Antagonists of the
N-methyl-D-aspartate (
NMDA) subtype of
glutamate receptor have been reported to potentiate the antiparkinsonian action of
levodopa and reverse
levodopa-induced motor fluctuations in animal models of
Parkinson's disease. To evaluate the effect of
NMDA receptor blockade on
dyskinesias complicating the response to long-term
levodopa therapy, we studied the selective antagonist
LY235959 in six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. Drugs were administered subcutaneously,
LY235959 at doses of 0.5, 1.0, 3.0, and 5.0 mg/kg and
levodopa/
benserazide at doses that produced moderate
dyskinesias while almost totally reversing parkinsonian signs. Compared with vehicle control
injections,
LY235959 (3.0 mg/kg) abolished
oral dyskinesias and diminished choreic
dyskinesias by 68% (p < 0.01). Lower doses had smaller effects, although still significant, on
oral dyskinesias (55% reduction at 1.0 mg/kg, p < 0.05). The highest
LY235959 dose (5.0 mg/kg) prolonged
oral dyskinesia suppression, but tended to increase
dystonia severity.
LY235959 had no effect on motor function when given alone and did not reduce the antiparkinsonian response to
levodopa. These findings suggest that
NMDA receptor blockade may ameliorate the dyskinetic complications of long-term
levodopa therapy, without diminishing the beneficial effects on parkinsonian signs.