Dopamine and the excitatory amino acids play important roles in the control of motor behavior by the basal ganglia; elucidating the manner in which these transmitter systems interact may provide new therapeutic approaches to the treatment of movement disorders such as Parkinson's disease. The 2-deoxyglucose autoradiographic technique was used to examine the effect of N-methyl-D-aspartate receptor blockade on regional cerebral metabolic responses to D1 and D2 dopamine receptor stimulation in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. The D1 agonist SKF 38393 (5 mg/kg, i.v.) increased glucose utilization markedly in entopeduncular nucleus and substantia nigra pars reticulata ipsilateral to the lesion, while the D2 agonist quinpirole (1 mg/kg, i.v.) had no effect in these striatal output regions. SKF 38393 and quinpirole reduced 2-deoxyglucose uptake to a similar extent in the lateral habenula, a region which receives afferent input from entopeduncular nucleus; quinpirole also decreased glucose utilization bilaterally in nucleus accumbens. Pretreatment with the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801 (0.1 mg/kg, i.v.), which had little effect on cerebral metabolism by itself, reduced the effect of SKF 38393 in entopeduncular nucleus and substantia nigra pars reticulata and prevented the effect of quinpirole in nucleus accumbens. MK-801 did not alter the SKF 38393-induced reduction in glucose utilization in lateral habenula, but did reduce the effect of quinpirole in this structure. When these drugs were administered in the same manner to a separate group of lesioned animals, MK-801 did not affect rotational behavior elicited by SKF 38393, but completely eliminated contralateral rotation and actually caused some ipsilateral rotation in response to quinpirole. These findings indicate that D1 and D2 receptor-associated brain mechanisms are differentially influenced by N-methyl-D-aspartate receptor stimulation. D2-mediated behavioral and cerebral metabolic responses appear to require concurrent N-methyl-D-aspartate receptor stimulation. On the other hand, the preservation of D1-mediated rotational behavior and reduced lateral habenula glucose metabolism in the presence of MK-801 despite attenuation of the effects of the D1 agonist in entopeduncular nucleus and substantia nigra pars reticulata suggests that D1 receptor-regulated neuronal pathways exhibit varying degrees of sensitivity to N-methyl-D-aspartate receptor blockade.