Excitatory amino acid receptor antagonists modify regional cerebral metabolic responses to levodopa in 6-hydroxydopamine-lesioned rats

Abstract

Excitatory amino acid receptor antagonists have been proposed as novel therapeutic agents to be used with levopoda in the treatment of Parkinson's disease. We examined the neural substrates for the interaction between levodopa and antagonists of either the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or N-methyl- d-aspartate type of excitatory amino acid receptor using 2-deoxyglucose autoradiography. Thus, we compared the effects of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (10 mg/kg, i.v.) and the N-methyl- d-aspartate antagonist MK-801 (0.1 mg/kg, i.v.) on cerebral metabolic responses to levodopa (25 mg/kg, i.v., with 12.5 mg/kg benserazide) in rats with a unilateral nigrostriatal pathway lesion. Levodopa increased glucose utilization ipsilateral to the lesion in substantia nigra pars reticula (up to 104%), entopeduncular nucleus (up 90%) and subthalamic nucleus (up 30%), indicating that levodopa alters striatal output through the striatonigral, striatoentopeduncular and striatopallidal pathways. Levodopa also decreased metabolic rate in lateral habenula (down 39%), a target of projections from entopeduncular nucleus, implying a reduction in basal ganglia output. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline and MK-801 by themselves did not affect glucose utilization in any of these regions. Pretreatment with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline reduced the effect of levodopa in substantia nigra pars reticulata but not in entopeduncular nucleus or subthalamic nucleus, while MK-801 attenuated the effect of levodopa in all three of these structures; neither 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline nor MK-801 altered the effect of levodopa in lateral habenula. When given at the same doses to a separate group of lesioned animals, neither 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline nor MK-801 affected rotational behavior elicited by levodopa. These findings indicate that α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and N-methyl- d-aspartate receptor antagonists differentially modify dopamine receptor-mediated striatal output, α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor blockade may preferentially attenuate the effect of dopamine receptor activation on the striatonigral pathway, while N-methyl- d-aspartate blockade appears to reduce the actions of dopamine on the striatonigral, striatoentopeduncular and striatopallidal pathways. However, the lack of effect of both 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline and MK-801 on levodopa-induced rotational behavior and reduced metabolic rate in the lateral habenula suggests that neither α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid nor N-methyl- d-aspartate receptor blockade diminishes the net effect of levodopa on basal ganglia output.