Systemically administered N-methyl-D-aspartate (NMDA) antagonists, MK-801 ((+)5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate) and CPP (3-[(+-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate), potentiate the ability of L-dopa (L-3,4-dihydroxyphenylalanine) to reverse akinesia and to alleviate muscular rigidity in monoamine-depleted rats. On the basis of these findings, it is proposed that NMDA antagonists may be beneficial as adjunctive treatment in the therapy of Parkinson's disease. CPP locally injected into the subthalamic nucleus, entopeduncular nucleus--the rat homologue of the internal pallidal segment--or substantia nigra pars reticulata of monoamine-depleted rats stimulates locomotor activity and alleviates rigidity, whereas local microinjection of CPP into the neostriatum is ineffective. These results make it unlikely that the neostriatum is the site of the antiparkinsonian action of NMDA antagonists in monoamine-depleted rats, whereas the subthalamic nucleus, internal pallidal segment, and substantia nigra pars reticulata appear to be important for the effects of NMDA antagonists.