Prevention of levodopa-induced dyskinesias by a selective NR1A/2B N-methyl-D-aspartate receptor antagonist in parkinsonian monkeys: Implication of preproenkephalin

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. © 2005 Movement Disorder Society