Antiparkinsonian actions of CP-101,606, an antagonist of NR2B subunit-containing N-methyl-D-aspartate receptors

In the setting of nigrostriatal dopamine depletion, glutamatergic pathways to the striatum and basal ganglia output nuclei become overactive. Systemic ally administered glutamate receptor antagonists may have direct antiparkin sonian actions in rodents, but there is little evidence for this in primate s. Glutamate antagonists may also potentiate conventional dopaminergic ther apies; however, there is concern that broad spectrum, nonselective antagoni sts may have unwanted side-effects. Because subunit-selective antagonists m ay avoid these liabilities, we have examined the antiparkinsonian effects o f a selective antagonist of the NR2B subunit of the NMDA receptor. In rats, CP-101,606 decreased haloperidol-induced catalepsy with an ED50 of about 0 .5 mg/kg. In MPTP-treated monkeys, CP-101,606 (1 mg/kg) reduced parkinsonia n motor symptoms by 20%. At a dose of 0.05 mg/kg, CP-101,606 markedly poten tiated the effect of a submaximal dose of levodopa, reducing motor symptoms by about 50% compared to vehicle and by about 30% compared to levodopa alo ne. No side-effects were apparent at any dose of CP-101,606. We conclude th at CP-101,606 has direct antiparkinsonian actions in both rodents and monke ys and it synergistically potentiates levodopa in MPTP-treated monkeys. Cli nical evaluation of selective NR2B antagonists may be warranted in Parkinso n's disease. (C) 2000 Academic Press.