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

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.

• Authors: Mohamed Khalil Tamim, Pershia Samadi, Marc Morissette, Laurent Grégoire, Bazoumana Ouattara, Daniel Lévesque, Claude Rouillard, Thérèse Di Paolo
• Journal: Neuropharmacology (Neuropharmacology) Vol. 58 Issue 1 Pg. 286-96 (Jan 2010) ISSN: 1873-7064 [Electronic] England
• PMID: 19576910 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiparkinson Agents
• Benzoxazoles
• Dopamine Uptake Inhibitors
• Enkephalins
• Iodine Isotopes
• Neuropeptides
• Piperidines
• Protein Precursors
• RNA, Messenger
• Ro 61-8048
• Sulfonamides
• Tachykinins
• Thiazoles
• pre-prodynorphin
• preprotachykinin
• RTI 121
• Docosahexaenoic Acids
• Levodopa
• besonprodil
• Naltrexone
• Dynorphins
• preproenkephalin
• Cocaine
• Dopamine

Topics

• Animals
• Antiparkinson Agents (adverse effects, pharmacology)
• Benzoxazoles (pharmacology, therapeutic use)
• Cocaine (analogs & derivatives, metabolism)
• Corpus Striatum (drug effects, metabolism)
• Disease Models, Animal
• Docosahexaenoic Acids (pharmacology, therapeutic use)
• Dopamine (metabolism)
• Dopamine Uptake Inhibitors (metabolism)
• Dynorphins (genetics, metabolism)
• Dyskinesia, Drug-Induced (drug therapy, etiology, pathology)
• Enkephalins (genetics, metabolism)
• Female
• Iodine Isotopes (metabolism)
• Levodopa (adverse effects)
• Macaca fascicularis
• Naltrexone (pharmacology, therapeutic use)
• Neuropeptides (metabolism)
• Ovariectomy
• Parkinsonian Disorders (drug therapy)
• Piperidines (pharmacology, therapeutic use)
• Protein Precursors (genetics, metabolism)
• RNA, Messenger (metabolism)
• Sulfonamides (pharmacology, therapeutic use)
• Tachykinins (genetics, metabolism)
• Thiazoles (pharmacology, therapeutic use)
• Time Factors