N-METHYL-D-ASPARTATE RECEPTOR BLOCKADE DIFFERENTIALLY MODIFIES REGIONAL CEREBRAL METABOLIC RESPONSES TO D(1)-DOPAMINE AND D(2)-DOPAMINE AGONISTS IN RATS WITH A UNILATERAL 6-HYDROXYDOPAMINE LESION

Dopamine and the excitatory amino acids play important roles in the co ntrol of motor behavior by the basal ganglia; elucidating the manner i n 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 ex amine the effect of N-methyl-D-aspartate receptor blockade on regional cerebral metabolic responses to D1 and D2 dopamine receptor stimulati on in rats with a unilateral 6-hydroxydopamine lesion of the nigrostri atal pathway. The D1 agonist SKF 38393 (5 mg/kg, i.v.) increased gluco se utilization markedly in entopeduncular nucleus and substantia nigra pars reticulata ipsilateral to the lesion, while the D2 agonist quinp irole (1 mg/kg, i.v.) had no effect in these striatal output regions. SKF 38393 and quinpirole reduced 2-deoxyglucose uptake to a similar ex tent in the lateral habenula, a region which receives afferent input f rom entopeduncular nucleus; quinpirole also decreased glucose utilizat ion bilaterally in nucleus accumbens. Pretreatment with the noncompeti tive N-methyl-D-aspartate receptor antagonist MK-801 (0.1 mg/kg, i.v.) , which had little effect on cerebral metabolism by itself, reduced th e effect of SKF 38393 in entopeduncular nucleus and substantia nigra p ars reticulata and prevented the effect of quinpirole in nucleus accum bens. MK-801 did not alter the SKF 38393-induced reduction in glucose utilization in lateral habenula, but did reduce the effect of quinpiro le in this structure. When these drugs were administered in the same m anner to a separate group of lesioned animals, MK-801 did not affect r otational behavior elicited by SKF 38393, but completely eliminated co ntralateral rotation and actually caused some ipsilateral rotation in response to quinpirole. These findings indicate that D1 and D2 recepto r-associated brain mechanisms are differentially influenced by N-methy l-D-aspartate receptor stimulation. D2-mediated behavioral and cerebra l metabolic responses appear to require concurrent N-methyl-D-aspartat e receptor stimulation. On the other hand, the preservation of D1-medi ated rotational behavior and reduced lateral habenula glucose metaboli sm in the presence of MK-801 despite attenuation of the effects of the D1 agonist in entopeduncular nucleus and substantia nigra pars reticu lata suggests that D1 receptor-regulated neuronal pathways exhibit var ying degrees of sensitivity to N-methyl-D-aspartate receptor blockade.