Effect of non-dopaminergic drug treatment on Levodopa induced dyskinesias in MPTP monkeys: common implication of striatal neuropeptides.
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.
Tamim
Mohamed Khalil
MK
Faculty of Pharmacy, Laval University, G1K 7P4 Québec, Canada.
Samadi
Pershia
P
Morissette
Marc
M
Grégoire
Laurent
L
Ouattara
Bazoumana
B
Lévesque
Daniel
D
Rouillard
Claude
C
Di Paolo
Thérèse
T
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000494:pharmacology*; D001583:Benzoxazoles / Q000494:pharmacology / Q000627:therapeutic use; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D005260:Female; D007456:Iodine Isotopes / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects*; D008252:Macaca fascicularis; D009271:Naltrexone / Q000494:pharmacology / Q000627:therapeutic use; D009479:Neuropeptides / Q000378:metabolism*; D010052:Ovariectomy; D020734:Parkinsonian Disorders / Q000188:drug therapy; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D015320:Tachykinins / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors
D000978:Antiparkinson Agents; D001583:Benzoxazoles; D018765:Dopamine Uptake Inhibitors; D004745:Enkephalins; D007456:Iodine Isotopes; D009479:Neuropeptides; D010880:Piperidines; D011498:Protein Precursors; D012333:RNA, Messenger; C110196:Ro 61-8048; D013449:Sulfonamides; D015320:Tachykinins; D013844:Thiazoles; C036448:pre-prodynorphin; C044206:preprotachykinin; C079213:RTI 121; D004281:Docosahexaenoic Acids; D007980:Levodopa; C481484:besonprodil; D009271:Naltrexone; D004399:Dynorphins; C033660:preproenkephalin; D003042:Cocaine; D004298:Dopamine