ hybridization. An increase of PPE and PPD mRNA levels was observed in anterior caudate nucleus of L-DOPA treated MPTP monkeys compared to controls and to Saline-treated MPTP monkeys whereas PPT-A mRNA levels were unchanged. Striatal PPE and PPD mRNA levels remained elevated in L-DOPA plus naltrexone-treated MPTP monkeys, while co-treatment with DHA, CI-1041 or Ro 61-8048 prevented their increase to various extents. Maximal dyskinesias scores of MPTP monkeys correlated significantly with striatal PPE and PPD mRNA levels but not with PPT-A mRNA levels. These results show that drugs displaying a wide range of pharmacological activities can modulate L-DOPA induced dyskinesias and this activity is correlated with striatal PPD and PPE mRNA levels suggesting a convergent mechanism.
Document Type: Article de recherche
Issue Date: 2 July 2009
Open Access Date: Restricted access
Document version: VoR
Permalink: http://hdl.handle.net/20.500.11794/17009
This document was published in: Neuropharmacology, Vol. 58 (1), 2010, 286-296 (2010)
https://doi.org/10.1016/j.neuropharm.2009.06.030
Alternative version: 10.1016/j.neuropharm.2009.06.030
19576910
Collection:Articles publiés dans des revues avec comité de lecture

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