Prevention of Levodopa-Induced Dyskinesias by a Selective NR1A/2B N-Methyl-d-aspartate Receptor Antagonist in Parkinsonian Monkeys: Implication of Preproenkephalin.
Morissette, Marc PhD 1,2,*; Dridi, Mehdi MSc 1,2; Calon, Frederic PhD 1,2; Tahar, Abdallah Hadj PhD 3; Meltzer, Leonard T. PhD 4; Bedard, Paul J. PhD 3,5; Di Paolo, Therese PhD 1,2
[Article] Movement Disorders. 21(1):9-17, January 2006.

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colon; Enkephalin is reported to play an important role in the pathophysiology of levodopa (LD) -induced dyskinesias. The present study investigated the effect of chronic treatment with a selective NR1A/2B N-methyl-d-aspartate (NMDA) receptor antagonist, CI-1041, on the expression of preproenkephalin-A (PPE-A) in brains of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -treated monkeys in relation to the development of LD-induced dyskinesias. Four MPTP-monkeys received LD/benserazide alone; they all developed dyskinesias. Four other MPTP-monkeys received LD/benserazide plus CI-1041; only one of them developed mild dyskinesias at the end of the fourth week of treatment. Four normal monkeys and four saline-treated MPTP monkeys were also included. MPTP-treated monkeys had extensive and similar striatal dopamine denervation. An increase of PPE-A mRNA levels assayed by in situ hybridization was observed in the lateral putamen (rostral and caudal) and caudate nucleus (rostral) of saline-treated MPTP monkeys compared to controls, whereas no change or a small increase was observed in their medial parts. Striatal PPE-A mRNA levels remained elevated in LD-treated MPTP monkeys, whereas cotreatment with CI-1041 brought them back to control values. These findings suggest that chronic blockade of striatal NR1A/2B NMDA receptors with CI-1041 normalizes PPE-A mRNA expression and prevents the development of LD-induced dyskinesias in an animal model of Parkinson disease.

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